Vaccines for preventing influenza in the elderly

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older. The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable.

Objectives

To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly.
To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly.
To document types and frequency of adverse effects associated with influenza vaccines in the elderly.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009).

Selection criteria

Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered.

Data collection and analysis

We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths.

Main results

We included 75 studies. Overall we identified 100 data sets. We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly.

Authors' conclusions

The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken.

摘要

背景

老年人中預防流感的疫苗

全世界都提倡於老年人施打流感疫苗。施打流感疫苗已被鎖定提供給老年人以及那些有較嚴重併發症風險之個案。

目標

我們的目標在於回顧流感疫苗在年齡65歲或以上的個體使用上的效果,效率與安全。

搜尋策略

我們利用了以下的資料庫作搜尋: 考科藍資料庫,考科藍對照試驗中央登錄系統(CENTRAL), 考科藍系統性回顧資料庫,以及效率回顧研究摘要的資料庫(Issue 1, 2006); MEDLINE(1966年一月至2006年3月的第三週);EMBASE(1974年至1979年的對話; SilverPlatter 至2005年十二月); 生物學摘要(SilverPlatter 1969年至2004年十二月); 以及科學期刊引用目錄(科學網1974年至2004年12月).

選擇標準

我們是針對評估流感(實驗室確認個案)或類流感疾病治療效果或安全性的隨機,準隨機試驗。任何跟流感疫苗有關,獨立地以任何劑量,調劑方式或時序投予,與安慰劑或沒有治療進行比較的都被接受考慮。

資料收集與分析

我們先依據實驗環境(社區或長照中心)進行分類,然後則是病毒循環程度以及疫苗的配對。我們進一步將有同時施打肺炎雙球菌多醣體疫苗(PPV)以及不同流感疫苗者加以分類。我們分析了以下的結果: 流感,類流感疾病,住院次,併發症以及死亡。

主要結論

在效果和效率的評估方面,有六十四篇研究被加入,形成九十六套資料。居住家里的老年人(擁有較佳的疫苗配對和高的病毒循環),針對類流感疾病的效果為23%(6%至36%)而針對流感則是沒有顯著差異(相對危險性1.04: 95%信賴區間 0.43至2.51). 我們發現疫苗保謢效果和類流感疾病的發作沒有相關。配對佳的疫苗能夠預防肺炎(VE 46%; 30%至58%),住院(VE 45%; 16%至64%)以及因流感或肺炎造成之死亡(VE 42%, 17%至59%)。住在社區的老年人,疫苗對流感(相對危險性0.19; 95%信賴區間0.02至2.01),類流感疾病(相對危險性1.05; 95%信賴區間0.58至1.89)或肺炎(相對危險性0.88; 95%信賴區間0.64至1.20)的預防沒有顯著成效。配對良好的疫苗能夠預防因流感和肺炎(VE26%; 12%至38%)造成的住院以及所有死因造成的死亡(VE42%; 24%至55%)。經過調整擾亂因子之後,疫苗的表現在因流感或肺炎住院(VE* 27%; 21%至33%),呼吸道疾病(VE* 22%; 15%至28%)以及心臟疾病(VE* 24%; 18%至30%); 以及所有死因造成的死亡(VE* 47%; 39%至54%) 都獲得改善。疫苗在公衛上的安全概況都顯示可被接受。

作者結論

在施打疫苗最有預防併發症效果的長照中心,施打疫苗運動的目標順利完成,至少在某種程度上。然而,根據可靠的證據顯示社區中施打疫苗需審慎。疫苗在預防任何原因的死亡有明顯過高的效率,反映健康狀況底線的不平衡以及兩組參與的成員有其他系統性的差異。

翻譯人

本摘要由臺灣大學附設醫院林祖燊翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

這項回顧研究在於觀察疫苗是否能夠預防季節性流感以及它在年齡65歲或更高的老年人所造成的併發症。全球建議在年長者使用疫苗,因齡65歲或更高的老年人有較高的風險產生併發症,住院以及因流感而死亡。這項回顧研究觀察了40年來一些來自實驗和非實驗有關流感疫苗研究的文獻。71篇文章被挑選以及先依據實驗的設計和環境(社區或長照中心)分類。這些文章進一步依病毒循環的程度和疫苗的配對分類。這些回顧研究的結果大都基於非實驗性(觀察性)研究,相對來說有較大的誤差,因為目前沒有太多品質佳的試驗。非活性三價流感疫苗是目前最常用的疫苗。目前疫苗最有效地預防臨床疾病以及併發症可在住在長照中心(例如養護中心)觀察得到。這些個案鄉,疫苗可以預防45%的肺炎,住院次數和流感導致之死亡。居住在開放社區中的老年人其效用則需要更審慎考慮,不論其實驗結果或是設計: 疫苗大約有25%的效用在於預防25%因流感住院或發生呼吸道疾病。這在所有死因的死亡率(一個敏感度較低的結果)有明顯好處只是來自於觀察性研究。同時有可能反映接種和非接種族群(例如社經特徵,健康狀況,行為態度)的差異甚於疫苗的實際效用。疫苗在公衛上的安全概況都顯示可被接受。

Résumé scientifique

Vaccins pour la prévention de la grippe chez les personnes âgées

Contexte

Au cours des quarante dernières années, les vaccins se sont avérés être la principale arme pour minimiser l'impact de la grippe chez les personnes âgées. Dans le monde, ils sont recommandés pour les personnes de 65 ans et plus. Le premier objectif de la vaccination antigrippale chez les personnes âgées est de réduire le risque de complications pour les plus vulnérables.

Objectifs

Évaluer l'efficacité des vaccins dans la prévention de la grippe, du syndrome d'allure grippale (SAG), des admissions à l'hôpital, des complications et de la mortalité chez les personnes âgées.
Identifier et évaluer les études comparatives portant sur les effets des vaccins antigrippaux chez les personnes âgées.
Consigner les types et la fréquence des effets indésirables associés aux vaccins antigrippaux chez les personnes âgées.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës (IRA) (Bibliothèque Cochrane 2009, numéro 4), ainsi que dans MEDLINE (janvier 1966 à la 1ère semaine d'octobre 2009), EMBASE (1974 à octobre 2009) et Web of Science (1974 à octobre 2009).

Critères de sélection

Les essais contrôlés randomisés (ECR) et quasi-ECR, les études de cohorte et les études cas témoins évaluant l'efficacité antigrippale (cas confirmés en laboratoire) ou l'efficacité contre le syndrome d'allure grippale (SAG), ou encore l'innocuité. Tout vaccin antigrippal administré indépendamment, avec toute dose, préparation ou tout calendrier de vaccination, comparé à un placebo ou à l'absence d'intervention était pris en considération.

Recueil et analyse des données

Les rapports ont d'abord été regroupés en fonction de l'environnement de l'étude (communautaire ou établissements de soins de longue durée), puis en fonction du niveau de circulation du virus et de la correspondance du vaccin. Nous les avons par la suite classés en fonction de la co-administration d'un vaccin antipneumococcique polysaccharidique (VAP) et des différents types de vaccins antigrippaux. Les critères d'évaluation suivants ont été analysés : grippe, syndrome d'allure grippale, admissions à l'hôpital, complications et décès.

Résultats principaux

Nous avons inclus 75 études. Globalement, ce sont 100 ensembles de données qui ont été identifiés. Un ECR évaluant l'efficacité potentielle et réelle a été recensé. Bien qu'il semble révéler un effet contre les symptômes grippaux, il n'était pas assez puissant pour détecter un effet sur les complications (1348 participants). Le reste de notre base de preuves incluait des essais contrôlés non randomisés. En raison de la faible qualité générale des essais contrôlés non randomisés et de la probable présence de biais, qui rendent l'interprétation de ces données difficiles et toute conclusion définitive potentiellement équivoque, il n'a pas été possible de parvenir à des conclusions claires en ce qui concerne les effets des vaccins sur les personnes âgées.

Conclusions des auteurs

Les preuves disponibles sont de mauvaise qualité et ne donnent aucune indication quant à l'innocuité, l'efficacité potentielle et réelle des vaccins antigrippaux pour les personnes de 65 ans et plus. Pour mettre fin à l'incertitude, un essai contre placebo randomisé, suffisamment puissant et financé par des fonds publics, réalisé sur plusieurs saisons devrait être entrepris.

Plain language summary

Vaccines for preventing seasonal influenza and its complications in people aged 65 or older

Influenza vaccination of elderly individuals is recommended worldwide as people aged 65 and older are at a higher risk of complications, hospitalisations and deaths from influenza. This review looked at evidence from experimental and non-experimental studies carried out over 40 years of influenza vaccination. We included 75 studies. These were grouped first according to study design and then the setting (community or long-term care facilities). The results are mostly based on non-experimental (observational) studies, which are at greater risk of bias, as not many good quality trials were available. Trivalent inactivated vaccines are the most commonly used influenza vaccines. Due to the poor quality of the available evidence, any conclusions regarding the effects of influenza vaccines for people aged 65 years or older cannot be drawn. The public health safety profile of the vaccines appears to be acceptable.

Résumé simplifié

Vaccins pour la prévention de la grippe saisonnière et ses complications chez les personnes de 65 ans et plus

La vaccination antigrippale des personnes âgées est recommandée dans le monde entier. À partir de 65 ans, elles présentent en effet un risque plus élevé de complications, d'hospitalisation et de décès. Cette revue portait sur les preuves provenant d'études expérimentales et non expérimentales réalisées au cours de 40 ans de vaccination antigrippale. Nous avons inclus 75 études. Elles ont d'abord été regroupées en fonction de la conception de l'étude puis en fonction de l'environnement (communautaire ou établissements de soins de longue durée). Compte tenu du peu d'essais de bonne qualité disponibles, les résultats se fondent principalement sur des études non expérimentales (observationnelles) qui présentent un risque de biais plus important. Parmi les vaccins antigrippaux, les vaccins trivalents inactivés sont les plus utilisés. Les preuves disponibles étant de faible qualité, aucune conclusion à l'égard des effets des vaccins antigrippaux sur les personnes de 65 ans et plus ne peut être tirée. Sur le plan de la santé publique, le profil d'innocuité des vaccins semble être acceptable.

Notes de traduction

Traduit par: French Cochrane Centre 1st December, 2012
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Streszczenie prostym językiem

Szczepienia ochronne w zapobieganiu grypie sezonowej i jej powikłaniom wśród osób w wieku 65 lat i starszych

Na całym świecie rekomenduje się szczepienia przeciwko grypie dla osób w wieku podeszłym ze względu na większe ryzyko powikłań, hospitalizacji i zgonu z powodu grypy wśród osób w wieku 65 lat i więcej. W przeglądzie przeanalizowano dane naukowe dotyczące szczepień przeciwko grypie, pochodzące zarówno z badań eksperymentalnych, jak i nieeksperymentalnych przeprowadzonych na przestrzeni 40 lat. Do przeglądu włączono 75 badań. Początkowo pogrupowano je według rodzaju badania, a następnie na podstawie miejsca, w którym zostały przeprowadzone (społeczność lub domy opieki długoterminowej). Ze względu na małą liczbę badań wysokiej jakości, wyniki oparto w większości na badaniach nieeksperymentalnych (obserwacyjnych), które obarczone są większym ryzykiem błędu systematycznego. Najczęściej stosuje się przeciw grypie szczepionki inaktywowane trójwalentne. Ze względu na niską jakość dostępnych danych naukowych, nie można wyciągnąć wniosków na temat skuteczności szczepień przeciwko grypie wśród osób w wieku 65 lat lub starszych. Profil bezpieczeństwa szczepienia z punktu widzenia zdrowia publicznego wydaje się akceptowalny.

Uwagi do tłumaczenia

Tłumaczenie: Joanna Błońska

Laički sažetak

Cjepiva za sprječavanje sezonske gripe i njenih komplikacija u osoba starijih od 65 godina

Cjepljenje starijih osoba cjepivom protiv gripe preporučuje se širom svijeta osobama starijima od 65 godine budući oni imaju veći rizik od komplikacija, primitka u bolnicu i smrti od gripe. Ovaj Cochrane sustavni pregled analizirao je dokaze iz eksperimentalnih i ne-eksperimentalnih studija koje su provedene kroz više od 40 godina tijekom provedbe cjepljenja protiv gripe. Uključeno je 75 studija. Studije su podijeljene u nekoliko skupina, ovisno o ustroju istrživanja i mjestu gdje je cijepljenje provedeno (u zajednici ili u domovima za dugoročnu skrb). Rezultati se uglavnom temelje na ne-eksperimentalnim istraživanjima (opservacijske studije u kojima nema intervencijske i kontrolne skupine nego se osobe samo promatraju). Stoga podatci u ovom sustavnom pregledu imaju veći rizik od pristranosti jer nije nađeno mnogo kliničkih pokusa odgovarajuće kvalitete. Najčešće je korišteno trivalentno inaktivirano cjepivo protiv gripe. Zbog slabe kvalitete dostupnih dokaza, ne mogu se donijeti zaključci o učincima cjepiva protiv gripe na osobe starije od 65 godina. Čini se da je cjepivo sigurno.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr 

Background

Description of the condition

Influenza vaccination of elderly individuals is recommended worldwide as people aged 65 and older are at higher risk of complications, hospitalisations and deaths from influenza.

Description of the intervention

Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades. In the year 2000, 40 out of 51 high-income or middle-income countries recommended vaccination for all persons aged 60 or 65 or older (van Essen 2003). Up to 290 million doses of vaccine were distributed worldwide in 2003 (WHO 2005). According to the Centres for Disease Control (CDC), the primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable (ACIP 2005; CDC 2004). To achieve this goal, CDC defined two higher priority groups: adults aged 65 years or older and residents of nursing homes and long-term care facilities. We present an up-to-date, comprehensive assessment of the effects of influenza vaccines in the elderly. The current pandemic has caused a heightened interest in influenza vaccines and their performance.

How the intervention might work

Vaccines work by simulating an infection and stimulating the body to produce antibodies against the threat and activate other defence mechanisms.

Why it is important to do this review

Due to the unique production cycle of influenza vaccines (they are produced and tested using surrogate outcomes - antibody stimulation - ahead of each influenza 'season'), past performance is probably the only reliable way to predict future performance. Of the two existing systematic reviews looking at the effects of influenza vaccines in the elderly, one is now over a decade old and its conclusions may be affected by the lack of inclusion of recent evidence (Gross 1995). The other review has several methodological weaknesses which may affect the authors' conclusions (for example, the exclusion of studies with denominators smaller than 30 and pooling of studies using different designs). This review also includes a limited number of studies (Vu 2002). An accurate assessment of the effects (efficacy, effectiveness and safety profile) of influenza vaccines is essential to allow rational choice between alternative strategies.

Objectives

  1. To identify and appraise all the comparative studies evaluating the effects of influenza vaccines in the elderly (aged 65 years and older), irrespective of setting.

  2. To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly.

  3. To document the types and frequency of adverse effects associated with influenza vaccines in the elderly.

Methods

Criteria for considering studies for this review

Types of studies

We considered randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies. For study design definitions see Appendix 1. To assess rare adverse effects we also looked for surveillance studies. Despite being non-comparative, they provide information about rare and severe events, possibly related to influenza vaccines.

Types of participants

Elderly participants aged 65 years or older, irrespective of settings. Studies which assessed efficacy in selected groups affected by a specific chronic pathology (i.e. diabetes or cardiac disease) were excluded as we were interested in the whole population. The question of whether these vaccines are effective in specific at risk populations is the topic of other reviews.

Types of interventions

  1. Vaccination with any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo, or with no intervention.

  2. We also considered new, as yet unlicensed, types of vaccines (for example, live attenuated and DNA vaccines).

  3. Vaccination of staff in order to protect patients and residents admitted into hospitals, nursing homes and long-term care facilities has been assessed by a separate review (Thomas 2010).

  4. We excluded studies in which a vaccine was administered after the beginning of the epidemic period.

  5. We excluded old oil adjuvant vaccine or vaccines with a content greater than 15 µg of haemagglutinin/strain/dose from the safety assessment.

Types of outcome measures

Primary outcomes
For treatment efficacy and effectiveness

We included outcomes occurring within the epidemic period (the six-month winter period, if not better specified). When authors presented data according to different levels of viral circulation, we only included data restricted to higher viral circulation.

  1. Cases of influenza, clinically defined from a list of likely respiratory and systemic signs and symptoms. We accepted the trial authors' definition of clinical illness because some states have their own official definition.

  2. Cases of influenza, laboratory confirmed (by means of viral isolation, serological supporting evidence, or both).

  3. Cases of influenza (as defined above) admitted to hospital.

  4. Deaths (total).

  5. Deaths due to influenza (as defined above) or to its complications.

  6. Other direct or indirect indicator of disease impact: pneumonia; hospitalisation due to any respiratory disease, hospitalisation due to heart disease.

We excluded studies with generic outcomes (deaths from all causes, for example) and long-term (one year) follow up as most illnesses were most likely due to causes other than influenza. We excluded studies reporting only serological outcomes.

Secondary outcomes
For adverse events
  1. Local events for aerosol vaccines (upper respiratory tract infection symptoms such as cough, coryza, sore throat, hoarseness) within seven days of vaccination.

  2. Local events for parenteral vaccines (tenderness/soreness, erythema, induration, arm stiffness) within seven days from vaccination.

  3. Systemic events (myalgia, fever, headache, fatigue, indisposition, rash, angioedema, asthma) within seven days from vaccination.

  4. Rare events (thrombocytopenia, neurological disorders, Guillan Barré Syndrome (GBS).

Search methods for identification of studies

Electronic searches

For this 2009 update we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects (The Cochrane Library 2009, Issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009).

We used the following search terms to search MEDLINE and CENTRAL. The search terms were combined with the Cochrane Highly Sensitive Search Strategy for identifying RCTs in MEDLINE: sensitivity- and precision-maximising version (2008) revision; Ovid format (Lefebvre 2008). This search was adapted for EMBASE (Appendix 5) and Web of Science (see Appendix 6). The below search terms were also combined with the SIGN (SIGN 2009) search strategy for identifying observational studies (see Appendix 7) and MEDLINE, EMBASE and Web of Science were searched for observational studies. Details of the previous search are in Appendix 4.

MEDLINE (OVID)

1 Influenza Vaccines/
2 Influenza, Human/tm, pc, im, mo, ep [Transmission, Prevention & Control, Immunology, Mortality, Epidemiology]
3 Influenza, Human/
4 exp Influenzavirus A/
5 exp Influenzavirus B/
6 (flu or influenza*).tw.
7 or/3-6
8 Vaccines/
9 vaccines, attenuated/ or vaccines, inactivated/ or exp vaccines, subunit/ or exp vaccines, synthetic/ or viral vaccines/
10 exp Immunization/
11 (vaccin* or immuni* or inocul*).tw.
12 exp Adjuvants, Immunologic/
13 (vaccin* adj5 adjuvant*).tw.
14 Squalene/
15 (aluminium or squalene or MF59 or virosom*).tw,nm.
16 or/8-15
17 7 and 16
18 1 or 2 or 17
19 exp Adult/
20 Men/
21 Women/
22 Retirement/
23 ((old* or age*) adj3 (people* or person* or adult* or women* or men* or citizen* or residen*)).tw.
24 (pension* or retire* or adult* or aged or elderly or senior* or geriatric*).tw.
25 long-term care/ or nursing care/ or palliative care/
26 homes for the aged/ or nursing homes/
27 nursing home*.tw.
28 or/19-27
29 28 and 18

Searching other resources

There were no language or publication restrictions. The search of CENTRAL included trial reports identified by the systematic search by hand of the journal Vaccine.

In order to identify additional published and unpublished studies:

  • we used the Science Citation Index to identify articles that cite the relevant studies;

  • we keyed the relevant studies into PubMed and used the Related Articles feature;

  • we searched the bibliographies of all relevant articles obtained, any published reviews and proceedings from relevant conferences for additional studies;

  • we explored Internet sources: NHS National Research Register (http://www.update-software.com/national/), the metaRegister of Clinical Trials (http://www.controlled-trials.com/) and the digital dissertations web site (http://wwwlib.umi.com/dissertations);

  • we searched the Vaccine Adverse Event Reporting System web site (http://www.vaers.org); and

  • we contacted vaccine manufacturers listed at the WHO web site.

Data collection and analysis

Selection of studies

Two review authors (TOJ, EF) independently applied inclusion criteria to all identified and retrieved articles.

Data extraction and management

Two review authors (EF and LAA) independently performed data extraction using a data extraction form (Appendix 3). Two review authors (TOJ, CDP) checked data and entered these into customised software.

We extracted data on the following:

  • methodological quality of studies;

  • study design (Appendix 1);

  • description of setting;

  • characteristics of participants;

  • description of vaccines (content and antigenic match);

  • description of viral circulation degree;

  • description of outcomes;

  • length of the follow up;

  • publication status;

  • date of study; and

  • location of study.

Assessment of risk of bias in included studies

Experimental studies

All review authors independently assessed the methodological quality of the included studies using criteria from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) and results were introduced into the sensitivity analysis.

We classified studies according to the following criteria:

Randomisation

A = individual participants allocated to vaccine or control group.
B = groups of participants allocated to vaccine or control group.

Generation of the allocation sequence

A = adequate, for example, table of random numbers or computer-generated random numbers.
B = inadequate, for example, alternation, date of birth, day of the week or case record number.
C = not described.

Allocation concealment

A = adequate - for example, numbered or coded identical containers administered sequentially, on-site computer system that can only be accessed after entering the characteristics of an enrolled participant, or serially numbered, opaque, sealed envelopes.
B = possibly adequate - for example, sealed envelopes that are not sequentially numbered or opaque.
C = inadequate - for example, open table of random numbers.
D = not described.

Blinding

A = adequate double-blinding - for example, placebo vaccine.
B = single-blind - that is to say, blinded outcome assessment.
C = no blinding.

Follow up

Average duration of follow up and number of losses to follow up.

Non-experimental studies

We made quality assessment of non-RCT studies in relation to the presence of potential confounders which could make interpretation of the results difficult. The quality of case-control and cohort studies (prospective and retrospective) was evaluated using the appropriate Newcastle-Ottawa Scales (NOS) (Appendix 2). Because of the lack of empirical evidence on the impact that the methodological quality has on the results of non-RCTs, this evaluation was only used at the analysis stage as a mean of interpretation of the results and a set of sensitivity analyses was performed for this scope. We classified studies as at low risk of bias (up to one inadequate item in the NOS), medium risk of bias (up to three inadequate items), high risk of bias (more than three inadequate items) and very high risk of bias (when there was no description of methods).

In case of disagreement between the review authors, TOJ arbitrated.

Measures of treatment effect

We summarised efficacy (against influenza) and effectiveness (against influenza-like illness) estimates as risk ratio (RR) (using a 95% confidence interval (CI)) or odds ratio (OR) (using a 95% CI). Absolute vaccine efficacy (VE) is expressed as a proportion, using the formula VE=1-RR or VE*=1-OR whenever significant. When not significant, we reported the relevant RR or OR.

Unit of analysis issues

Aggregation of data was dependent on the sensitivity and homogeneity of definitions of exposure, populations and outcomes used. Where studies were found to be homogenous, we carried out a meta-analysis of these studies within each design category.

We analysed non-RCT and quasi-RCT evidence separately from RCT evidence. The study results are described individually in the Results section.

We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching (when trial authors presented data according to different levels of viral circulation, only data relating to higher viral circulation were included). A period was considered 'epidemic' when the weekly incidence rate exceeded the seasonal threshold. A vaccine was defined as 'matching' when the vaccine strains were antigenically similar to the wild circulating strains. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines (live, inactivated, with adjuvant).

When possible, we did a quantitative analysis adjusted for confounders if the cohort or case-control studies used the same methods of adjustment (logistic regression) for the same confounders. We constructed a comparison with effect sizes adjusted for the effects of possible known confounders and their standard error, which we derived from the reported confidence intervals (CIs) (Greenland 1987) and did quantitative analysis with the inverse of the variance (Higgins 2008).

Findings of one case-control study (Mullooly 1994) reporting data stratified by risk factors for influenza, were included by use of the inverse variance combining stratum-specific effect size and overall effect size.

Dealing with missing data

Whenever we identified non-reporting or partial reporting of data we tried to contact the first or corresponding author of the study and requested missing data.

Assessment of heterogeneity

We calculated the I2 statistic for every pooled estimate to assess the effect on statistical heterogeneity. The I2 statistic can be interpreted as the proportion of total variation among effect estimates that is due to heterogeneity, rather than sampling error and it is intrinsically independent of the number of studies. When the I2 statistic is less than 30% there is little concern about statistical heterogeneity (Higgins 2002; Higgins 2003).

Assessment of reporting biases

We assessed possible publication bias through visual inspection of funnel plots. We also carried out a complete re-extraction of all studies and re-assessed their methodological quality. We also assessed concordance between data presented and conclusions and direction of conclusions (in favour or not of the performance of influenza vaccines). We also looked at the relationship between these variables and study funding and journal of publication (see Discussion - 'Potential biases in the review section').

Data synthesis

We pooled whole, split and sub-unit vaccines, as in community studies this information was not reported. When a study reported data for more than one influenza season or for more than one setting, we considered these separately, creating separate data sets. We used random-effect models throughout to take account of the between-study variance in our findings (DerSimonian 1986).

Subgroup analysis and investigation of heterogeneity

To investigate the causes of heterogeneity we did a further analysis. To assess the effect of viral circulation and vaccine matching on overall heterogeneity, we calculated heterogeneity within each grouping and compared its sum with the overall heterogeneity (Greenland 1987).

Sensitivity analysis

A sub-analysis of studies describing a better defined epidemic period was performed for most significant comparisons. We then tested effect size from cohort studies conducted in long-term care facilities (where data are more plentiful), stratified by methodological quality of the studies.

Results

Description of studies

Results of the search

In the 2009 updated search, we identified 1435 reports of potentially relevant studies. We retrieved 18 studies for further evaluation; four were included and 14 excluded for various reasons. For the 2009 update we identified two case-control studies (Jordan 2007; Puig-Barbera 2007) and two cohort studies (Hara 2006; Leung 2007) fulfilling the inclusion criteria.

In the 2005 review, we identified 4400 titles of reports of potentially relevant studies and screened these for retrieval. We excluded 4088 reports by screening of titles and abstracts; we retrieved 312 reports for detailed assessment; 241 reports did not fulfil inclusion criteria.

Included studies

We included 75 studies in this review: 68 studies were used to assess efficacy/effectiveness and eight were included in the safety assessment (one RCT was included in both assessments).

The 65 studies included in the efficacy/effectiveness assessment were split into subsets by influenza season or setting or vaccine type, resulting in 100 data sets.

Five RCTs resulted in five data sets (Allsup 2001; Edmondson 1971; Govaert 1994; Rudenko 2001; Stuart 1969).

Fifty-one cohort studies resulted in 80 data sets (Arden 1988; Arroyo 1984; Aymard 1979a; Aymard 1979b; Caminiti 1994; Cartter 1990a; Cartter 1990b; Cartter 1990c; Christenson 2001a; Christenson 2001b; Christenson 2004a; Christenson 2004b; Coles 1992; Comeri 1995; Consonni 2004a; Consonni 2004b; Cuneo Crovari 1980; Currier 1988; D'Alessio 1969; Davis 2001a; Davis 2001b; Deguchi 2001; Feery 1976; Fleming 1995; Fyson 1983a ; Fyson 1983b; Gavira Iglesias 1987; Gené Badia 1991; Goodman 1982; Gross 1988; Hak 2002a; Hak 2002b; Hara 2006; Horman 1986; Howarth 1987a; Howarth 1987b; Howells 1975a; Howells 1975b; Howells 1975c; Isaacs 1997; Kaway 2003; Leung 2007; Lopez Hernandez 1994; Mangtani 2004b; Mangtani 2004c; Mangtani 2004d; Mangtani 2004e; Mangtani 2004f; Mangtani 2004g; Mangtani 2004h; Mangtani 2004i; Mangtani 2004j; Meiklejohn 1987; Monto 2001; Morens 1995; Mukerjee 1994; Murayama 1999; Nichol 1994a; Nichol 1994b; Nichol 1994c; Nichol 1998a; Nichol 1998b; Nichol 2003a; Nichol 2003b; Nicholson 1999; Nordin 2001a; Nordin 2001b; Patriarca 1985a; Patriarca 1985b; Pregliasco 2002; Ruben 1974; Saah 1986a; Saah 1986b; Saah 1986c; Saito 2002a; Saito 2002b; Shapiro 2003; Strassburg 1986; Taylor 1992; Voordouw 2003).

Twelve case-control studies resulted in 14 data sets (Ahmed 1995; Ahmed 1997; Crocetti 2001; Fedson 1993a; Fedson 1993b; Foster 1992; Jordan 2007; Mullooly 1994; Ohmit 1999; Ohmit 1995a; Ohmit 1995b; Puig-Barberà 1997; Puig-Barberà 2004; Puig-Barbera 2007).

Roughly half (n = 52) the data sets reported A/H3N2 virus circulating, 4% (n = 4) B viruses, 1% (n = 1) A/H1N1, 1% (n = 1) A/H2N2, and 7% (n = 7) reported A/H3N2 and A/H1N1 circulating at the same time. The remaining 37% (n = 35) of the data sets did not provide sufficient information on circulating subtypes.

Twenty-four studies, resulting in 39 data sets, collected information about the health conditions of vaccinated and unvaccinated persons and reported stratified results or adjusted rates. Participants suffering from lung disease, heart disease, renal disease, diabetes and other endocrine disorders, immunodeficiency or immunosuppressive diseases, cancer, dementia or stroke, vasculitis and rheumatic disease were considered as belonging to risk groups.

Included studies used the recommended and licensed vaccine formulation even if some authors did not declare vaccine composition.

In the RCTs, placebo was the comparison. All cohort studies compared the effects of vaccination against no vaccination.

Seven studies included in our safety assessment are described below:
Four RCTs (Govaert 1993; Keitel 1996; Margolis 1990a; Treanor 1994).
Three surveillance studies with a non-comparative design assessing rare events (Guillan Barré Syndrome (GBS)) (Kaplan 1982; Lasky 1998; Schonberger 1979) were commented on in the text but were not included in our meta-analysis. One RCT assessed a vaccine which has not been in production for decades (Stuart 1969). Its harms data were not extracted.

Excluded studies

The most frequent reasons for exclusion were lack of presentation of original data, lack of placebo or standard care comparator and presence of antibody titres as outcomes. A complete list with reasons for exclusion is available in the 'Characteristics of excluded studies' table.

Risk of bias in included studies

The results of our risk of bias assessment were as follows:

Cohort/case-control studies

Low risk of bias 18
Medium risk of bias 31
High risk of bias 11
Very high risk of bias 3

Surveillance studies

For three surveillance studies assessing rare side effects, we did not perform quality evaluation. All were population-based studies with good case findings and case definitions.

Allocation

Experimental studies

Allocation concealment: adequate 3
Allocation concealment: unclear 1
Allocation concealment: inadequate 0
Allocation concealment: not described 5

Blinding

See Discussion 'Potential biases in the review process'.

Incomplete outcome data

The vast majority of evidence for our review stems from non-RCTs. In most of the trials, the quality of the text was such that we had difficulty in understanding what went on (Jefferson 2009).

Selective reporting

Selective reporting including major inconsistencies between different parts of the text were a common feature. See Discussion 'Potential biases in the review process'.

Other potential sources of bias

See Discussion 'Potential biases in the review process'.

Effects of interventions

RCTs

We identified five RCTs published over four decades and just over 5000 observations (Allsup 2004; Edmondson 1971; Govaert 1994; Rudenko 2001; Stuart 1969). Given the heterogeneous nature of the vaccines tested (monovalent, trivalent, live, or inactivated aerosol vaccines), setting, follow up and outcome definition, no firm conclusions can be drawn from this body of evidence. Follow up is only specified in three trials (Govaert 1994; Rudenko 2001; Stuart 1969) and ranges from 42 to 180 days. Two trials had adequate randomisation and allocation concealment, and one trial had adequate measures to prevent attrition bias. The results of the most recent trial (Allsup 2004) are difficult to interpret because of the presence of selection bias. Based on the results of a meta-analysis of two trials (Allsup 2004; Govaert 1994), inactivated vaccines were more effective than placebo against influenza-like illness (ILI) in conditions of high viral circulation among elderly individuals living in the community (vaccine efficacy (VE) 43%; 21% to 58%; Analysis 13.1.1). The vaccines were also effective against influenza (VE 58%; 34% to 73%; Analysis 13.2) (Edmondson 1971; Govaert 1994; Rudenko 2001).

Cohort studies in long-term care facilities

Thirty cohort studies in long-term care facilities contributed data to 41 data sets (Arden 1988; Arroyo 1984; Aymard 1979a; Aymard 1979b; Cartter 1990a; Cartter 1990b; Cartter 1990c; Coles 1992; Cuneo Crovari 1980; Currier 1988; Taylor 1992; Deguchi 2001; Feery 1976; Fyson 1983a; Fyson 1983b; Goodman 1982; Gross 1988; Horman 1986; Howarth 1987a; Howarth 1987b; Howells 1975a; Howells 1975b; Howells 1975c; Isaacs 1997; Leung 2007, Meiklejohn 1987; Monto 2001; Morens 1995; Mukerjee 1994; Murayama 1999; Patriarca 1985a; Patriarca 1985b; Ruben 1974; Saah 1986a; Saah 1986b; Saah 1986c; Saito 2002a; Saito 2002b; Strassburg 1986; Taylor 1992) and over 34,000 observations. These studies were very focused and were fairly well resourced: 35 data sets reported virologic surveillance that confirmed influenza virus circulation and 22 data sets had short follow up (less than three months). They assessed the effects of vaccines in residential communities. The resident population is described in about half of the included data sets as predominantly aged older than 75 years, with multiple chronic pathologies and a high dependency level. However, breakdown of potential confounding factors (such as age, sex, smoking status and underlying chronic disease) is rarely reported by vaccine exposure, making correction of confounders impossible.

Studies recorded during outbreaks or periods of high viral circulation

Of the 41 data sets, 30 data sets (Arden 1988; Arroyo 1984; Aymard 1979a; Aymard 1979b; Cartter 1990a; Cartter 1990b; Cartter 1990c; Coles 1992; Cuneo Crovari 1980; Currier 1988; Leung 2007, Taylor 1992; Feery 1976; Fyson 1983a; Fyson 1983b; Goodman 1982; Gross 1988; Horman 1986; Isaacs 1997; Meiklejohn 1987; Monto 2001; Morens 1995; Mukerjee 1994; Murayama 1999; Patriarca 1985a; Ruben 1974; Saah 1986a; Saah 1986b; Strassburg 1986; Taylor 1992) with a total of 9879 observations were recorded during outbreaks or periods of high viral circulation. In 28 data sets the influenza virus subtype is positively identified (A/H3N2 in 25 data sets). The focus of 22 data sets (Arden 1988; Arroyo 1984; Cartter 1990a; Cartter 1990b; Cartter 1990c; Coles 1992; Cuneo Crovari 1980; Currier 1988; Feery 1976; Fyson 1983a; Fyson 1983b; Goodman 1982; Horman 1986; Isaacs 1997; Meiklejohn 1987; Morens 1995; Murayama 1999; Ruben 1974; Saah 1986a; Saah 1986b; Strassburg 1986; Taylor 1992) from 19 studies was on assessment of the effect of vaccination on single epidemic foci. Viral circulation was confirmed by isolates, increases in antibody titres, or observation of an epidemic of influenza-like illness in an institution at the same time as influenza A or B circulation in the surrounding community. A high proportion of cases classified as influenza-like illnesses were probably influenza cases. Twenty-two data sets (Arden 1988; Aymard 1979a; Cartter 1990a; Cartter 1990b; Cartter 1990c; Feery 1976; Fyson 1983a; Fyson 1983b; Goodman 1982; Gross 1988; Hara 2006, Horman 1986; Isaacs 1997; Meiklejohn 1987; Monto 2001; Morens 1995; Mukerjee 1994; Murayama 1999; Patriarca 1985a; Saah 1986b; Strassburg 1986; Taylor 1992) from 18 studies provided information about vaccine content match with circulating influenza viruses. We thus grouped our analyses by viral circulation and vaccine match.

Twenty-two data sets assessed the effectiveness of influenza vaccines in preventing influenza-like illnesses (Analysis 1.1 and Analysis 1.2). In these data sets, follow up was restricted to an outbreak period (mean duration 443,116 days) and authors reported a virologic surveillance that confirmed influenza virus circulation.

The overall effectiveness of vaccines (VE) against influenza-like illnesses was 23% (6% to 36%; Analysis 1.1.1) when vaccine matching was good and not significantly different from no vaccination (RR 0.80; 95% CI 0.60 to 1.05; Analysis 1.1.2) when matching was poor or unknown. Heterogeneity was high, even within the same influenza season and within the same institution when data from different accommodation blocks were analysed. We noted no association (correlation coefficient 0.09) between vaccine coverage and attack rate of influenza-like illness (Figure 1).

Figure 1.

Efficacy of the vaccines against influenza was tested in only six data sets (1250 observations) (Cuneo Crovari 1980; Feery 1976; Gross 1988; Morens 1995; Ruben 1974; Taylor 1992) and was not significant both for vaccine matching (RR 1.04 ; 95% CI 0.43 to 2.51; Analysis 1.2.1) and when matching was absent or unknown (RR 0.47; 95% CI 0.22 to 1.04; Analysis 1.2.2).

The effectiveness of the vaccines in preventing pneumonia was assessed in 13 data sets (Analysis 1.3.1 and Analysis 1.3.2; 8446 observations). All of them reported virologic surveillance and eight had follow ups shorter than three months (Arroyo 1984; Coles 1992; Currier 1988; Horman 1986; Meiklejohn 1987; Morens 1995; Patriarca 1985a; Taylor 1992). Well-matched vaccines were 46% (30% to 58%; Analysis 1.3.1) effective in preventing pneumonia (Gross 1988; Horman 1986; Meiklejohn 1987; Morens 1995; Monto 2001; Patriarca 1985a; Saah 1986b; Taylor 1992). When matching was poor or unknown (Arroyo 1984; Currier 1988; Coles 1992; Leung 2007; Saah 1986a), vaccines had no effect (RR 0.68; 95% CI 0.39 to 1.21; Analysis 1.3.2). Excluding studies with the longest follow up (Gross 1988; Saah 1986a; Saah 1986b: six months) did not affect our conclusions.

Eight data sets (Arden 1988; Cartter 1990a; Cartter 1990b; Cartter 1990c; Meiklejohn 1987; Murayama 1999; Patriarca 1985a; Taylor 1992) assessed the effectiveness of well-matched vaccines in preventing hospitalisation for influenza or pneumonia. All of them had a brief and well-defined follow up; effectiveness was 45% (16% to 64%; Analysis 1.4.1). Two studies reported a non-significant effect (Coles 1992; Leung 2007, Analysis 1.4.2) when the vaccine did not match the circulating strain or was not reported.

Vaccination had a significant effect on the prevention of deaths due to influenza or pneumonia, though this was in the presence of considerable heterogeneity between the 20 data sets (Arroyo 1984; Cartter 1990a; Cartter 1990b; Cartter 1990c; Coles 1992; Feery 1976; Fyson 1983a; Fyson 1983b; Goodman 1982; Horman 1986; Meiklejohn 1987; Monto 2001; Morens 1995; Murayama 1999; Patriarca 1985a; Ruben 1974; Saah 1986a; Saah 1986b; Strassburg 1986; Taylor 1992; Analysis 1.5.1 and Analysis 1.5.2). Eighteen studies reported virologic surveillance to confirm influenza virus circulation; of these, 16 had a follow up shorter than three months and two had a four-month follow up (Feery 1976; Monto 2001). Two studies lacked virologic surveillance and had a six-month follow up (Saah 1986a; Saah 1986b).

The vaccine was effective if it was a good match (VE 42%; 17% to 59%; Analysis 1.5.1), otherwise it was not effective (RR 0.34; 95% CI 0.11 to 1.02; Analysis 1.5.2).

Excluding two studies with a six-month follow up and absence of viral surveillance (Saah 1986a; Saah 1986b) affects the summary estimate more than the efficacy in the "epidemic-matching" group, which drops from 42% to 39% (95% CI 12 to 58).

The effectiveness in reducing all-cause mortality was assessed in only one small study with a six-month follow up (Gross 1988) and was significant (60%; 23% to 79%; Analysis 1.6.1).

Studies carried out during low viral circulation

Eleven data sets assessing the effects of influenza vaccines in 350 institutional facilities during low viral circulation comprised of 27,283 observations (Caminiti 1994; Deguchi 2001; Howarth 1987a; Howarth 1987b; Howells 1975a; Howells 1975b; Howells 1975c; Patriarca 1985b; Saito 2002a; Saito 2002b; Saah 1986c). Apart from Patriarca 1985, in this subgroup we found studies with the longest (five to six months) and most poorly defined follow up. Two of these studies (Deguchi 2001; Saah 1986c) did not report virologic surveillance.

The vaccines were 33% effective (2% to 54%; Analysis 1.1.3) in preventing influenza-like illnesses (ILI) (Caminiti 1994; Patriarca 1985b; Saito 2002a; Saito 2002b) but had no significant effects in preventing influenza (RR 0.23, 95% CI 0.05 to 1.03; Analysis 1.2.3). This observations is based on two data sets from a single, relatively small, study (691 observations) (Howarth 1987a; Howarth 1987b). Both comparisons are from well-matched vaccines.

We identified a few data sets that assessed the effectiveness of vaccines in preventing complications. Four briefly reported data sets from two studies (Howells 1975a; Howells 1975b; Howells 1975c; Saah 1986c) carried out in situations of low viral circulation and poor vaccine matching report a combined effectiveness of 65% (32% to 82%; Analysis 1.3.4) in preventing pneumonia.

During periods of low viral circulation, vaccines did prevent hospital admission for pneumonia or influenza (VE 68%; 24% to 86%; Analysis 1.4.3). However, one of the included studies (Deguchi 2001) is at high risk of bias - meaning that this outcome may not be accurate. The study was set in 301 nursing homes, comprising 22,462 elderly participants during the non-epidemic 1998 to 1999 season in Japan. The same study has a large weight in the analysis of effectiveness against deaths by influenza and pneumonia (VE 71%; 43% to 85%; Analysis 1.5.3 and Analysis 1.5.4) (Caminiti 1994; Deguchi 2001; Howells 1975a; Howells 1975b; Howells 1975c; Patriarca 1985b; Saah 1986c).

Cohort studies in community-dwelling elderly

We included 21 studies with 40 data sets in elderly participants living in open communities (Christenson 2001a; Christenson 2001b; Christenson 2004a; Christenson 2004b; Comeri 1995; Consonni 2004a; Consonni 2004b; Davis 2001a; Davis 2001b; Davis 2001c; Fleming 1995; Gavira Iglesias 1987; Gené Badia 1991; Hak 2002a; Hak 2002b; Hara 2006, Kaway 2003; Lopez Hernandez 1994; Mangtani 2004b; Mangtani 2004c; Mangtani 2004d; Mangtani 2004e; Mangtani 2004f; Mangtani 2004g; Mangtani 2004h; Mangtani 2004i; Mangtani 2004j; Nichol 1994a; Nichol 1994b; Nichol 1994c; Nichol 1998a; Nichol 1998b; Nichol 2003a; Nichol 2003b; Nicholson 1999; Nordin 2001a; Nordin 2001b; Pregliasco 2002; Shapiro 2003; Voordouw 2003). The studies contained over three million observations mainly collected using data-linkage from insurance reimbursement, hospital or primary care data bases; 13 of them reported data stratified or adjusted by risk factors and other potential confounders. These studies had long follow ups: 12 data sets had a follow up =< three months, 13 data sets had a follow up ranging from four to five months, eight data sets had a follow up ranging from six to seven months; four data sets had a follow up ranging from eight to 12 months and two data sets were without a well-defined follow up. In nine data sets, follow up was defined by relying on virologic surveillance and three data sets had laboratory confirmation of cases. On the basis of this large body of evidence, we divided our analysis into six separate comparisons.

Inactivated influenza vaccines in all community-dwelling elderly

Our second comparison relies on one million observations in 20 data sets from 16 studies (Christenson 2001a; Christenson 2004a; Comeri 1995; Davis 2001c; Fleming 1995; Gavira Iglesias 1987; Gené Badia 1991; Hara 2006, Kaway 2003; Lopez Hernandez 1994; Mangtani 2004a; Nichol 1994a; Nichol 1994b; Nichol 1994c; Nichol 1998b; Nichol 2003a; Nichol 2003b; Nicholson 1999; Shapiro 2003; Voordouw 2003).

In elderly individuals living in the community, inactivated influenza vaccines were not effective against ILI, influenza or pneumonia. No comparison provided enough data for stratification by viral circulation and vaccine matching.

Eight data sets (784,643 observations) with medium to long follow up (135 to 365 days) addressed vaccine effectiveness against hospitalisations for influenza or pneumonia (Christenson 2001a; Christenson 2004a; Nichol 1994a; Nichol 1994b; Nichol 1994c; Nichol 1998b; Nichol 2003a; Nichol 2003b). Well-matched vaccines prevented hospital admissions for these illnesses (VE 26%; 12% to 38%; Analysis 2.4.1) but not for cardiac disease (RR 0.87; 95% CI 0.67 to 1.12; Analysis 2.9). Excluding the only study with a one-year follow up (Christenson 2004a), effectiveness in preventing hospital admissions is increased to 29% (95% CI 14 to 42).

Death from respiratory disease was not significantly affected. Seven data sets (Fleming 1995; Gené Badia 1991; Lopez Hernandez 1994; Nichol 2003a; Nichol 2003b; Shapiro 2003; Voordouw 2003) with a follow up ranging from 75 to 210 days, assessed the effect on mortality for all causes (VE: 42%; 24% to 55%; Analysis 2.8). Excluding four data sets with a follow up equal to or longer than six months (Gené Badia 1991; Lopez Hernandez 1994; Voordouw 2003) or a non-defined follow up (Shapiro 2003), the efficacy falls from 42% to 39% (95% CI 28 to 49).

Inactivated influenza vaccines in community-dwelling elderly at risk of influenza complications

In the third comparison, we assessed the effectiveness of inactivated influenza vaccines in elderly individuals living in the community and at risk of complications associated with influenza. Patients with any of the following underlying conditions were considered at risk of complications: lung disease, heart disease, renal disease, diabetes and other endocrine disorders, immunodeficiency or immunosuppressive diseases, cancer, dementia or stroke, vasculitis, or rheumatic disease. Seven data sets from six studies were relevant. The only significant effect was that for deaths from all causes (VE: 61%; 3% to 84%; Analysis 3.6) from 68,032 observations with high heterogeneity (I2 statistic 94.1%) (Fleming 1995; Shapiro 2003; Voordouw 2003).

Inactivated influenza vaccines in community-dwelling elderly without risk of influenza complications

In this stratum, six studies with seven data sets (Fleming 1995; Hak 2002a; Hak 2002b; Mangtani 2004a; Nichol 1998a; Shapiro 2003; Voordouw 2003) contributed several hundred thousand observations. However, most outcomes were only assessed by one study. The only notable results are the vaccines' effectiveness in preventing hospital admission for influenza or pneumonia (VE: 50%; 37% to 60%; Analysis 4.3) although this observation is based only on one data set Nichol 1998a with 101,619 observations, and there is a lack of effect on all-cause mortality (RR 0.65; 95% CI 0.33 to 1.29; 43,821 observations; Analysis 4.6) (Fleming 1995; Shapiro 2003; Voordouw 2003).

Inactivated influenza vaccines in all community-dwelling elderly (adjusted for confounders)

This is another data set with seven studies contributing 19 data sets (Davis 2001a; Davis 2001b; Davis 2001c; Fleming 1995; Mangtani 2004b; Mangtani 2004c; Mangtani 2004d; Mangtani 2004e; Mangtani 2004f; Mangtani 2004g; Mangtani 2004h; Mangtani 2004i; Mangtani 2004j; Nichol 1998a; Nichol 2003a; Nichol 2003b; Nordin 2001a; Nordin 2001b; Voordouw 2003) with over a million observations from several consecutive influenza seasons. Most of the studies included in this analysis used data linkage and adjusted their OR calculations to allow for the effect of confounding of several variables (sex, age, smoking, co-morbidities). The effects of the vaccines are all significant.

Hospitalisations for influenza or pneumonia: eight data sets, all but one with a follow up lasting 135 days (Davis 2001a; Davis 2001b; Davis 2001c; Nichol 1998a; Nichol 2003a; Nichol 2003b; Nordin 2001b) (OR 0.73; 95% CI 0.67 to 0.79, based on 949,215 observations (Analysis 7.1)). Excluding the only data set (Nordin 2001a) with the longest follow up (eight months) does not change the result.

Hospitalisations for respiratory diseases: OR 0.78; 95% CI 0.72 to 0.85 (Analysis 7.2). Data sets have a follow up of 135 days or less, so a sensitivity analysis appears to be superfluous.

Hospitalisation for cardiac disease: OR 0.76; 95% CI 0.70 to 0.82 (Analysis 07.3). Data sets have a follow up of 135 days or less, so a sensitivity analysis appears to be superfluous.

Mortality for all causes: seven data sets (Fleming 1995; Nichol 1998a; Nichol 2003a; Nichol 2003b; Nordin 2001a; Nordin 2001b; Voordouw 2003) with follow up ranging from 75 to 240 days (OR 0.53; 95% CI 0.46 to 0.61 (Analysis 7.4)). Excluding data sets with a follow-up period equal to or longer than six months (Nordin 2001a; Voordouw 2003) does not change the final result.

Inactivated influenza and polysaccharide vaccine (PPV) on community-dwelling elderly

Three studies assessed the impact of inactivated influenza and concomitant PPV (Christenson 2001b; Christenson 2004b; Consonni 2004b) on hospitalisations for influenza or pneumonia or respiratory diseases (VE = 33%; 30 to 36 %, based on 518,748 observations; Analysis 5.2) and two data sets (Christenson 2001b; Consonni 2004b) assessed the effect on all causes mortality (VE = 56%; 54% to 59%; Analysis 5.4).

The addition of PPV did not appear to improve the performance of influenza vaccines significantly.

Adjuvant influenza vaccines in all community-dwelling elderly

Two small studies with a combined denominator of 498 assessed the impact of vaccines containing a virosomal adjuvant in preventing influenza-like illness (ILI) (VE 70%, 44% to 84%; Analysis 6.1) and hospitalisations (RR 0.17; 95% CI 0.02 to 1.28; Analysis 6.2.3) during a year of low viral circulation but with a vaccine with a good match (Consonni 2004a; Pregliasco 2002). The study by Consonni 2004a also assessed the impact on mortality for all causes and found no effect (RR 2.10; 95% CI 0.10 to 43.10; Analysis 6.3.3). This is not surprising given its population size of 129 patients (too small for any significant effect to be evident).

Case-control studies

We included 12 studies contributing 14 data sets (Ahmed 1995; Ahmed 1997; Crocetti 2001; Fedson 1993a; Fedson 1993b; Foster 1992; Jordan 2007; Mullooly 1994; Ohmit 1995a; Ohmit 1995b; Ohmit 1999; Puig-Barberà 1997; Puig-Barberà 2004; Puig-Barbera 2007). Eight data sets from seven studies assessed the effects of inactivated influenza vaccines on community-dwelling elderly (Ahmed 1995; Ahmed 1997; Crocetti 2001; Fedson 1993a; Fedson 1993b; Puig-Barberà 1997; Jordan 2007, Puig-Barbera 2007), five looked at the co-administration of inactivated influenza with polysaccharide vaccine (PPV) on institutionalised elderly (Foster 1992; Mullooly 1994; Ohmit 1995a; Ohmit 1995b; Ohmit 1999), one of adjuvant influenza with PPV on community-dwelling elderly (Puig-Barberà 2004) and one of adjuvanted influenza vaccines (MF59) alone Puig-Barbera 2007. Only three of these studies, all assessing influenza and pneumococcal vaccines, had a long follow up (six months). Since all data sets adjusted their ORs for likely confounding factors, we structured our analysis on five strata, further subdividing each analysis by viral circulation and vaccine matching whenever possible.

Inactivated influenza vaccines on community-dwelling elderly

Before adjustment, inactivated influenza vaccines were associated with an increased risk of admission for any respiratory disease (OR 1.08; 95% CI 0.92 to 1.26; 20,582 observations; Analysis 8.2.1) (Ahmed 1997; Fedson 1993a; Fedson 1993b) and did not prevent hospital admission for influenza and pneumonia in elderly individuals living in the community (OR 0.89; 95% CI 0.69 to 1.15; 1074 observations; Analysis 8.1) (Crocetti 2001; Puig-Barberà 1997) or affect hospitalisation for influenza-like illness (Analysis 8.2.2) (Jordan 2007) or affect mortality from influenza and pneumonia, though this conclusion is based on a relatively small data set of 1092 observations (Ahmed 1995; Analysis 8.3.1). The single study on adjuvanted vaccines showed no effect on pneumonia no better defined (Analysis 8.4.1) (Puig-Barbera 2007).

Inactivated influenza vaccines on community-dwelling elderly - adjusted analysis

After adjustment, however, the vaccines did reduce the risk of death from influenza and pneumonia (OR 0.74; 95% CI 0.60 to 0.92; Analysis 11.3) (Ahmed 1995; Mullooly 1994) and prevent admission for influenza and pneumonia (OR 0.59; 95% CI 0.47 to 0.74; Analysis 11.01) (Crocetti 2001; Foster 1992; Mullooly 1994; Puig-Barberà 1997; Puig-Barberà 2004) and for all respiratory diseases (OR 0.71; 95% CI 0.56 to 0.90; Analysis 11.02) (Ahmed 1997; Fedson 1993a; Fedson 1993b).

Inactivated influenza and (PPV) vaccines

Similarly, before adjustment inactivated influenza and concomitant PPV in individuals living in the community did not prevent hospital admission for influenza and pneumonia (OR 0.97; 95% CI 0.85 to 1.09; Analysis 9.1) (Foster 1992; Ohmit 1995a; Ohmit 1995b; Puig-Barberà 2004), whereas after adjustment they did (OR 0.68; 95% CI 0.54 to 0.86; Analysis 12.1) (Ohmit 1995a; Ohmit 1995b). One study assessed the effect of influenza and PPV vaccines on influenza-like illness: VE 48%; 32% to 60%; 1198 observations; Analysis 10.1 (Ohmit 1999).

Possible causes of observed heterogeneity - post hoc analysis

Of the 15 main comparisons with 61 outcome combinations, we noted in a subsequent analysis that seven comparisons with 20 outcome combinations had an I2 statistic of greater than 30% and that the heterogeneity of these studies could be explained by grouping by viral circulation and vaccine matching.

Safety

We included data on local and systemic side effects. For local side effects we included tenderness, sore arm, swelling, erythema and induration. Similar local symptoms were pooled in the analysis due to small data sets. Systemic symptoms were general malaise, fever, headache, nausea and respiratory tract symptoms.

Four RCTs (Govaert 1993; Keitel 1996; Margolis 1990a; Treanor 1994; Analysis 17) reported data about local and systemic adverse events observed within a week from administration of parenteral inactivated vaccine (2606 observations). Treanor 1994 also reported data about live aerosol vaccine (Analysis 18). All side effects reported in trials were included in the analysis, even if they were not significant. Vaccines usually induced systemic side effects (general malaise, fever, nausea, headache) more frequently than placebo, but no outcome showed statistically significant results. Local adverse events, such as tenderness and sore arm, were significantly more frequent in the treatment arm than in the placebo arm. The only studies assessing rare adverse events were three surveillance studies assessing Guillan Barré Syndrome with neither cohort nor case-control design (Kaplan 1982; Lasky 1998; Schonberger 1979) (Table 1). Case finding was carried out by interviewing neurologists or by searching discharge diagnoses databases. Vaccination rates in the relevant populations were estimated from specific survey or from national immunisation survey. All studies were conducted in the USA and assessed the entire population irrespective of age. Lasky 1998 and Schonberger 1979 reported outcome stratified by age, allowing data extraction for elderly people. We reported the results of these studies in the 'Guillain Barré Syndrome' table (Table 1). The strong and significant association between A/New Jersey/76 swine vaccine and Guillan Barré Syndrome, during the 1976 to 1977 influenza season was not confirmed in subsequent seasons when other vaccines not containing A/New Jersey/76 were used.

Table 1. Guillain Barré Syndrome
StudyInfluenza seasonVaccinePopulationAgeRR (95% CI)
Schonberger 19791976 to 1977A/New Jersey/76 or A/New Jersey/76 and A/Victoria/75 swine vaccineAll the USA pop.> 64 years5.2 (3.9 to 7.0)
Kaplan 19821979 to 1980Inactivated trivalentAll the USA pop.> 18 years0.6 (0.45 to 1.32)
Kaplan 19821980 to 1981Inactivated trivalentAll the USA pop.> 18 years1.4 (0.80 to 1.76)
Lasky 19981992 to 1994Inactivated trivalent21 million> 64 years1.5 (0.7 to 3.3)

Discussion

Summary of main results

Our findings show that according to reliable evidence, the effectiveness of trivalent inactivated influenza vaccines in elderly individuals is modest, irrespective of setting, outcome, population and study design. Our estimates are consistently below those usually quoted for economic modelling or decision making. In view of the known variability of incidence and effect of influenza, we constructed a large number of comparisons and strata to minimise possible heterogeneity between studies and aid comparability. We also performed sub-analysis of studies describing better defined epidemic periods. Despite our attempts, we noted significant residual heterogeneity among studies that could be explained only in part by different study designs, methodological quality, settings, viral circulation, vaccine types and matching, age, population types and risk factors. We think the residual heterogeneity could be the result of the unpredictable nature of the spread of influenza and influenza-like illness (ILI) and the bias caused by the non-randomised nature of our evidence base. Our sensitivity analysis did not affect the final result.

Overall completeness and applicability of evidence

Whatever the causes of observed variability, we believe that the decision to vaccinate against influenza cannot be made on the basis of the results from single studies, or reporting observations from a few seasons. Rather, it should be taken on the basis of all available evidence. The conclusions drawn from studies done in individuals who live in long-term care facilities are different from those drawn from studies in individuals who live in the community. Studies done in residents of care homes often indicate the inevitably improvised nature of efforts to study the effect of vaccination during an epidemic. The resident population is usually more homogeneous than that in the community: older, with similar viral exposure and risk levels. Despite a remaining heterogeneity and an overestimation of the effects as a result of study design, it is possible to detect a gradient of effectiveness, in which vaccines have little effect on cases of ILI, but have greater effect on its complications. This finding suggests that control of influenza through vaccination is a possibility. However, the effectiveness of vaccines in the community is modest, irrespective of adjustment for systematic differences between vaccine recipients and non-recipients. The difficulties of achieving good coverage in those who most need it or the diluting effect on vaccines for influenza of other agents circulating in the community (causing ILI, clinically indistinguishable from influenza), might be to blame. We noted empirical proof of both these possibilities, with differential vaccine uptake among the same population (linked to age, sex and health status) and a low effect on ILI throughout our data sets even in periods of supposedly high influenza viral circulation, when the proportion of cases of ILI caused by influenza are highest and the possible benefits of vaccination should be greatest.

Safety does not appear to be a particular problem: the public health safety profile of the vaccines is acceptable. However relatively few studies reported assessing safety outcomes.

Quality of the evidence

The main problem with interpreting our substantial dataset is caused by the relative scarcity of randomised controlled trials (RCTs). Only one trial (Govaert 1994) assessed currently available vaccines and reached satisfactory completion. The remainder of the dataset consists of evidence from non-RCTs.

Our main concern was the quality of the non-RCTs which probably affected the estimates of effect reported in our review. The findings of the cohort studies that we included are likely to have been affected to a varying degree by selection bias. Differential uptake of influenza vaccines is linked to several factors (anxiety over unwanted effects, disease threat perception, societal and economic conditions, education, health status) and hence to outcome. Confounding by indication (people with chronic illness or people who are perceived to be frailer than others are more likely to be vaccinated) might reduce the estimated vaccine efficacy. People with terminal illness or with socio-economic disadvantages are less likely to be vaccinated and this fact might enhance vaccine efficacy. Both these interpretations are based on empirical evidence. For example, one cohort study (Gené Badia 1991) had difficulties achieving high coverage in those most at need. Differential vaccine uptake and the resulting selection bias is the most likely explanation for the high effectiveness of influenza vaccines in preventing deaths from all causes. A good example of the potential effect of such confounders is the apparently counter-intuitive effectiveness of the vaccines in elderly individuals living in the community. In this population, vaccine effectiveness shows an implausible sequence: the vaccines are apparently ineffective in the prevention of influenza, ILI, pneumonia, hospital admissions or deaths from any respiratory disease but are effective in the prevention of hospital admission for influenza and pneumonia and in the prevention of deaths from all causes.

Non-RCT evidence in this review is open to any alternative interpretation and consistently fails to give satisfactory answers. Since the publication of our 2006 review (Rivetti 2006), several empirical studies looking at the effect of selection bias in retrospective cohorts (variously called selection bias, confounding by indication or healthy user effect) have been published. Some confirmed the presence and effect of confounders (Eurich 2008; Fukushima 2008; Glezen 2006, Hirota 2008; Jackson 2006a; Jackson 2006b; Jackson 2006c; Jackson 2006d; Jackson 2006e). Other studies, mainly carried out by the authors of cohort studies in question, failed to find any effect of confounding on mortality once adjustment had been carried out (Groenwold 2008; Groenwold 2009; Hak 2006; Nichol 2007). For example, proof of bias was provided by a study evaluating the risk of hospitalisation and death in vaccinated compared with unvaccinated seniors during influenza and non-influenza periods (Jackson 2006a). Consistent with other published studies, during influenza season, vaccination was associated with a 44% reduction in risk of all-cause mortality. However, in the period before the influenza season, vaccination was associated with a 61% reduction in risk of this outcome. The reduction in risk before the influenza season indicates the presence of bias due to preferential selection of vaccination by relatively healthy seniors, and the strength of that bias is sufficient to account entirely for the association found during the influenza season. In a second, nested case-control study, seniors with functional markers of frailty (such as dependence on washing) were found to be at a greatly increased risk of death and were less likely to have received influenza vaccine, indicating that these factors are important sources of bias in assessment of influenza vaccine effectiveness (Jackson 2006b).

Regardless of the results of empirical studies, the sheer implausibility of the effectiveness sequence which ends with high estimates of effect against mortality from all causes, points to considerable confounding and calls into question the reliability of using such non-specific outcomes. Systematic differences between the intervention and control arms of cohort studies are likely to be the result of a baseline imbalance in health status and other known and unknown systematic differences in the two groups of participants. The rationale of the work starts from the observation that the 47% reduction in risk of all-cause mortality in elderly community dwellers observed in our review, exceeds by far the estimated possible impact of influenza on winter-seasonal mortality of 5% in an average season (Glezen 2006). Until improvement of cohort study design is available, the use in non-RCT studies of highly non-specific outcome indicators, such as all-cause mortality, is likely to lead to unrealistic estimates of the effects of the vaccines.

Evidence from RCTs, in which bias is reduced to a minimum, is scant and badly reported. Unfortunately, because of the global recommendations on influenza vaccination, placebo-controlled trials, which could clarify the effects of influenza vaccines in individuals, are no longer considered possible on ethical grounds.

Potential biases in the review process

The publication of our 2006 review (Rivetti 2006) sparked a discussion which continues to this day. Because we are conscious that (despite the inconclusive evidence) we could have introduced our own biases into the reviewing process we re-extracted and reassessed all studies included in this and all other reviews of influenza vaccine studies (259 primary studies, reporting 274 datasets). We worked independently in two teams of two, extracting directly into pre-set forms with rigid criteria but using the same quality assessment scales used in the original version of the review. As well as assessing quality of study design we assessed concordance between data presented and conclusions and direction of conclusions (in favour or not of the performance of influenza vaccines). We also looked at the relationship between these variables and study funding and journal of publication. We found that higher quality studies were significantly more likely to show concordance between data presented and conclusions (odds ratio 16.35, 95% CI 4.24 to 63.04) and less likely to favour effectiveness of vaccines (0.04, 0.02 to 0.09). Government funded studies were less likely to have conclusions favouring the vaccines (0.45, 0.26 to 0.90). A higher mean journal impact factor was associated with complete or partial industry funding compared with government or private funding and no funding (differences between means 5.04). Study size was not associated with concordance, content of take home message, funding or study quality. Higher citation index factor was associated with partial or complete industry funding (Jefferson 2009).

We concluded that the general quality of influenza vaccines studies is very low and that publication in prestigious journals is associated with partial or total industry funding. We could not explain this association with study quality, size or its status (registration trials using surrogate outcomes such as antibody titres were not included in the review). As our elderly dataset formed a major part of our overview of influenza vaccines studies, it is likely that that data presented in this review are so biased as to be virtually uninterpretable.

Agreements and disagreements with other studies or reviews

Nichol provides a useful overview of reviews of influenza vaccines in all age groups (Nichol 2008). For the elderly she identified our review and a review by Vu (Vu 2002). Although the point estimates appear approximately similar across the reviews both Vu and Nichol fail to assess study quality and interpret results accordingly.

Authors' conclusions

Implications for practice

Until such time as the role of vaccines for preventing influenza in the elderly is clarified, more comprehensive and effective strategies for the control of acute respiratory infections should be implemented. These should rely on several preventive interventions that take into account the multi-agent nature of influenza-like illness (ILI) and its context (such as personal hygiene, provision of electricity and adequate food, water and sanitation). The effect of vaccination of high-risk groups should also be further assessed.

Implications for research

Investment in the development of better vaccines than are presently available should be linked to better knowledge of the causes and patterns of ILI in different communities. The additional effects of vaccinating carers in reducing transmission in nursing homes should be assessed. The effect of vaccination of high-risk groups should also be further assessed.

To resolve the uncertainty of the role of vaccines, an adequately powered, publicly-funded, high quality placebo-controlled trial run over several seasons should be undertaken.

Acknowledgements

The authors also wish to thank the following people for commenting on the draft of earlier reviews: Amy Zelmer, Laila Tata, Wendy Keitel, Lohne Simonsen, Sree Nair and Geoff Spurling. Vittorio Demicheli, Roger Thomas, Daniela Rivetti, Melanie Rudin and Alessandro Rivetti contributed to the earlier version of the review. For this 2009 update we wish to thank Maryann Napoli, Anne Lyddiat, Wendy Keitel, Ludovic Reveiz, Mark Jones and Chris Del Mar for commenting on the updated draft.

Data and analyses

Download statistical data

Comparison 1. Influenza vaccines versus no vaccination - Cohort studies in nursing homes
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI2612388Risk Ratio (M-H, Random, 95% CI)0.76 [0.66, 0.88]
1.1 Outbreak - vaccine matching (circulating strains)165963Risk Ratio (M-H, Random, 95% CI)0.77 [0.64, 0.94]
1.2 Outbreak - vaccine matching absent or unknown64096Risk Ratio (M-H, Random, 95% CI)0.80 [0.60, 1.05]
1.3 No outbreak - vaccine matching42329Risk Ratio (M-H, Random, 95% CI)0.67 [0.46, 0.98]
1.4 No outbreak - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Influenza81941Risk Ratio (M-H, Random, 95% CI)0.65 [0.32, 1.29]
2.1 Outbreak - vaccine matching4658Risk Ratio (M-H, Random, 95% CI)1.04 [0.43, 2.51]
2.2 Outbreak - vaccine matching absent or unknown2592Risk Ratio (M-H, Random, 95% CI)0.47 [0.22, 1.04]
2.3 No outbreak - vaccine matching2691Risk Ratio (M-H, Random, 95% CI)0.23 [0.05, 1.03]
2.4 No outbreak - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Pneumonia1710274Risk Ratio (M-H, Random, 95% CI)0.53 [0.43, 0.66]
3.1 Outbreak - vaccine matching84482Risk Ratio (M-H, Random, 95% CI)0.54 [0.42, 0.70]
3.2 Outbreak - vaccine matching absent or unknown53991Risk Ratio (M-H, Random, 95% CI)0.68 [0.39, 1.21]
3.3 No outbreak - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.4 No outbreak - matching absent or unknown41801Risk Ratio (M-H, Random, 95% CI)0.35 [0.18, 0.68]
4 Hospitalisation for ILI or pneumonia1228032Risk Ratio (M-H, Random, 95% CI)0.51 [0.32, 0.81]
4.1 Outbreak - vaccine matching82027Risk Ratio (M-H, Random, 95% CI)0.55 [0.36, 0.84]
4.2 Outbreak - vaccine matching absent or unknown23301Risk Ratio (M-H, Random, 95% CI)0.82 [0.43, 1.58]
4.3 No outbreak - vaccine matching222704Risk Ratio (M-H, Random, 95% CI)0.32 [0.14, 0.76]
4.4 No outbreak - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Deaths from flu or pneumonia2732179Risk Ratio (M-H, Random, 95% CI)0.46 [0.33, 0.63]
5.1 Outbreak - vaccine matching166127Risk Ratio (M-H, Random, 95% CI)0.58 [0.41, 0.83]
5.2 Outbreak - vaccine matching absent or unknown41089Risk Ratio (M-H, Random, 95% CI)0.34 [0.11, 1.02]
5.3 No outbreak - vaccine matching323162Risk Ratio (M-H, Random, 95% CI)0.27 [0.09, 0.87]
5.4 No outbreak - vaccine matching absent or unknown41801Risk Ratio (M-H, Random, 95% CI)0.30 [0.14, 0.67]
6 All deaths1305Risk Ratio (M-H, Random, 95% CI)0.40 [0.21, 0.77]
6.1 Outbreak - vaccine matching1305Risk Ratio (M-H, Random, 95% CI)0.40 [0.21, 0.77]
6.2 Outbreak - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.3 No outbreak - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.4 No outbreak - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7 Influenza cases (clinically defined without clear definition)724238Risk Ratio (M-H, Random, 95% CI)0.52 [0.27, 1.02]
7.1 Outbreak - vaccine matching2271Risk Ratio (M-H, Random, 95% CI)0.70 [0.11, 4.56]
7.2 Outbreak - vaccine matching absent or unknown1155Risk Ratio (M-H, Random, 95% CI)0.23 [0.09, 0.59]
7.3 No outbreak - vaccine matching122462Risk Ratio (M-H, Random, 95% CI)0.40 [0.35, 0.46]
7.4 No outbreak - vaccine matching absent or unknown31350Risk Ratio (M-H, Random, 95% CI)0.72 [0.41, 1.28]
Analysis 1.1.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 1 ILI.

Analysis 1.2.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 2 Influenza.

Analysis 1.3.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 3 Pneumonia.

Analysis 1.4.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 4 Hospitalisation for ILI or pneumonia.

Analysis 1.5.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 5 Deaths from flu or pneumonia.

Analysis 1.6.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 6 All deaths.

Analysis 1.7.

Comparison 1 Influenza vaccines versus no vaccination - Cohort studies in nursing homes, Outcome 7 Influenza cases (clinically defined without clear definition).

Comparison 2. Influenza vaccines versus no vaccination - Cohort studies in community-dwellers
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI49613Risk Ratio (M-H, Random, 95% CI)0.75 [0.42, 1.33]
1.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Non epidemic year - vaccine matching24636Risk Ratio (M-H, Random, 95% CI)1.08 [0.58, 2.03]
1.4 Non epidemic year - vaccine matching absent or unknown1268Risk Ratio (M-H, Random, 95% CI)0.85 [0.16, 4.55]
1.5 Epidemic year - vaccine not matching14709Risk Ratio (M-H, Random, 95% CI)0.44 [0.24, 0.81]
2 Influenza218249Risk Ratio (M-H, Random, 95% CI)0.19 [0.02, 2.01]
2.1 Epidemic year - vaccine matching1427Risk Ratio (M-H, Random, 95% CI)0.05 [0.01, 0.37]
2.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Non epidemic year - vaccine matching117822Risk Ratio (M-H, Random, 95% CI)0.5 [0.27, 0.91]
2.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Pneumonia218090Risk Ratio (M-H, Random, 95% CI)0.88 [0.64, 1.20]
3.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Non epidemic year - vaccine matching117822Risk Ratio (M-H, Random, 95% CI)0.87 [0.63, 1.19]
3.4 Non epidemic year - vaccine matching absent or unknown1268Risk Ratio (M-H, Random, 95% CI)3.0 [0.16, 57.42]
4 Hospitalisation for flu or pneumonia9784643Risk Ratio (M-H, Random, 95% CI)0.73 [0.62, 0.85]
4.1 Epidemic year - vaccine matching6727776Risk Ratio (M-H, Random, 95% CI)0.74 [0.62, 0.88]
4.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Non epidemic year - vaccine matching125532Risk Ratio (M-H, Random, 95% CI)0.55 [0.37, 0.83]
4.4 Non epidemic year - vaccine matching absent or unknown126626Risk Ratio (M-H, Random, 95% CI)0.73 [0.54, 0.99]
4.5 Epidemic year - vaccine not matching14709Risk Ratio (M-H, Random, 95% CI)0.89 [0.33, 2.40]
5 Hospitalisation for any respiratory disease5567299Risk Ratio (M-H, Random, 95% CI)0.88 [0.54, 1.43]
5.1 Epidemic year - vaccine matching3515141Risk Ratio (M-H, Random, 95% CI)0.78 [0.37, 1.64]
5.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5.3 Non epidemic year - vaccine matching125532Risk Ratio (M-H, Random, 95% CI)0.94 [0.79, 1.12]
5.4 Non epidemic year - vaccine matching absent or unknown126626Risk Ratio (M-H, Random, 95% CI)1.16 [1.01, 1.34]
6 Deaths from flu or pneumonia1163391Risk Ratio (M-H, Random, 95% CI)0.87 [0.70, 1.09]
6.1 Epidemic year - vaccine matching1163391Risk Ratio (M-H, Random, 95% CI)0.87 [0.70, 1.09]
6.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7 Deaths from respiratory disease1426668Risk Ratio (M-H, Random, 95% CI)1.32 [1.25, 1.39]
7.1 Epidemic year - vaccine matching1426668Risk Ratio (M-H, Random, 95% CI)1.32 [1.25, 1.39]
8 All deaths8409468Risk Ratio (M-H, Random, 95% CI)0.61 [0.47, 0.80]
8.1 Epidemic year - vaccine matching4300332Risk Ratio (M-H, Random, 95% CI)0.59 [0.50, 0.70]
8.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8.3 Non epidemic year - vaccine matching3104427Risk Ratio (M-H, Random, 95% CI)0.65 [0.30, 1.39]
8.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8.5 Epidemic year - vaccine not matching14709Risk Ratio (M-H, Random, 95% CI)3.89 [0.90, 16.89]
9 Hospitalisation for heart disease6433934Risk Ratio (M-H, Random, 95% CI)0.87 [0.67, 1.12]
9.1 Epidemic year - vaccine matching4381776Risk Ratio (M-H, Random, 95% CI)0.74 [0.56, 0.97]
9.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
9.3 Non epidemic year - vaccine matching125532Risk Ratio (M-H, Random, 95% CI)1.06 [0.81, 1.38]
9.4 Non epidemic year - vaccine matching absent or unknown126626Risk Ratio (M-H, Random, 95% CI)1.59 [1.07, 2.36]
10 Combined outcome: all deaths or severe respiratory illness3290819Risk Ratio (M-H, Random, 95% CI)0.71 [0.58, 0.85]
10.1 Epidemic year - vaccine matching2132365Risk Ratio (M-H, Random, 95% CI)0.80 [0.42, 1.55]
10.2 Epidemic year - vaccine matching absent or unknown1158454Risk Ratio (M-H, Random, 95% CI)0.74 [0.69, 0.80]
Analysis 2.1.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 1 ILI.

Analysis 2.2.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 2 Influenza.

Analysis 2.3.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 3 Pneumonia.

Analysis 2.4.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 4 Hospitalisation for flu or pneumonia.

Analysis 2.5.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 5 Hospitalisation for any respiratory disease.

Analysis 2.6.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 6 Deaths from flu or pneumonia.

Analysis 2.7.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 7 Deaths from respiratory disease.

Analysis 2.8.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 8 All deaths.

Analysis 2.9.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 9 Hospitalisation for heart disease.

Analysis 2.10.

Comparison 2 Influenza vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 10 Combined outcome: all deaths or severe respiratory illness.

Comparison 3. Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza16423Risk Ratio (M-H, Random, 95% CI)0.40 [0.14, 1.17]
1.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Non epidemic year - vaccine matching16423Risk Ratio (M-H, Random, 95% CI)0.40 [0.14, 1.17]
1.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Pneumonia16423Risk Ratio (M-H, Random, 95% CI)1.22 [0.76, 1.94]
2.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Non epidemic year - vaccine matching16423Risk Ratio (M-H, Random, 95% CI)1.22 [0.76, 1.94]
2.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Hospitalisation for influenza or pneumonia145932Risk Ratio (M-H, Random, 95% CI)0.74 [0.63, 0.86]
3.1 Epidemic year - vaccine matching145932Risk Ratio (M-H, Random, 95% CI)0.74 [0.63, 0.86]
3.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4 Hospitalisation for any respiratory disease2189004Risk Ratio (M-H, Random, 95% CI)0.85 [0.80, 0.92]
4.1 Epidemic year - vaccine matching2189004Risk Ratio (M-H, Random, 95% CI)0.85 [0.80, 0.92]
4.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Deaths from respiratory disease1142464Risk Ratio (M-H, Random, 95% CI)0.92 [0.86, 0.98]
5.1 Epidemic year - vaccine matching1142464Risk Ratio (M-H, Random, 95% CI)0.92 [0.86, 0.98]
6 All deaths368032Risk Ratio (M-H, Random, 95% CI)0.39 [0.16, 0.97]
6.1 Epidemic year - vaccine matching12344Risk Ratio (M-H, Random, 95% CI)0.13 [0.02, 0.92]
6.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.3 Non epidemic year - vaccine matching265688Risk Ratio (M-H, Random, 95% CI)0.47 [0.17, 1.28]
6.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7 Hospitalisation for heart disease145932Risk Ratio (M-H, Random, 95% CI)0.92 [0.83, 1.03]
7.1 Epidemic year - vaccine matching145932Risk Ratio (M-H, Random, 95% CI)0.92 [0.83, 1.03]
7.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8 Combined outcome: all deaths or severe respiratory illness2146248Risk Ratio (M-H, Random, 95% CI)0.60 [0.49, 0.74]
8.1 Epidemic year - vaccine matching154438Risk Ratio (M-H, Random, 95% CI)0.54 [0.49, 0.60]
8.2 Epidemic year - vaccine matching absent or unknown191810Risk Ratio (M-H, Random, 95% CI)0.67 [0.61, 0.72]
Analysis 3.1.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 1 Influenza.

Analysis 3.2.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 2 Pneumonia.

Analysis 3.3.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 3 Hospitalisation for influenza or pneumonia.

Analysis 3.4.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 4 Hospitalisation for any respiratory disease.

Analysis 3.5.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 5 Deaths from respiratory disease.

Analysis 3.6.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 6 All deaths.

Analysis 3.7.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 7 Hospitalisation for heart disease.

Analysis 3.8.

Comparison 3 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - risk groups, Outcome 8 Combined outcome: all deaths or severe respiratory illness.

Comparison 4. Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza111399Risk Ratio (M-H, Random, 95% CI)0.57 [0.27, 1.17]
1.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Non epidemic year - vaccine matching111399Risk Ratio (M-H, Random, 95% CI)0.57 [0.27, 1.17]
1.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Pneumonia111399Risk Ratio (M-H, Random, 95% CI)0.59 [0.37, 0.92]
2.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Non epidemic year - vaccine matching111399Risk Ratio (M-H, Random, 95% CI)0.59 [0.37, 0.92]
2.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Hospitalisation for influenza or pneumonia1101619Risk Ratio (M-H, Random, 95% CI)0.50 [0.40, 0.63]
3.1 Epidemic year - vaccine matching1101619Risk Ratio (M-H, Random, 95% CI)0.50 [0.40, 0.63]
3.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4 Hospitalisation for any respiratory disease2376324Risk Ratio (M-H, Random, 95% CI)0.84 [0.55, 1.27]
4.1 Epidemic year - vaccine matching2376324Risk Ratio (M-H, Random, 95% CI)0.84 [0.55, 1.27]
4.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Deaths from respiratory disease1281424Risk Ratio (M-H, Random, 95% CI)1.41 [1.31, 1.53]
5.1 Epidemic year - vaccine matching1281424Risk Ratio (M-H, Random, 95% CI)1.41 [1.31, 1.53]
6 All deaths343821Risk Ratio (M-H, Random, 95% CI)0.65 [0.33, 1.29]
6.1 Epidemic year - vaccine matching17047Risk Ratio (M-H, Random, 95% CI)1.09 [0.26, 4.49]
6.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.3 Non epidemic year - vaccine matching236774Risk Ratio (M-H, Random, 95% CI)0.59 [0.27, 1.30]
6.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7 Hospitalisation for heart disease1101619Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.01]
7.1 Epidemic year - vaccine matching1101619Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.01]
7.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.4 Non epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8 Combined outcome: all deaths or severe respiratory illness2135180Risk Ratio (M-H, Random, 95% CI)0.62 [0.54, 0.70]
8.1 Epidemic year - vaccine matching168536Risk Ratio (M-H, Random, 95% CI)0.65 [0.54, 0.78]
8.2 Epidemic year - vaccine matching absent or unknown166644Risk Ratio (M-H, Random, 95% CI)0.58 [0.48, 0.71]
Analysis 4.1.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 1 Influenza.

Analysis 4.2.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 2 Pneumonia.

Analysis 4.3.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 3 Hospitalisation for influenza or pneumonia.

Analysis 4.4.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 4 Hospitalisation for any respiratory disease.

Analysis 4.5.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 5 Deaths from respiratory disease.

Analysis 4.6.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 6 All deaths.

Analysis 4.7.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 7 Hospitalisation for heart disease.

Analysis 4.8.

Comparison 4 Influenza vaccines versus no vaccination - Cohort studies - community-dwellers - no risk groups, Outcome 8 Combined outcome: all deaths or severe respiratory illness.

Comparison 5. Influenza and pneumococcal vaccines versus no vaccination - Cohort studies in community-dwellers
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI1374Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]
1.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Non epidemic year - vaccine matching1374Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]
2 Hospitalisation for influenza or pneumonia or respiratory disease3518748Risk Ratio (M-H, Random, 95% CI)0.67 [0.64, 0.70]
2.1 Epidemic year - vaccine matching2518374Risk Ratio (M-H, Random, 95% CI)0.67 [0.63, 0.71]
2.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Non epidemic year - vaccine matching1374Risk Ratio (M-H, Random, 95% CI)0.90 [0.10, 7.97]
3 Deaths from influenza or pneumonia1259627Risk Ratio (M-H, Random, 95% CI)0.43 [0.33, 0.57]
3.1 Epidemic year - vaccine matching1259627Risk Ratio (M-H, Random, 95% CI)0.43 [0.33, 0.57]
3.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Non epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4 All deaths2260001Risk Ratio (M-H, Random, 95% CI)0.44 [0.41, 0.46]
4.1 Epidemic year - vaccine matching1259627Risk Ratio (M-H, Random, 95% CI)0.44 [0.41, 0.46]
4.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Non epidemic year - vaccine matching1374Risk Ratio (M-H, Random, 95% CI)1.60 [0.08, 30.65]
Analysis 5.1.

Comparison 5 Influenza and pneumococcal vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 1 ILI.

Analysis 5.2.

Comparison 5 Influenza and pneumococcal vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 2 Hospitalisation for influenza or pneumonia or respiratory disease.

Analysis 5.3.

Comparison 5 Influenza and pneumococcal vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 3 Deaths from influenza or pneumonia.

Analysis 5.4.

Comparison 5 Influenza and pneumococcal vaccines versus no vaccination - Cohort studies in community-dwellers, Outcome 4 All deaths.

Comparison 6. Influenza vaccines with adjuvant versus no vaccination - Cohort studies in community-dwellers
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI2498Risk Ratio (M-H, Random, 95% CI)0.30 [0.16, 0.56]
1.1 Epidemic year - vaccine matching1263Risk Ratio (M-H, Random, 95% CI)0.20 [0.07, 0.54]
1.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Non epidemic year - vaccine matching1235Risk Ratio (M-H, Random, 95% CI)0.38 [0.18, 0.82]
2 Hospitalisation for influenza or pneumonia or respiratory disease2498Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.28]
2.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Non epidemic year - vaccine matching2498Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.28]
3 All deaths1235Risk Ratio (M-H, Random, 95% CI)2.10 [0.10, 43.10]
3.1 Epidemic year - vaccine matching00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Epidemic year - vaccine matching absent or unknown00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Non epidemic year - vaccine matching1235Risk Ratio (M-H, Random, 95% CI)2.10 [0.10, 43.10]
Analysis 6.1.

Comparison 6 Influenza vaccines with adjuvant versus no vaccination - Cohort studies in community-dwellers, Outcome 1 ILI.

Analysis 6.2.

Comparison 6 Influenza vaccines with adjuvant versus no vaccination - Cohort studies in community-dwellers, Outcome 2 Hospitalisation for influenza or pneumonia or respiratory disease.

Analysis 6.3.

Comparison 6 Influenza vaccines with adjuvant versus no vaccination - Cohort studies in community-dwellers, Outcome 3 All deaths.

Comparison 7. Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hospitalisation for influenza or pneumonia8 Odds Ratio (Random, 95% CI)0.73 [0.67, 0.79]
1.1 Epidemic - vaccine matching6 Odds Ratio (Random, 95% CI)0.71 [0.65, 0.77]
1.2 Non epidemic - vaccine not matching1 Odds Ratio (Random, 95% CI)0.90 [0.58, 1.38]
1.3 Epidemic year - vaccine matching absent or unknown1 Odds Ratio (Random, 95% CI)0.82 [0.68, 0.98]
2 Hospitalisation for any respiratory disease13 Odds Ratio (Random, 95% CI)0.78 [0.72, 0.85]
2.1 Epidemic matching vaccine9 Odds Ratio (Random, 95% CI)0.71 [0.67, 0.74]
2.2 Non epidemic non matching2 Odds Ratio (Random, 95% CI)0.91 [0.76, 1.08]
2.3 Non epidemic year and matching vaccine2 Odds Ratio (Random, 95% CI)0.94 [0.84, 1.06]
3 Hospitalisation for heart disease6 Odds Ratio (Random, 95% CI)0.76 [0.70, 0.82]
3.1 Epidemic year - vaccine matching5 Odds Ratio (Random, 95% CI)0.75 [0.70, 0.82]
3.2 Non epidemic - vaccine not matching1 Odds Ratio (Random, 95% CI)0.80 [0.55, 1.16]
4 All deaths7 Odds Ratio (Random, 95% CI)0.53 [0.46, 0.61]
4.1 Epidemic year - vaccine matching5 Odds Ratio (Random, 95% CI)0.47 [0.42, 0.53]
4.2 Epidemic year - vaccine matching absent or unknown1 Odds Ratio (Random, 95% CI)0.65 [0.57, 0.75]
4.3 Non epidemic year - vaccine matching1 Odds Ratio (Random, 95% CI)0.76 [0.60, 0.97]
5 Combined outcome: all deaths or severe respiratory illness1 Odds Ratio (Random, 95% CI)0.70 [0.37, 1.34]
5.1 Epidemic year - vaccine matching1 Odds Ratio (Random, 95% CI)0.70 [0.37, 1.34]
Analysis 7.1.

Comparison 7 Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates, Outcome 1 Hospitalisation for influenza or pneumonia.

Analysis 7.2.

Comparison 7 Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates, Outcome 2 Hospitalisation for any respiratory disease.

Analysis 7.3.

Comparison 7 Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates, Outcome 3 Hospitalisation for heart disease.

Analysis 7.4.

Comparison 7 Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates, Outcome 4 All deaths.

Analysis 7.5.

Comparison 7 Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates, Outcome 5 Combined outcome: all deaths or severe respiratory illness.

Comparison 8. Influenza vaccines versus no vaccination - Case-control studies in community
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hospitalisations for influenza or pneumonia21074Odds Ratio (M-H, Random, 95% CI)0.89 [0.69, 1.15]
1.1 Outbreak - vaccine matching (circulating strains)00Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Outbreak - vaccine matching absent or unknown1825Odds Ratio (M-H, Random, 95% CI)0.92 [0.69, 1.22]
1.3 No outbreak - vaccine matching1249Odds Ratio (M-H, Random, 95% CI)0.82 [0.48, 1.40]
2 Hospitalisations for any respiratory disease421378Odds Ratio (M-H, Random, 95% CI)1.08 [0.95, 1.23]
2.1 Outbreak - vaccine matching320582Odds Ratio (M-H, Random, 95% CI)1.08 [0.92, 1.26]
2.2 No outbreak - not matching1796Odds Ratio (M-H, Random, 95% CI)1.02 [0.68, 1.52]
3 Deaths from influenza or pneumonia11092Odds Ratio (M-H, Random, 95% CI)0.74 [0.53, 1.04]
3.1 Outbreak - vaccine matching11092Odds Ratio (M-H, Random, 95% CI)0.74 [0.53, 1.04]
4 Pneumonia (no better defined)1519Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.33]
4.1 Outbreak - partially matching1519Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.33]
Analysis 8.1.

Comparison 8 Influenza vaccines versus no vaccination - Case-control studies in community, Outcome 1 Hospitalisations for influenza or pneumonia.

Analysis 8.2.

Comparison 8 Influenza vaccines versus no vaccination - Case-control studies in community, Outcome 2 Hospitalisations for any respiratory disease.

Analysis 8.3.

Comparison 8 Influenza vaccines versus no vaccination - Case-control studies in community, Outcome 3 Deaths from influenza or pneumonia.

Analysis 8.4.

Comparison 8 Influenza vaccines versus no vaccination - Case-control studies in community, Outcome 4 Pneumonia (no better defined).

Comparison 9. Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in community
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hospitalisations for influenza or pneumonia46629Odds Ratio (M-H, Random, 95% CI)0.97 [0.85, 1.09]
1.1 Outbreak - vaccine matching23617Odds Ratio (M-H, Random, 95% CI)0.95 [0.69, 1.31]
1.2 No outbreak - vaccine matching23012Odds Ratio (M-H, Random, 95% CI)0.93 [0.80, 1.08]
Analysis 9.1.

Comparison 9 Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in community, Outcome 1 Hospitalisations for influenza or pneumonia.

Comparison 10. Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in nursing homes
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI11198Odds Ratio (M-H, Random, 95% CI)0.52 [0.40, 0.68]
1.1 Outbreak - vaccine matching11198Odds Ratio (M-H, Random, 95% CI)0.52 [0.40, 0.68]
Analysis 10.1.

Comparison 10 Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in nursing homes, Outcome 1 ILI.

Comparison 11. Influenza vaccines versus no vaccination - Case-control studies in community - adjusted rates
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hospitalisations for influenza or pneumonia5 Odds Ratio (Random, 95% CI)0.59 [0.47, 0.74]
1.1 Epidemic - vaccine matching1 Odds Ratio (Random, 95% CI)0.55 [0.36, 0.85]
1.2 Non epidemic - vaccine not matching0 Odds Ratio (Random, 95% CI)0.0 [0.0, 0.0]
1.3 Epidemic year - vaccine matching absent or unknown2 Odds Ratio (Random, 95% CI)0.68 [0.58, 0.79]
1.4 Non epidemic - vaccine matching2 Odds Ratio (Random, 95% CI)0.37 [0.16, 0.87]
2 Hospitalisations for any respiratory disease3 Odds Ratio (Random, 95% CI)0.71 [0.56, 0.90]
2.1 Epidemic - vaccine matching3 Odds Ratio (Random, 95% CI)0.71 [0.56, 0.90]
2.2 Non epidemic - vaccine matching0 Odds Ratio (Random, 95% CI)0.0 [0.0, 0.0]
2.3 Non epidemic year - vaccine matching0 Odds Ratio (Random, 95% CI)0.0 [0.0, 0.0]
3 Deaths from pneumonia or influenza2 Odds Ratio (Random, 95% CI)0.74 [0.60, 0.92]
3.1 Epidemic year - vaccine matching1 Odds Ratio (Random, 95% CI)0.76 [0.60, 0.97]
3.2 Epidemic year - vaccine matching absent or unknown1 Odds Ratio (Random, 95% CI)0.67 [0.42, 1.07]
Analysis 11.1.

Comparison 11 Influenza vaccines versus no vaccination - Case-control studies in community - adjusted rates, Outcome 1 Hospitalisations for influenza or pneumonia.

Analysis 11.2.

Comparison 11 Influenza vaccines versus no vaccination - Case-control studies in community - adjusted rates, Outcome 2 Hospitalisations for any respiratory disease.

Analysis 11.3.

Comparison 11 Influenza vaccines versus no vaccination - Case-control studies in community - adjusted rates, Outcome 3 Deaths from pneumonia or influenza.

Comparison 12. Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in community - adjusted rates
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hospitalisations for influenza or pneumonia2 Odds Ratio (Random, 95% CI)0.68 [0.54, 0.86]
1.1 Epidemic - vaccine matching1 Odds Ratio (Random, 95% CI)0.68 [0.50, 0.93]
1.2 Non epidemic - vaccine not matching0 Odds Ratio (Random, 95% CI)0.0 [0.0, 0.0]
1.3 Epidemic year - vaccine matching absent or unknown0 Odds Ratio (Random, 95% CI)0.0 [0.0, 0.0]
1.4 Non epidemic - vaccine matching1 Odds Ratio (Random, 95% CI)0.69 [0.49, 0.97]
Analysis 12.1.

Comparison 12 Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in community - adjusted rates, Outcome 1 Hospitalisations for influenza or pneumonia.

Comparison 13. Influenza vaccines versus placebo - RCT - parenteral vaccine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI46894Risk Ratio (M-H, Random, 95% CI)0.59 [0.47, 0.73]
1.1 Outbreak - vaccine matching (circulating strains) - community - healthy22047Risk Ratio (M-H, Random, 95% CI)0.57 [0.42, 0.79]
1.2 Outbreak - vaccine matching - community - risk groups1490Risk Ratio (M-H, Random, 95% CI)0.87 [0.49, 1.53]
1.3 Outbreak - vaccine matching - nursing home - healthy14180Risk Ratio (M-H, Random, 95% CI)0.54 [0.37, 0.80]
1.4 Outbreak - vaccine matching - psychiatric hospital1177Risk Ratio (M-H, Random, 95% CI)0.35 [0.13, 0.92]
2 Influenza32217Risk Ratio (M-H, Random, 95% CI)0.42 [0.27, 0.66]
2.1 Outbreak - vaccine matching - community - healthy and ill11838Risk Ratio (M-H, Random, 95% CI)0.41 [0.23, 0.74]
2.2 outbreak - vaccine matching - psychiatric hospital1177Risk Ratio (M-H, Random, 95% CI)0.35 [0.12, 1.06]
2.3 No outbreak - vaccine matching - nursing home - healthy and ill1202Risk Ratio (M-H, Random, 95% CI)0.50 [0.20, 1.25]
3 Pneumonia1699Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.1 Outbreak - vaccine matching - community - healthy1699Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4 All deaths1699Risk Ratio (M-H, Random, 95% CI)1.02 [0.11, 9.72]
4.1 Outbreak - vaccine matching - community - healthy1699Risk Ratio (M-H, Random, 95% CI)1.02 [0.11, 9.72]
Analysis 13.1.

Comparison 13 Influenza vaccines versus placebo - RCT - parenteral vaccine, Outcome 1 ILI.

Analysis 13.2.

Comparison 13 Influenza vaccines versus placebo - RCT - parenteral vaccine, Outcome 2 Influenza.

Analysis 13.3.

Comparison 13 Influenza vaccines versus placebo - RCT - parenteral vaccine, Outcome 3 Pneumonia.

Analysis 13.4.

Comparison 13 Influenza vaccines versus placebo - RCT - parenteral vaccine, Outcome 4 All deaths.

Comparison 14. Vaccine versus placebo - inactivated aerosol vaccine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI1176Risk Ratio (M-H, Random, 95% CI)0.84 [0.41, 1.71]
1.1 Outbreak - vaccine matching - psychiatric hospital1176Risk Ratio (M-H, Random, 95% CI)0.84 [0.41, 1.71]
2 Influenza1176Risk Ratio (M-H, Random, 95% CI)0.89 [0.40, 1.99]
2.1 outbreak - vaccine matching - psychiatric hospital1176Risk Ratio (M-H, Random, 95% CI)0.89 [0.40, 1.99]
Analysis 14.1.

Comparison 14 Vaccine versus placebo - inactivated aerosol vaccine, Outcome 1 ILI.

Analysis 14.2.

Comparison 14 Vaccine versus placebo - inactivated aerosol vaccine, Outcome 2 Influenza.

Comparison 15. Vaccine versus placebo - live aerosol vaccine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza1220Risk Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.17]
1.1 No outbreak - vaccine matching - nursing home - healthy and ill1220Risk Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.17]
Analysis 15.1.

Comparison 15 Vaccine versus placebo - live aerosol vaccine, Outcome 1 Influenza.

Comparison 16. Sensitivity analysis Comparison 01: subgroup analysis by study quality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ILI259211Risk Ratio (M-H, Random, 95% CI)0.75 [0.65, 0.87]
1.1 Quality A84502Risk Ratio (M-H, Random, 95% CI)0.78 [0.65, 0.94]
1.2 Quality B133854Risk Ratio (M-H, Random, 95% CI)0.82 [0.65, 1.03]
1.3 Quality C3389Risk Ratio (M-H, Random, 95% CI)0.66 [0.43, 1.00]
1.4 Quality D1466Risk Ratio (M-H, Random, 95% CI)0.44 [0.35, 0.57]
Analysis 16.1.

Comparison 16 Sensitivity analysis Comparison 01: subgroup analysis by study quality, Outcome 1 ILI.

Comparison 17. Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 General malaise42560Risk Ratio (M-H, Random, 95% CI)1.18 [0.87, 1.61]
2 Fever32519Risk Ratio (M-H, Random, 95% CI)1.57 [0.92, 2.71]
3 Upper respiratory tract symptoms2713Risk Ratio (M-H, Random, 95% CI)1.35 [0.90, 2.01]
4 Headache32519Risk Ratio (M-H, Random, 95% CI)1.10 [0.76, 1.58]
5 Nausea1672Risk Ratio (M-H, Random, 95% CI)1.75 [0.74, 4.12]
6 Local tenderness/sore arm42560Risk Ratio (M-H, Random, 95% CI)3.56 [2.61, 4.87]
7 Swelling - erythema - induration21847Risk Ratio (M-H, Random, 95% CI)8.23 [3.98, 17.05]
Analysis 17.1.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 1 General malaise.

Analysis 17.2.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 2 Fever.

Analysis 17.3.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 3 Upper respiratory tract symptoms.

Analysis 17.4.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 4 Headache.

Analysis 17.5.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 5 Nausea.

Analysis 17.6.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 6 Local tenderness/sore arm.

Analysis 17.7.

Comparison 17 Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events, Outcome 7 Swelling - erythema - induration.

Comparison 18. Influenza vaccines versus placebo - RCT - live aerosol vaccine - adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 General malaise145Risk Ratio (M-H, Random, 95% CI)3.09 [0.18, 53.20]
2 Fever145Risk Ratio (M-H, Random, 95% CI)1.71 [0.09, 33.24]
3 Upper respiratory tract symptoms145Risk Ratio (M-H, Random, 95% CI)1.62 [0.42, 6.29]
4 Lower respiratory tract symptoms145Risk Ratio (M-H, Random, 95% CI)2.91 [0.41, 20.48]
Analysis 18.1.

Comparison 18 Influenza vaccines versus placebo - RCT - live aerosol vaccine - adverse events, Outcome 1 General malaise.

Analysis 18.2.

Comparison 18 Influenza vaccines versus placebo - RCT - live aerosol vaccine - adverse events, Outcome 2 Fever.

Analysis 18.3.

Comparison 18 Influenza vaccines versus placebo - RCT - live aerosol vaccine - adverse events, Outcome 3 Upper respiratory tract symptoms.

Analysis 18.4.

Comparison 18 Influenza vaccines versus placebo - RCT - live aerosol vaccine - adverse events, Outcome 4 Lower respiratory tract symptoms.

Appendices

Appendix 1. Included studies design

A case-control study is a retrospective epidemiological study usually used to investigate the association between two variables (for example hospitalisation for pneumonia and influenza vaccination). Study participants who have experienced an event) (adverse, or disease-related) are compared with participants who have not. Any differences in the presence or absence of hypothesised risk or protective variables are observed.

A cohort study is an epidemiological study where groups of individuals are identified who vary in their exposure to an intervention or hazard, and are then followed to assess outcomes. Association between exposure and outcome are then estimated. Cohort studies are best performed prospectively, but can also be undertaken retrospectively if suitable data records are available.

A randomised controlled trial (RCT) is any study on humans in which the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using random allocation.

A quasi-randomised clinical trial is any study on humans in which the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using some quasi-random method of allocation (such as alternation, date of birth or case record number).

Appendix 2. Methodological quality of non-randomised studies

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
CASE-CONTROL STUDIES

Selection

  1. Is the case definition adequate?

    1. yes, with independent validation

    2. yes, e.g. record linkage or based on self reports

    3. no description

  2. Representation of the cases

    1. consecutive or obviously representative series of cases

    2. potential for selection biases or not stated

  3. Selection of controls

    1. community controls

    2. hospital controls

    3. no description

  4. Definition of controls

    1. no history of disease (endpoint)

    2. no description of source

Comparability

  1. Comparability of cases and controls on the basis of the design or analysis

    1. study controls for _______________ (select the most important factor)

    2. study controls for any additional factor (this criteria could be modified to indicate specific control for a second important factor)

Exposure

  1. Ascertainment of exposure

    1. secure record (e.g. surgical records)

    2. structured interview where blind to case/control status

    3. interview not blinded to case/control status

    4. written self-report or medical record only

    5. no description

  2. Same method of ascertainment for cases and controls

    1. yes

    2. no

  1. Non-response rate

    1. same rate for both groups

    2. non-respondents described

    3. rate different and no designation

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
COHORT STUDIES

Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability

Selection

  1. Representation of the exposed cohort

    1. truly representative of the average _______________ (describe) in the community

    2. somewhat representative of the average ______________ in the community

    3. selected group of users e.g. nurses, volunteers

    4. no description of the derivation of the cohort

  2. Selection of the non-exposed cohort

    1. drawn from the same community as the exposed cohort

    2. drawn from a different source

    3. no description of the derivation of the non-exposed cohort

  3. Ascertainment of exposure

    1. secure record (e.g. surgical records)

    2. structured interview

    3. written self-report

    4. no description

  4. Demonstration that outcome of interest was not present at start of study

    1. yes

    2. no

Comparability

  1. Comparability of cohorts on the basis of the design or analysis

    1. study controls for _____________ (select the most important factor)

    2. study controls for any additional factor * (this criteria could be modified to indicate specific control for a second important factor)

Outcome

  1. Assessment of outcome

    1. independent blind assessment

    2. record linkage

    3. self-report

    4. no description

  2. Was follow up long enough for outcomes to occur

    1. yes (select an adequate follow-up period for outcome of interest)

    2. no

  3. Adequacy of follow up of cohorts

    1. complete follow up - all subjects accounted for

    2. subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an adequate %) follow up, or description provided of those lost) *

    3. follow up rate < ____% (select an adequate %) and no description of those lost

    4. no statement

Appendix 3. Data extraction form

PART 1

Background Information and Description of study
Reviewer:
Study unique identifier:
Published: Y/N
Journal: (if applicable)
Year of publication:
Period study conducted:
Abstract/full paper:
Country or countries of study:
Number of studies included in this paper:
Funding source (delete non applicable items):
Government, Pharmaceutical, Private, Unfunded, Unclear:
Paper/abstract numbers of other studies with which these data are linked:
Reviewer's assessment of study design (delete non applicable items):

Study Category - Study Design
Experimental - RCT/CCT; HCT ; X cross-over RCT
Non-randomised analytical (specifically designed to assess association) - Prospective/
Retrospective Cohort ; Case Control ; X sectional
Non-randomised comparative (not specifically designed to assess association) - Case X Over/Time series ;
Ecological study; Indirect comparison (before and after)
Non-comparative EXCLUDE

Does the study present data distributed by age group/occupation/health status? (Yes/No)
Sub group distribution:
Age group Y/N
Occupation Y/N
Health status Y/N
Gender Y/N
Risk group Y/N

Description of study
Methods
Participants
Interventions/exposure
Outcomes
Notes

PART 2a

Methodological Quality Assessment RCT and CCT only
Randomisation:
A = individual participants allocated to vaccine or control group.
B = groups of participants allocated to vaccine or control group.

Generation of the allocation sequence:
A = adequate, e.g. table of random numbers or computer-generated random numbers.
B = inadequate, e.g. alternation, date of birth, day of the week, or case record number.
C = not described.

Allocation concealment:
A = adequate, e.g. numbered or coded identical containers administered sequentially, on-site computer system that can only be accessed after entering the characteristics of an enrolled participant, or serially numbered, opaque, sealed envelopes.
B = possibly adequate, e.g. sealed envelopes that are not sequentially numbered or opaque.
C = inadequate, e.g. open table of random numbers.
D = not described.

Blinding:
A = adequate double-blinding, e.g. placebo vaccine.
B = single-blind, i.e. blinded outcome assessment.
C = no blinding.

Follow up:

Average duration of follow up and number of losses to follow up.

PART 2b

Description of interventions and outcomes RCT and CCT only
Vaccines used
Vaccines and composition | Product and manufacturer | Schedule & dosage and status | Route of administration
Arm 1
Arm 2
Arm 3
Arm 4
Placebo
Rule: index vaccine goes in the Arm 1 line, placebo in the last line

Status: primary, secondary or tertiary immunisation.

Vaccine Batch Numbers

Details of Participants
Enrolled | Missing | Reasons | Inclusion in analysis | Notes
Active arm 1
Active arm 2
Active arm 3
Active arm 4
Controls

Outcomes List - Efficacy and Effectiveness
Outcome | How defined | Description/Follow up/Notes

Outcomes List - Safety
Outcome | How defined | Description/Follow up/Notes

Investigators to be contacted for more information? Yes/No

Contact details (principal investigator, fill in only if further contact is necessary):

PART 2c

Data extraction and manipulation (to be used for dichotomous or continuous outcomes) RCT and CCT only
Comparison
Outcomes | n/N Index Arm | n/N Comparator
Outcomes | n/N Index Arm | n/N Comparator
Outcomes | n/N Index Arm | n/N Comparator

Notes (for statistical use only)

PART 3a

Methodological Quality Assessment. Non-randomised studies only

Newcastle - Ottawa quality assessment scale (case-control and cohort studies ; see Appendix 2)

PART 3b

Description of interventions and outcomes. Non-randomised longitudinal studies only
Vaccines used
Vaccines and composition | Product and manufacturer | Schedule & dosage and status | Route of administration
Group 1
Group 2
Group 3
Group 4
Comparator

Rule: index vaccine goes in the Group 1 line, placebo in the last line

Vaccine Batch Numbers

Details of Participants
Enrolled | Missing | Reasons | Inclusion in analysis | Notes
Group 1
Group 2
Group 3
Group 4
Comparator

Outcomes List - Effectiveness
Outcome | How defined (including length of follow up) | Description/Follow up/Notes

Outcomes List - Safety
Outcome | How defined (including length of follow up) | Description/Follow up/Notes

Investigators to be contacted for more information? Yes/No

Contact details (principal investigator, fill in only if further contact is necessary):

PART 3c

Data extraction and manipulation (to be used for dichotomous outcomes). Non-randomised longitudinal studies only

Comparison
Outcomes | n/N Index Group | n/N Comparator

Notes (for statistical use only)

PART 3d

Description of studies. Case-control studies only

Event 1
How defined | Enrolled | Missing | Reasons | Inclusion in analysis
Cases n =
Controls n =

Exposure
How defined | How ascertained | Notes
Vaccine Exposure 1
Vaccine Exposure 2

Event 2
How defined | Enrolled | Missing | Reasons | Inclusion in analysis
Cases n =
Controls n =

Exposure
How defined | How ascertained | Notes
Vaccine Exposure 1
Vaccine Exposure 2

Notes (for statistical use only)

Part 3e

Data extraction and manipulation. Case-control studies only

Status | Numerator | Denominator
Cases
Control

Notes (for statistical use only)

Appendix 4. Previous search

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2006, issue 1); MEDLINE (January 1966 to March Week 3 2006); EMBASE (Dialog 1974 to 1979; SilverPlatter 1980 to December 2005); Biological Abstracts (SilverPlatter 1969 to December 2004); and Science Citation Index (Web of Science 1974 to December 2004).

The following MEDLINE search terms were combined with a methodological search filter for high sensitivity in identifying randomised controlled trials in MEDLINE (Dickersin 1994) and adapted to search the other above mentioned electronic databases.

MEDLINE (OVID)

1 exp Influenza Vaccines/
2 Influenza, Human/ep [Epidemiology]
3 Influenza, Human/im [Immunology]
4 Influenza, Human/mo [Mortality]
5 Influenza, Human/pc [Prevention & Control]
6 Influenza, Human/tm [Transmission]
7 influenza vaccin$.ti,ab.
8 (influenza or flu).ti,ab.
9 (vaccin$ or immuni$ or inocul$ or efficacy or effectiveness).ti,ab.
10 and/8-9
11 or/1-7,10
12 RANDOMIZED CONTROLLED TRIAL.pt.
13 CONTROLLED CLINICAL TRIAL.pt.
14 RANDOMIZED CONTROLLED TRIALS.sh.
15 RANDOM ALLOCATION.sh.
16 DOUBLE BLIND METHOD.sh.
17 SINGLE-BLIND METHOD.sh.
18 or/12-17
19 Animals/
20 Humans/
21 19 not 20
22 18 not 21
23 CLINICAL TRIAL.pt.
24 exp Clinical Trials/
25 (clin$ adj25 trial$).ti,ab.
26 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
27 PLACEBOS.sh.
28 placebo$.ti,ab.
29 random$.ti,ab.
30 or/23-29
31 30 not 21
32 exp Research Design/
33 exp Comparative Study/
34 exp Evaluation Studies/
35 exp Follow-Up Studies/
36 exp Prospective Studies/
37 prospectiv$.ti,ab.
38 volunteer$.ti,ab.
39 exp Case-Control Studies/
40 (cases and controls).ti,ab.
41 case control stud$.ti,ab.
42 exp Cohort Studies/
43 cohort stud$.ti,ab.
44 observational.ti,ab.
45 or/32-44
46 45 not 21
47 or/22,31,46
48 11 and 47

Appendix 5. EMBASE search strategy

26. #23 AND #26
25. #24 OR #25
24. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross-over':ab,ti OR 'cross over':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
23. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR
'crossover procedure'/exp
22. #15 AND #22
21. #16 OR #17 OR #18 OR #19 OR #20
20. 'aged care':ab,ti OR 'nursing home':ab,ti OR 'nursing homes':ab,ti
19. 'nursing home'/exp OR 'hospice'/de OR 'residential home'/de
18. pension*:ab,ti OR retire*:ab,ti OR adult*:ab,ti OR aged:ab,ti OR elderly:ab,ti OR senior*:ab,ti OR geriatric*:ab,ti
17. ((old* OR age*) NEAR/3 (people* OR person* OR adult* OR women OR men OR citizen* OR residen*)):ab,ti
16. 'adult'/de OR 'aged'/exp OR 'pensioner'/exp
15. #1 OR #14
14. #5 AND #13
13. #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12
12. aluminium:ab,ti OR squalene:ab,ti OR mf59:ab,ti OR virosom*:ab,ti
11. 'squalene'/de
10. (vaccin* NEAR/5 adjuvant*):ab,ti
9. 'immunological adjuvant'/de
8. vaccin*:ab,ti OR immuni*:ab,ti OR inocul*:ab,ti
7. 'immunization'/de OR 'vaccination'/de OR 'active immunization'/de OR 'immunoprophylaxis'/de OR 'mass
immunization'/de
6. 'vaccine'/de OR 'acellular vaccine'/de OR 'dna vaccine'/de OR 'inactivated vaccine'/de OR 'live vaccine'/de OR 'subunit vaccine'/de OR 'virus vaccine'/de OR 'virosome vaccine'/de OR 'recombinant vaccine'/de
5. #2 OR #3 OR #4
4. flu:ab,ti OR influenza*:ab,ti
3. 'influenza virus a'/exp OR 'influenza virus b'/exp
2. 'influenza'/exp
1. 'influenza vaccine'/de

Appendix 6. Web of Science search strategy

Topic=(influenza or flu or influenzavirus) AND Topic=(vaccine* or immuni* or inocul* or adjuvant* or squalene or aluminium or MF59 or virosom*) AND Topic=(aged or elderly or senior* or geriatric* or retire* or pension* or old* people or old* person* or old* adult* or old* men or old* women or old* citizen* or old* residen* or nursing home*)

Refined by: Topic=(random* or placebo* or rct or single blind* or double blind*)

Timespan = 2006 to 2009.

Appendix 7. SIGN filter for observational studies

SIGN Scottish Intercollegiate Guidelines Network [Internet]. Edinburgh: c2001-2009; [Last modified 03 August 2009; accessed 02 October 2009]. Available from http://www.sign.ac.uk/methodology/filters.html on 02 October 2009 (SIGN 2009)

The Observational Studies search filter used by SIGN has been developed in-house to retrieve studies most likely to meet SIGN's methodological criteria.

MEDLINE

1Epidemiologic studies/
2Exp case control studies/
3Exp cohort studies/
4Case control.tw.
5(cohort adj (study or studies)).tw.
6Cohort analy$.tw.
7(Follow up adj (study or studies)).tw.
8(observational adj (study or studies)).tw.
9Longitudinal.tw.
10Retrospective.tw.
11Cross sectional.tw.
12Cross-sectional studies/
13Or/1-12

EMBASE

1Clinical study/
2Case control study
3Family study/
4Longitudinal study/
5Retrospective study/
6Prospective study/
7Randomised controlled trials/
86 not 7
9Cohort analysis/
10(Cohort adj (study or studies)).mp.
11(Case control adj (study or studies)).tw.
12(follow up adj (study or studies)).tw.
13(observational adj (study or studies)).tw.
14(epidemiologic$ adj (study or studies)).tw.
15(cross sectional adj (study or studies)).tw.
16Or/1-5,8-15

Feedback

Vaccines for preventing influenza in the elderly

Summary

Dear Dr Rivetti,

We have several questions about the review 'Vaccines for preventing influenza in the elderly'.

Although the authors recognized that "The findings of the cohort studies that we included are likely to have been affected to a varying degree by selection bias.", the reviewers drew conclusions that "in long-term care facilities, where vaccination is most effective against complications," based on the results of cohort studies that is not compatible with the strict prospective study method of RCT.

However they argued that RCT can minimize the bias, they concluded that extracted RCTs can offer no definitive evidence due to their scant and bad reports. If so, they should suggest a well-designed placebo controlled RCT of influenza vaccination for preventing influenza in the elderly.

Moreover they insist that placebo-controlled RCT is no longer possible on ethical ground, because the influenza vaccinations are globally recommended.
The statement is very surprising. If it is true, RCTs are no longer possible after the recommendations or medical interventions have been globally implemented, even though they are clearly erroneous. We think the idea is against Cochrane Collaboration's principle.

On the contrary, we cannot ethically accept the scant and bad situation itself of RCTs on the vaccine, because flu vaccinations have been awkwardly recommended all over the world without high level evidence.

The reviewers discussed that "Consistent with other published studies, during influenza season, vaccination was associated with a 44% reduction in risk of all-cause mortality during influenza season. However, in the period before influenza vaccination was associated with a 61% reduction in risk of this outcome."

In fact, Japanese cohort studies which evaluated the influenza vaccine have also large selection bias favorable to the vaccinated group in various outcomes including mortality, fever and absence from school.

For examples, in the cohort study of over 65 years old at Geriatric Health Service Facility
1) vaccination associated with a 51.9% relative risk reduction in all-cause mortality during influenza season; but the mortality in the vaccinated group was 61.5% lower during extra-influenza season. This study also showed a 37.8% relative risk reduction in fever during influenza season, but fever rate in the vaccinated group was 37.3% lower during extra-influenza season.

In Japanese cohort studies which evaluated the effectiveness of the influenza vaccine for children
2) the vaccination was associated with a 12.2% relative risk reduction in fever during influenza season, but it also showed a 17.3% reduction prior to influenza season.

Moreover Takahashi K et al. reported the absence rate of vaccinated and unvaccinated students in Mie prefecture during influenza season and during prior to influenza season.
3) In the study of elementary school vaccination was associated with a 26.1% relative risk reduction in absence during influenza season, but it associated with a 23.7% reduction prior to influenza season. In the study of junior high school it associated with a 29.1% relative risk reduction during influenza season but it also associated a 31% reduction during prior to influenza season.

According to these cohort studies, the vaccinated groups revealed more increase of mortality, fever rate, or absence rate during influenza season relative to the extra-influenza season.

In conclusion, "no firm conclusions can be drawn from" the cohort studies, because of its large bias as the review authors suggest. However the cohort studies may become more reliable after the outcomes during influenza season corrected at least with the outcomes during non-influenza season, their results cannot replace evidences from well-designed placebo controlled RCT.

References
1) Hitoshi Kamiya. Summary and Group Report 1998-1999 'Study of the effectiveness of the influenza vaccine' (Koseik Kagaku Kenkyuhi Hozyokin Zigyou Zisseki Houkokusyo) [The study was supported by federal funds from the Japanese Ministry of Health, Labor and Welfare]

2) Hitoshi Kamiya 'Study of the effectiveness of influenza vaccine in infants and young children.' 2001 (Heisei 12, (Koseik Kagaku Kenkyuhi Hozyokin Zigyou Zisseki Houkokusyo) [The study was supported by federal funds from the Japanese Ministry of Health, Labor and Welfare]

3) Kosei Takahashi et al. Evaluation of the effectiveness of influenza vaccine by the absence rates of the elementary and junior high school students. Kusurino Hiroba 1988:96;2

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

Thank you for the comments. For the review we identified few RCTs and with small Ns. We stated that we needed to base our conclusions mostly on the large number of observational studies, and recommended that large well-designed and well-executed RCTs should be undertaken.

Daniela Rivetti
Alessandro Rivetti
Vittorio Demichelli
Tom Jefferson
Roger Thomas
Carlo Di Pietrantonj
Melanie Rudin

Contributors

Keiji Hayashi
Feedback comment and reply added 25 July 2007

What's new

Last assessed as up-to-date: 6 October 2009.

DateEventDescription
7 October 2009New citation required and conclusions have changedThree new authors (EF, LAA, ST) joined the review team while previous authors no longer contributed to this update. Our conclusion partly changed. In part this was due to the re-evaluation of the whole topic and partly because of the ambiguity in the previous text which readers found confusing.
7 October 2009New search has been performedSearches conducted. We identified 18 potential trials. We included four new trials, two case-control studies (Jordan 2007; Puig-Barbera 2007) and two cohort studies (Hara 2006; Leung 2007). We excluded 13 new trials (Castilla 2006; Garcia Garcia 2009; Hara 2008; Isahak 2007; Landi 2006; Manzoli 2007; Moreno 2009; Nichol 2007; Ortqvist 2007; Skull 2009; Tsai 2007; van Vuuren 2009; Voordouw 2006). One excluded trial (Vila-Corcoles 2005) was formerly awaiting classification.

History

Protocol first published: Issue 3, 2004
Review first published: Issue 3, 2006

DateEventDescription
8 May 2008AmendedConverted to new review format.
25 July 2007Feedback has been incorporatedFeedback comment and reply added to review.
29 March 2006New search has been performedSearches conducted.

Contributions of authors

Tom Jefferson (TOJ) and Daniela Rivetti (DR) wrote the original protocol.
Roger E Thomas (RT) participated in the final draft of the original protocol and the review.
TOJ, DR and Vittorio Demicheli (VD) designed the original review.
Alessandro Rivetti (AR) conducted the original searches.
TOJ, DR and VD applied inclusion criteria.
TOJ, DR and Melanie Rudin (MR) extracted the original data.
VD arbitrated and checked the data extraction.

For this 2009 update:
Carlo Di Pietrantonj (CDP) undertook the meta-analysis and did statistical testing of the reviews and its 2009 update.
TOJ wrote the first review and its update.
Lubna Al Ansary (LAA) and Eliana Ferroni (EF) extracted the data.
Sarah Thorning (ST) conducted the updated searches.
All authors contributed to the final updated review.

Declarations of interest

TOJ owned shares in Glaxo SmithKline and received consultancy fees from Sanofi Synthelabo and Roche. All other review authors have no conflicts to declare.

See Appendix 1 for included studies designs.
See Appendix 2 for methodological quality of non-randomised studies.
See Appendix 3 for the data extraction form.

Sources of support

Internal sources

  • ASL 20 (Alessandria), ASL 19 (Asti), Regione Piemonte, Italy.

External sources

  • National Health and Medical Research Council (NHMRC), Australia.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ahmed 1995

MethodsCase-control study conducted in England, during the 1989 to 1990 influenza season, in the community. Data sources were: death certificates, general practitioner records. Follow-up period was 4 November 1989 to 23 February 1990. Cases died from influenza during the 1989 epidemic; controls died in the same period a year later and were matched for age, sex and residence
Participants1092 people 16 years or older; 412 cases and 1256 controls were identified; 315 and 777 were included in the analysis respectively
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesCertified influenza death
NotesTwo exposure definitions were used: current vaccinees and previous vaccinees (vaccinated between 1985 and 1989) the first was used; pneumococcal vaccination was very unlikely; circulating strain was A/England/308/89. The season was an epidemic one. The study controls for confounders in analysis: health status, previous vaccination. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Ahmed 1997

MethodsCase-control study conducted in England, during the 1989 to 1990 influenza season, in the community. Data sources were: hospital and general practitioner records. Follow-up period was 1 December 1989 to 31 January 1990. Cases were hospitalised and their discharge diagnosis or cause of death was pneumonia, influenza, emphysema or bronchitis; community controls were matched for age and sex. Specific controls were matched for cases who died: controls died 6 to 12 months later
Participants445 patients admitted to hospital (303 cases were identified; 156 cases and 289 controls were included in the analysis respectively), 16 years or older
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia, influenza, emphysema or bronchitis (ICD 466, 480.9 to 482.9, 485 to 492.8)
NotesTwo exposure definitions were used: current vaccinees and previous vaccinees (vaccinated between 1985 and 1989): the first was used; pneumococcal vaccination was very unlikely; circulating strain was A/England/308/89. The season was an epidemic one. The study controls for confounders in analysis: health status, previous vaccination. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Allsup 2004

MethodsExperimental study conducted in Liverpool, UK during the 1999 to 2000 influenza season, randomised, single-blind, placebo-controlled. Computer random number generation. Opaque envelopes were sealed and serially numbered to assign participants to intervention. Data sources were self-administered questionnaire and medical records. Follow-up period was the entire winter season
Participants729 community-dwelling elderly without risk factors (552 treated and 177 controls, all included in the analysis), 65 to 74 years old
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sidney/5/97: B/Beijing/184/93. All patients received pneumococcal vaccine too. Vaccine strains matched the circulating strains
OutcomesClinically defined ILI (all of the following symptoms: sudden onset, fever, cough, prostration, weakness, myalgia, widespread aches), pneumonia, hospitalisation for any respiratory illness, death from all causes
NotesThe study year was an epidemic one; the vaccine was the recommended one
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Arden 1988

MethodsAuthors investigated an outbreak in a nursing home, in Atlanta, USA, during the 1984 to 1985 influenza season; active surveillance; medical records were reviewed. Follow-up period was 26/1/85 to 1/2/85. Pharyngeal swab and paired sera were collected to confirm diagnosis
Participants55 nursing home residents (31 treated and 24 controls, all included in the analysis) mean age 85 years
InterventionsParenteral influenza vaccine: A/Philippines/2/82; A/Chile/83; B/URSS/84. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever 38.7 °C or greater, cough, coryza, sore throat); hospitalisation from ILI; ILI severity (not extracted)
Notes7 days after the outbreak started all residents were given amantadine. Successive outcome were not accounted for. The circulating strain was related to A/Philippines/2/82
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Arroyo 1984

MethodsAuthors investigated an outbreak in a nursing home, in Columbia, UK, during the 1982 to 1983 influenza season; active surveillance by home staff. Follow-up period was 31 January 1983 to 25 February 1983. Pharyngeal swab and paired sera were collected to confirm diagnosis from 13 and 32 patients respectively
Participants116 nursing home residents (26 treated and 90 controls, all included in the analysis) with underlying illnesses 30 to 108 years old (mean age 71 years)
InterventionsParenteral influenza vaccine: A/Brazil/11/78; A/Bangkok/1/79; B/Singapore/79. Vaccine strains did not match circulating strains
OutcomesILI (any acute respiratory tract infection occurring during outbreak, with or without fever), pneumonia, death from respiratory disease
Notes10 patients were given amantadine: not indicated if vaccinees or unvaccinated. The circulating strain was related to A/Philippines/2/82
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Aymard 1979a

MethodsAuthors investigated an outbreak in a geriatric hospital in France, during the 1976 to 1977 influenza season
Participants100 nursing home residents (50 treated and 50 controls, all included in the analysis)
InterventionsBivalent parenteral vaccine: A/Vic/3/75; B/HK/1/72. Vaccine strains matched circulating strains
OutcomesDisease and deaths without further specifications
NotesPart of a surveillance study conducted in several communities; poor description of methods; circulating strains were mostly A/Vic/3/75 like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Aymard 1979b

MethodsAuthors investigated an outbreak in a geriatric hospital in France, during the 1977 to 1978 influenza season
Participants155 nursing home residents (85 treated and 70 controls, all included in the analysis)
InterventionsBivalent parenteral vaccine: A/Vic/3/75; B/HK/1/73. Vaccine strains did not matched circulating strains
OutcomesDisease and deaths without further specifications
NotesPart of a surveillance study conducted in several communities; poor description of methods; circulating strains were mostly A/Tex/1/77 like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Caminiti 1994

MethodsProspective prospective cohort study conducted in Italy during the 1990 to 1991 influenza season; medical charts, hospital records and death certificate archives were reviewed. Follow-up period was 1 December 1990 to 30 April 1991. 110 subjects were tested for serological follow up. Throat swabs were obtained from ill residents
Participants242 nursing home residents (169 treated and 73 controls, all included in the analysis; 77 and 33 were tested for serological follow up respectively) 55 to 99 years old
InterventionsParenteral influenza vaccine:A/Guizhou/54/89; A/Singapore/6/86; B/Yagamata/16/88. Vaccine strains matched the circulating strains
OutcomesClinically defined ILI (fever + at least 2 of the following: cough, coryza, sore throat, myalgia, headache, shivering), hospitalisation for ILI, hospitalisation for all respiratory illness, deaths from respiratory illness
NotesCirculating strain: B/Yagamata-like. Vaccinated and control groups were roughly comparable as underlying disease: vaccinated persons had more chronic respiratory diseases. The influenza season was relatively mild. Data were reported by health status
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Cartter 1990a

MethodsAuthors investigated an outbreak in a skilled care nursing home, in Connecticut, USA, during the 1984 to 1985 influenza season; medical records were reviewed. Follow-up period was 1 December 1984 to 15 January 1985. paired sera specimens were obtained from some ill residents
Participants131 residents (96 treated and 48 controls, 96 and 35 included in the analysis respectively) 65 to 95 years old
InterventionsParenteral influenza vaccine: A/Philippines/2/82; A/Chile/83; B/URSS/100/82. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater, cough, coryza, sore throat); hospitalisation from ILI; deaths occurred within 2 weeks of ILI with no different explanation
NotesAmantadine was not used. There was serological evidence of A(H3N2) influenza infections
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Cartter 1990b

MethodsAuthors investigated an outbreak in a skilled nursing home, in Connecticut, USA, during the 1984 to 1985 influenza season; medical records were reviewed. Follow-up period was 15 January 1985 to 15 February 1985. Throat swab and paired sera specimens were obtained from some ill residents
Participants85 residents (30 treated and 55 controls, all included in the analysis) 33 to 95 years old
InterventionsParenteral influenza vaccine: A/Philippines/2/82; A/Chile/83; B/URSS/100/83. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater, cough, coryza, sore throat); hospitalisation from ILI; deaths occurred within 2 weeks of ILI with no different explanation
Notes9 days after the outbreak started amantadine prophylaxis was given to most of the remaining well residents. Successive outcome were not accounted for. The circulating strain was related to A/Philippines/2/82
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Cartter 1990c

MethodsAuthors investigated an outbreak in a multiple-level care facility in Connecticut, USA, during the 1984 to 1985 influenza season; medical records were reviewed. Follow-up period was 1 February 1985 to 10 April 1985. Throat swab and paired sera specimens were obtained from some ill residents
Participants458 residents (332 treated and 151 controls, 332 and 126 included in the analysis respectively) 64 to 104 years old
InterventionsParenteral influenza vaccine: A/Philippines/2/82; A/Chile/83; B/URSS/100/84. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater, cough, coryza, sore throat); hospitalisation from ILI; deaths occurred within 2 weeks of ILI with no different explanation
Notes42 days after the outbreak started amantadine prophylaxis was given to most of the remaining well residents. Successive outcomes were not accounted for. The circulating strain was related to A/Philippines/2/82
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Christenson 2001a

MethodsProspective cohort study conducted in Stockholm, Sweden during the 1998 to 1999 influenza season, in the community. Data sources were: vaccination database; discharge diagnoses database. Follow-up period was 1 December 1998 to 31 May 1999. 23% of vaccinees received flu vaccine alone, 76% of vaccinated received flu and pneumococcal vaccine. 841 persons had only pneumococcal vaccine. Only flu vaccinated were included in analysis
Participants182,609 community-dwelling elderly (23,224 treated and 159,385 controls included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sydney/5/97; B/Harbin/7/94. Vaccine strains matched the circulating strain
OutcomesHospitalisation from influenza (ICD-X: J10.0, J10.1, J10.8, J11.0, J11.1, J11.8), hospitalisation from pneumonia (ICD-X: J12- J18, J69.0, A48.1); deaths from influenza and deaths from pneumonia were not available for this comparison
NotesVaccinated people had higher education, more underlying diseases and smoked less. Circulating strain was A/Sydney (H3N2). The season was probably an epidemic one. 6% of the population lived in a nursing home. The study controls for age in analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Christenson 2001b

MethodsProspective cohort study conducted in Stockholm, Sweden during the 1998 to 1999 influenza season in the community. Data sources were: vaccination database; discharge diagnoses database. Follow-up period was 1 December 1998 to 31 May 1999. 23% of vaccinees received flu vaccine alone, 76% of vaccinated received flu and pneumococcal vaccine. 841 persons had only pneumococcal vaccine. All data were included in a separate analysis
Participants259,627 community-dwelling elderly (100,242 treated and 159,385 controls included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sydney/5/97; B/Harbin/7/94; pneumococcal vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from influenza (ICD-X: J10.0, J10.1, J10.8, J11.0, J11.1, J11.8) deaths from influenza, hospitalisation from pneumonia (ICD-X: J12- J18, J69.0, A48.1), deaths from pneumonia; all deaths
NotesVaccinated people had higher education, more underlying diseases and smoked less. Circulating strain was A/Sydney (H3N2). The season was probably an epidemic one. 6% of the population lived in a nursing home. The study controls for age in analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Christenson 2004a

MethodsProspective cohort study conducted in Sweden, Stockholm, during the 1999 to 2000 influenza season, in the community. Data sources were: vaccination database; discharge diagnoses database. Follow-up period was December 1999 to November 2000. 23% of vaccinated received flu vaccine alone, 58% of vaccinated received flu and pneumococcal vaccine. 19% of vaccinated received pneumococcal vaccine alone. Only flu vaccinated were included in analysis.
Participants163,391 community-dwelling elderly (29,346 treated and 134,045 controls were included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sydney/5/97; B/Harbin/7/94. Vaccine strains matched the circulating strain
OutcomesHospitalisation from influenza (ICD-X: J10.0, J10.1, J10.8, J11.0, J11.1, J11.8) in hospital deaths from influenza, hospitalisation from pneumonia (ICD-X: J12- J18, J69.0, A48.1), in hospital deaths from pneumonia
NotesVaccinated people had higher education, more underlying diseases and smoked less. Circulating strain was A/Sydney(H3N2). The season was probably an epidemic one. 6% of the population lived in a nursing home
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Christenson 2004b

MethodsProspective cohort study conducted in Stockholm, Sweden during the 1999 to 2000 influenza season, in the community. Data sources were: vaccination database; discharge diagnoses database. Follow-up period was December 1999 to May 2000. 23% of vaccinees received flu vaccine alone, 58% of vaccinated received flu and pneumococcal vaccine. 19% of vaccinated received pneumococcal vaccine alone. All data were included in a separate analysis
Participants258,747 community-dwelling elderly (124,702 treated and 134,045 controls were included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sydney/5/97; B/Harbin/7/94; pneumococcal vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from influenza (ICD-X: J10.0, J10.1, J10.8, J11.0, J11.1, J11.8), hospitalisation from pneumonia (ICD-X: J12- J18, J69.0, A48.1); in hospital deaths from influenza and in hospital deaths from pneumonia were not available for the 6-month period
NotesVaccinated people had higher education, more underlying diseases and smoked less. Circulating strain was A/Sydney (H3N2). The season was probably an epidemic one. 6% of the population lived in a nursing home
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Coles 1992

MethodsAuthors investigated an outbreak in a skilled nursing home, in New York, USA during the 1987 to 1988 influenza season; individual charts were reviewed. Follow-up period was 26 December 1987 to 25 January 1988. Throat swab and paired sera specimens were obtained from some ill residents
Participants124 nursing home residents (112 treated and 12 controls, all included in the analysis) 20 to 100 years old (mean age 85 years). 105 patients had 1 or more underlying medical conditions
InterventionsParenteral influenza vaccine: A/Taiwan/1/86; A/Leningrad/360//86; B/Ann Arbor/1/86. Vaccine strains did not match the circulating strain
OutcomesClinically defined ILI (fever 100 °F or greater, cough, coryza, sore throat, pneumonia); pneumonia; hospitalisation from ILI; flu-related deaths
NotesVaccinated and not vaccinated subjects were similar as underlying conditions. The circulating strain was Shanghai/11/87. Only 1 patient received amantadine prophylaxis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Comeri 1995

MethodsRetrospective cohort study conducted in Italy, during the 1991 to 1992 influenza season, in the community. Data sources were: self-administered questionnaire; vaccination registry. Follow-up period was 1 December 1991 to 29 February 1992. Random samples of vaccinated and control subjects were extracted from vaccination and population registries
Participants213 community-dwelling elderly (150 treated and 63 controls; number of subjects included in the analysis unknown), 65 years or older
InterventionsParenteral influenza vaccine. Matching unknown, probably yes according to literature data
OutcomesClinically defined ILI (fever, cough, sore throat, myalgia, headache, weakness)
NotesVery poor description of methods, poor definitions, data extracted from percentages
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Consonni 2004a

MethodsProspective cohort study conducted in Italy, during the 2002 to 2003 influenza season, in the community. Data sources were: self-administered questionnaire; phone interviews. Follow-up period went from enrollment to April 2003. Ambulatory patients were enrolled at random to undergo either adjuvant or subunit influenza vaccine plus antipneumococcal vaccine. A control group of unvaccinated patients was also enrolled. Only flu vaccinated were included in analysis
Participants235 ambulatory patients (166 vaccinated with adjuvant vaccine; 69 controls; all included in analysis), 65 years or older
InterventionsAdjuvant virosomal vaccine. Vaccine strains probably matched the circulating strain
OutcomesClinically defined ILI (fever 38 °C or more + at least 1 systemic symptom: headache, discomfort, myalgia, chills or sweating, weakness + at least 1 respiratory symptom: cough, sore throat, nasal congestion); hospitalisation for all respiratory diseases, all deaths. ARI (acute respiratory infection) was also defined
NotesVaccinated people had higher impairment. None information about flu activity: probably not epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Consonni 2004b

MethodsProspective cohort study conducted in Italy, during the 2002 to 2003 influenza season, in the community. Data sources were: self-administered questionnaire; phone interviews. Follow-up period went from enrollment to April 2004. Ambulatory patients were enrolled at random to undergo either adjuvant or subunit influenza vaccine plus antipneumococcal vaccine. A control group of unvaccinated patients was also enrolled. All data were included in a separate analysis
Participants374 ambulatory patients (166 vaccinated with adjuvant vaccine; 139 vaccinated with flu + pneumo vaccine; 69 controls; all included in analysis), 66 years or older
InterventionsAdjuvant virosomal vaccine; subunit influenza vaccine; anti-pneumococcal vaccine. Vaccine strains probably matched the circulating strain
OutcomesClinically defined ILI (fever 38 °C or more + at least 1 systemic symptom: headache, discomfort, myalgia, chills or sweating, weakness + at least 1 respiratory symptom: cough, sore throat, nasal congestion); hospitalisation for all respiratory diseases, all deaths. ARI (acute respiratory infection) was also defined
NotesVaccinated people had higher impairment. None information about flu activity: probably not epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Crocetti 2001

MethodsCase-control study conducted in Italy, during the 1994 to 1995 influenza season, in the community. Data sources were: database discharge diagnoses, mailed questionnaire. Follow-up period was 1 December 1994 to 31 March 1995. Cases were resident discharged from hospital with pneumonia and influenza; community controls were matched for age, sex and residence
Participants825 residents in the province of Florence (275 cases and 550 controls were included in analysis; non-response rate was 15% in each group), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains did not match the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487)
NotesPneumococcal vaccination was very unlikely. The season was an epidemic one. The study controls for confounders in analysis: disability, socio-economic factors and smoking habits. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Cuneo Crovari 1980

MethodsProspective cohort study conducted in Italy during the 1978 to 1979 influenza season. Authors investigated an outbreak in a nursing home; individual cards were reviewed. Follow-up period was 1 November 1978 to 31 May 1979. Throat swab and paired sera specimens were obtained from residents
Participants196 nursing home residents (86 treated and 110 controls, all included in the analysis) 60 years or older
InterventionsParenteral influenza vaccine: A/Texas/1/77; A/URSS/90/77; B/Hong Kong/8/73. Matching between vaccine and circulating strains is unknown
OutcomesPositive culture or 4-fold antibody titre increase with or without symptoms. Only symptomatic cases were included in the analysis
NotesPoor reporting of methods; no confounders control. The circulating strain was related to B/Hong Kong/5/72
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Currier 1988

MethodsAuthors investigated an outbreak in an intermediate and domiciliary care nursing home, in Maryland, USA during the 1987 to 1988 influenza season; medical records were reviewed. Follow-up period was 8 January 1988 to 26 January 1988. Throat swabs and acute sera specimens were obtained from some ill residents
Participants126 nursing home residents (87 treated and 34 controls were included in the analysis, for 5 residents data on immunisation status were not available) mean age 87 years
InterventionsParenteral influenza vaccine: A/Taiwan/1/86; A/Leningrad/360/86; B/Ann Arbor/1/86. Vaccine strains did not match the circulating strain
OutcomesClinically defined ILI (fever 99.8 °F or greater + 1 of the following: cough, congestion, sore throat) or throat positive culture; pneumonia; deaths were also reported but not by immunisation status
NotesVaccinated and not vaccinated subjects were similar as underlying conditions, only senile dementia was more frequent in vaccinees. The circulating strain was A/Leningrad-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

D'Alessio 1969

MethodsProspective outbreak investigation study conducted in USA during the 1967 to 1968 influenza season. Authors investigated an outbreak in a nursing home. Follow-up period was December 1967 and January 1968. Throat swab and sera specimens were obtained from all ill residents and from an additional group of 27 residents with no illness
Participants176 nursing home residents (131 treated and 31 controls were included in the analysis, for 14 residents data on immunisation status were not available)
InterventionsParenteral influenza vaccine: A2/Japan/170/62; A2/Taiwan/1/64; B/Massachusetts/3/66. Matching between vaccine and circulating strains is unknown
OutcomesClinically defined ILI (fever 37.8 °C or greater, headache, cough, sore throat, myalgia and prostration)
NotesPoor reporting; no confounders control. The circulating strain was A2/Wis/1/68
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Davis 2001a

MethodsProspective cohort study conducted in Hawaii, during the 1994 to 1995 influenza season, in the community. Data sources were: insurance claim records. Follow-up period was 15 November 1994 to 31 March 1995. Only 10% of vaccinated subjects and 3% of unvaccinated subjects received pneumococcal vaccination
Participants77,951 person periods members of a medical care program (44,271 treated and 33,680 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains probably did not match the circulating strain (literature data)
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487) hospitalisation from all respiratory conditions (ICD 460-62, 465-466, 480-487, 500-518), hospitalisation from congestive heart failure (ICD 428)
NotesOR were adjusted by age and health status. Frequencies data were not available. To perform quantitative analysis adjusted data were used. The season had low epidemic levels
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Davis 2001b

MethodsProspective cohort study conducted in Hawaii, during the 1995 to 1996 influenza season, in the community. Data sources were: insurance claim records. Follow-up period was 15 November 1995 to 31 March 1996. Only 10% of vaccinated subjects and 3% of unvaccinated subjects received pneumococcal vaccination
Participants77,951 person periods members of a medical care programme (44,271 treated and 33,680 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains probably matched the circulating strain (literature data)
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions (ICD 460-62, 465-466, 480-487, 500-518), hospitalisation from congestive heart failure (ICD 428)
NotesOR were adjusted by age and health status. Frequencies data were not available. To perform quantitative analysis adjusted data were used. The season was probably an epidemic one
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Davis 2001c

MethodsProspective cohort study conducted in Hawaii, during the 1996 to 1997 influenza season, in the community. Data sources were: insurance claim records. Follow-up period was 15 November 1996 to 31 March 1997. Only 10% of vaccinated subjects and 3% of unvaccinated subjects received pneumococcal vaccination
Participants77,951 person periods members of a medical care programme (44,271 treated and 33,680 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains probably matched the circulating strain (literature data)
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions (ICD 460-62, 465-466, 480-487, 500-518), hospitalisation from congestive heart failure (ICD 428)
NotesOR were adjusted by age and health status. Frequencies data were not available. To perform quantitative analysis adjusted data were used. The season was probably an epidemic one
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Deguchi 2001

MethodsProspective cohort study conducted in Japan during the 1998 to 1999 influenza season. Follow-up period was 1 November 1998 to 31 March 1999. 301 nursing homes were surveyed during an epidemic season; only few residences had an outbreak of respiratory infections. Reports of illness were provided by study-site staff
Participants22,462 residents in 301 nursing homes (10,739 treated and 11,723 controls, all included in the analysis) 65 years or older
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sydney/5/97; B/Mie/1/93. Vaccine strains probably matched circulating strains
OutcomesClinical ILI (any of the following symptoms: fever, runny nose, sore throat, cough, headache, muscle aches, chills, vomiting, decreased activity, irritability, wheezing, pulmonary congestion); hospitalisation due to severe illness, deaths due to influenza
NotesPoor description of methods, poor definitions, some cases were laboratory confirmed, but number of cases was not indicated. Groups were comparable as age and gender. Health status was not investigated
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Edmondson 1971

MethodsExperimental study conducted in Virginia, USA during the 1968 to 1969 influenza season. 4 arms: parenteral vaccine, aerosol vaccine, both, placebo. Methods are described in another work
Participants266 elderly psychiatric patients (90 in the parenteral arm, 89 in the aerosol arm, 88 in the arm with both administrations, 87 in the placebo arm)
InterventionsMonovalent inactivated A2 Hong Kong influenza vaccine. Vaccine strains probably matched the circulating strains
OutcomesClinically defined ILI (fever + 1 or 2 respiratory symptoms or at least 2 systemic symptoms, lasting longer than 1 day; 3 respiratory symptoms or 2 respiratory symptoms + 2 systemic symptoms, lasting longer than 2 days); laboratory confirmed influenza
NotesThe study year was an epidemic one; circulating strain was A2 HK
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Fedson 1993a

MethodsCase-controlled study conducted in Manitoba, Canada during the 1982 to 1983 influenza season, in the community. Data sources were: insurance claim records. Follow-up period was 1 December 1982 to 28 February 1983. Cases were admitted to the hospital with a lower respiratory tract condition as first diagnosis; community controls were matched for age, sex and residence
Participants10,471 non institutionalised persons, 70% were older than 65 years (2619 cases and 7828 controls, all included in analysis)
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from a lower respiratory tract condition (ICD 466, 480-487, 490-496, 500-519), deaths from any respiratory condition, deaths from all causes. Data about deaths were not reported
NotesCirculating strain: A:/Bangkok/1/79-like. The season was an epidemic one. The study controls for confounders in analysis: health status. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Fedson 1993b

MethodsCase-control study conducted in Manitoba, Canada during the 1985 to 1986 influenza season, in the community. Data sources were: insurance claim records. Follow-up period was 1 December 1985 to 15 February 1986. Cases were admitted to the hospital with a lower respiratory tract condition as first diagnosis; community controls were matched for age, sex and residence
Participants9666 non-institutionalised persons, 70% were older than 65 years (2417 cases and 7249 controls, all included in analysis)
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from a lower respiratory tract condition (ICD 466, 480-487, 490-496, 500-519), deaths from any respiratory condition, deaths from all causes. Data about deaths were not reported
NotesCirculating strain: A/Philippines/2/82-like. The season was an epidemic one. The study controls for confounders in analysis: health status. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Feery 1976

MethodsProspective cohort study conducted in Melbourne, Australia during the 1976 influenza season. Authors investigated an outbreak in a nursing home. Follow-up period was from mid-April to mid-August. Throat swabs and paired sera specimens were obtained from residents
Participants222 nursing home residents (154 treated and 68 controls, all included in the analysis); elderly
InterventionsParenteral influenza vaccine: A/Victoria/3/75; A/Scotland/840/74; B/Hong Kong/8/73. Vaccine strains matched circulating strains
OutcomesLaboratory confirmed influenza, deaths from influenza
NotesPoor reporting; no confounders control. The circulating strain was A/Victoria/3/75
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Fleming 1995

MethodsRetrospective cohort study conducted in UK, during the 1989 to 1990 influenza season, in the community. Data source was the general practitioner database. Follow-up period was 1 November 1989 to 15 January 1990. As vaccine used in 1988 and 1989 were antigenically closely related, 2 exposure definitions were used: recently vaccinated and previously vaccinated
Participants9391 residents who had at least a general practitioner's consultation in previous months (599 treated and 8792 controls, all included in the analysis), 55 years or older
InterventionsParenteral influenza vaccine: A/Shanghai/1197-like. Vaccine strains matched the circulating strain
OutcomesDeath, death or severe respiratory illness, death or any respiratory illness without further specification
NotesImportant epidemic year. The study controls for confounders in analysis: age, gender, health status. Data were stratified by health status: people with minor underlying conditions are considered as healthy. Subjects vaccinated during the previous year are considered as "non vaccinated". Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Foster 1992

MethodsCase-controlled study conducted in Michigan, USA during the 1989 to 1990 influenza season, in the community. Data sources were: discharge diagnoses, mailed questionnaire. Follow-up period was 1 November 1989 to 30 April 1990. Cases were admitted to the hospital with pneumonia or influenza; community controls were randomly selected
Participants1907 non-institutionalised persons (1354 cases and 2389 controls, were identified; 721 and 1786 were included in analysis respectively), 65 years or older
InterventionsParenteral influenza vaccine; 35% of cases and 28% of controls received pneumococcal vaccination. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480.8-483, 484.7-487.1)
NotesCirculating strain: A/Shanghai/11/87. The season was an epidemic one. The study controls for confounders in analysis: health status, flu activity, pneumococcal vaccination, smoke. Peak data were used. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Fyson 1983a

MethodsAuthors investigated an outbreak in a nursing home, in Canada, during the 1982 to 1983 influenza season; active surveillance. Follow-up period was 3 November 1982 to 17 January 1983. Throat swab and paired sera specimens were obtained from some residents
Participants545 chronically ill nursing home residents (321 treated and 224 controls, all included in the analysis); 18 to 103 years old, mean age 80 years
InterventionsParenteral influenza vaccine, whole and subvirion: A/Brazil/11/78; A/Bangkok/1/79; B/Singapore/222/79. Vaccine strains probably matched circulating strains
OutcomesAcute respiratory symptoms: fever, congestion, cough, sore throat, general malaise, without a clear definition; death from pneumonia
NotesPoor reporting; no confounders control. Circulating strain: A/Bangkok/1/79-like; no other viruses were identified
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Fyson 1983b

MethodsAuthors investigated an outbreak in a nursing home in Canada during the 1982 to 1983 influenza season; partial surveillance for delayed notification of outbreak. Follow-up period was 30 November 1982 to 9 January 1983. Throat swab and paired sera specimens were obtained from some residents
Participants171 female, chronically ill nursing home residents (53 treated and 118 controls, all included in the analysis); 19 to 105 years old
InterventionsParenteral whole influenza vaccine: A/Brazil/11/78; A/Bangkok/1/79; B/Singapore/222/80. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI without further specification; death from pneumonia
NotesPoor reporting; no confounders control. Circulating strain: A/Bangkok/1/79-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Gavira Iglesias 1987

MethodsProspective cohort study conducted in Spain, during the 1984 to 1985 influenza season, in the community. Data source was a questionnaire retrospectively applied by investigators in June to July 1985 (door-to-door survey). The whole population of a rural village was investigated
Participants268 community-dwelling (188 treated and 80 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine: A/Philippines/2/82; A/Chile/1/83; B/USSR/100/83. Matching unknown
OutcomesClinically defined ILI (fever 39 °C or more, chills, general malaise, myalgia, headache, arthralgia, conjunctivitis, lasting 3 days or more)
NotesNone of the observed deaths was due to flu-related illness. The season had low epidemic levels. Subgroup analysis was performed but only for the whole population
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Gené Badia 1991

MethodsProspective cohort study conducted in Spain, during the 1988 to 1989 influenza season, in the community. Data sources were: the health centre register, death certificate archives, hospital records. Follow-up period was 1 November 1988 to 30 May 1989. In the first of the 4 health centres all elderly residents were enrolled; in the others only patients approaching the center for health reasons were enrolled
Participants4558 people enrolled at 4 health centres (1998 treated and 2560 controls, all included in the analysis), 65 years or older, mean age 74 years
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesAll hospitalisations and hospitalisation from cardio respiratory causes (ICD 401-414 and 460-519); death from all causes. Only deaths for all causes are included in analysis
NotesThe season was an epidemic one
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Goodman 1982

MethodsAuthors investigated an outbreak in a nursing home, in Atlanta, USA during the 1980 to 1981 influenza season; medical charts and hospital charts were reviewed. Follow-up period was 12 December 1980 to 21 January 1981. Throat swab and paired sera specimens were obtained from some residents
Participants120 nursing home residents (36 treated and 84 controls, all included in the analysis); 47 to 95 years old (median age 80 years). Patients required intermediate and skilled nursing care
InterventionsParenteral influenza vaccine: A/Bangkok/1/79; A/Brazil/11/78; B/Singapore/222/78. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever 37.7 °C or greater or cough in the outbreak period (12 December 1980 to 21 January 1981), death from ILI. Hospitalisation and pneumonia were also accounted for but results were not presented by immunisation status
NotesNo confounders control. The circulating strain was A/Bangkok/1/79-like. Serological teste were negative for other pathogens
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Govaert 1993

MethodsExperimental study conducted in Netherlands, during the 1991 to 1992 influenza season, randomised, double-blind, placebo-controlled; randomisation scheme was stratified according to health status. Follow-up period was 48 hours after vaccination. Adverse reaction were self-reported on postal questionnaire completed 4 weeks after vaccination
Participants1838 not known as belonging to high-risk group (927 treated and 911 controls; 23 and 9 dropped out respectively), 60 years or older
InterventionsParenteral influenza recommended vaccine: A/Singapore/6/86; A/Beijing/357/89; B/Beijing/1/97; B/Panama/45/90
OutcomesLocal: swelling, itching, warm feeling, pain when touched, constant pain, discomfort. Systemic: fever, headache, malaise, other complaints
NotesSide effects were reported for all subjects and by risk condition. Data regarding all population were included
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Govaert 1994

MethodsExperimental study conducted in Netherlands, during the 1991 to 1992 period, in the community. Follow-up period was 1 November 1991 to 30 April 1992. Randomised, double-blind, placebo-controlled; randomisation scheme was stratified according to health status
Participants1838 persons not known as belonging to high-risk group (927 treated and 911 controls; 25 and 22 drop out respectively), 60 years or older
InterventionsParenteral influenza recommended vaccine: A/Singapore/6/86; A/Beijing/357/89; B/Beijing/1/97; B/Panama/45/90. Vaccine strains matched the circulating strains
OutcomesClinically defined ILI; laboratory confirmed ILI; several definition for clinical and laboratory ILI were tested: the Dutch Sentinel Stations definition is used (fever 37.8 °C or greater + cough or coryza or sore throat or headache or myalgia)
NotesThe study year was an epidemic one; data were stratified by health status. Intention-to-treat analysis was performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Gross 1988

MethodsProspective cohort study conducted in New York, USA during the 1982 to 1983 influenza season. Authors investigated an outbreak in a nursing home; independent blind assessment was conducted. Follow-up period was 1 November 1982 to 30 April 1983. 305 of the 525 residents volunteered to participate to study; diagnosis was made without knowledge of vaccination status
Participants305 nursing home residents, mostly ambulatory (181 treated and 124 controls, 138 and 94 had serological surveillance respectively); groups were comparable for health status and drug use; mean age 85 years
InterventionsParenteral influenza vaccine: A/Bangkok/1/79; A/Brazil/11/78; B/Singapore/222/79. Vaccine strains matched circulating strains (slight drift)
OutcomesLaboratory confirmed influenza (4-fold increase in antibody titre), Rx confirmed pneumonia, deaths from all causes
NotesPneumococcal vaccine was rarely used. Amantadine was not used. The circulating strain was A/Arizona/80, closely related to A/Bangkok/1/79. Laboratory confirmed cases were analysed by intention-to-treat
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Hak 2002a

MethodsProspective cohort study conducted in USA , during the 1996 to 1997 influenza season, in the community. Data source was a managed care organisation database. Follow-up period was 5 October 1996 to 3 May 1997
Participants122,974 members of a medical care programme continuously enrolled for the 1-year period (71,005 treated and 51,969 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine matched the circulating strain
OutcomesCombined outcome: hospitalisation from influenza and pneumonia (ICD 480-487) or death from all causes
Notes"The study controls for confounders in analysis: age, gender, health status. Data were presented by health status. None information about pneumococcal vaccination. The season was an epidemic one"
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Hak 2002b

MethodsProspective cohort study conducted in USA , during the 1997 to 1998 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 23 November 1997 to 4 April 1998
Participants158,454 members of a medical care programme continuously enrolled for the 1-year period (92,001 treated and 66,453 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine did not match the circulating strain
OutcomesCombined outcome: hospitalisation from influenza and pneumonia (ICD 480-487) or death from all causes
NotesThe study controls for confounders in analysis: age, gender, health status. Data were presented by health status. None information about pneumococcal vaccination. The season was an epidemic one; circulating strain: A/Sydney-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Hara 2006

MethodsProspective cohort study conducted in Saga, Japan. 10,000 community-dwelling elderly were randomly selected from a population registry, and a letter was sent to them about the explanation for the study and request for participation. The eligibility criteria to participate to study were as follows: not being hospitalised, not being institutionalised, not being having any long-term absence, not living alone, and possible to contact by telephone at least once a month
ParticipantsAmong 10,000 elderly citizens, 7357 responded and 4787 agreed to participate and also matched our eligibility criteria. The vaccination status of the study subjects was identified by self-reporting verification and a list of recipients of partially funded vaccination. After all 3240 subjects (3230 subjects were self-reported and 10 subjects were known with verification) were vaccinated and 1547 non-vaccinated. The vaccination coverage was 67.7%
InterventionsInfluenza vaccination versus no vaccination
OutcomesILI, clinical influenza, hospitalisation for all causes, hospitalisation for influenza or pneumonia (IP), and total death
NotesThe author concludes that influenza vaccination was found to be associated with a decreased ILI during the epidemic period in community-dwelling elderly. The above risk reduction was greater under low-risk conditions. The results were inconclusive for preventing hospitalisation and death, due to an inadequate sample size. However, our findings support the finding that all elderly individuals substantially benefit from vaccination even in a season of mild influenza activity and also when the antigenic match between the vaccine strains and the circulating strains are not closely matched.

Horman 1986

MethodsAuthors investigated an outbreak in a nursing home, in Maryland, USA during the 1980 to 1981 influenza season; residents' medical records were reviewed. Follow-up period was 8 December 1980 to 13 January 1981. Throat swab and paired sera specimens were obtained from some residents
Participants159 nursing home residents 62 to 100 years old (100 treated and 59 controls, all included in the analysis); most of the resident were chronically ill; risk status did not vary between vaccinees and unvaccinated
InterventionsParenteral influenza vaccine: A/Brazil; A/Bangkok; B/Singapore. Vaccine strains matched circulating strains
OutcomesClinically defined ILI (2 case definitions; more specific definition was used: fever + cough or chest congestion), pneumonia without further specification and case-fatality rate
NotesVaccination was not offered to staff. 36% of the observed deaths during the epidemic period occurred from causes other than flu. Circulating strains: A/Taiwan/1/79-like, very similar to the vaccine strain A/Bangkok. Isolation attempt for other pathogens were unsuccessful
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Howarth 1987a

MethodsProspective cohort study conducted in Australia in 17 nursing homes, during the 1983 influenza season. Follow-up period was autumn to spring; blinded assessment of illness was performed
Participants326 residents in 17 nursing homes (229 treated and 97 controls, all included in the analysis), 44 to 99 years old
InterventionsParenteral influenza vaccine: A/Victoria/186/82; A/Philippines/2/82; B/Singapore/222/79. Vaccine strains matched circulating strains
OutcomesLaboratory confirmed influenza (4-fold increase in antibody titre)
NotesPoor description of methods; part of another study. The circulating strain was A/Philippines/2/82. None information about flu activity
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Howarth 1987b

MethodsProspective cohort study conducted in Australia in 17 nursing homes, during the 1984 influenza season. Follow-up period was autumn to spring; blinded assessment of illness was performed
Participants365 residents in 17 nursing homes (184 treated and 181 controls, all included in the analysis), 44 to 99 years old
InterventionsParenteral influenza vaccine: A/Dunedin/27/83; A/Philippines/2/82; B/Singapore/222/80. Vaccine strains matched circulating strains
OutcomesLaboratory confirmed influenza (4-fold increase in antibody titre)
NotesPoor description of methods; part of another study. The circulating strain was A/Philippines/2/82. None information about flu activity
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Howells 1975a

MethodsProspective cohort study conducted in UK in several nursing homes, during the 1971 to 1972 influenza season; all residents were under constant surveillance. Throat swab and paired sera specimens were obtained whenever possible
Participants490 nursing homes residents (134 treated and 356 controls, all included in the analysis) 60 years or older
InterventionsParenteral influenza vaccine: A2/HK/68; B/Vic.98926/70. Matching between vaccine and circulating strains is unknown
OutcomesRespiratory illness and pneumonia without definition, deaths from pneumonia
NotesVery poor description of methods; groups were roughly comparable as age and general health. No information about flu activity and laboratory confirmation
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Howells 1975b

MethodsProspective cohort study conducted in UK in several nursing homes, during the 1972 to 1973 influenza season; all residents were under constant surveillance. Throat swab and paired sera specimens were obtained whenever possible
Participants390 nursing homes residents (123 treated and 267 controls, all included in the analysis) 60 years or older
InterventionsParenteral influenza vaccine: A2/HK/68; B/Vic.98926/71. Matching between vaccine and circulating strains is unknown
OutcomesRespiratory illness and pneumonia without definition, deaths from pneumonia
NotesVery poor description of methods; groups were roughly comparable as age and general health. None information about flu activity and laboratory confirmation
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Howells 1975c

MethodsProspective cohort study conducted in UK in several nursing homes, during the 1973 to 1974 influenza season; all residents were under constant surveillance. Throat swab and paired sera specimens were obtained whenever possible
Participants470 nursing homes residents (183 treated and 287 controls, all included in the analysis) 60 years or older
InterventionsParenteral influenza vaccine: A/Eng/42/72; B/Vic.98926/71; B/Hong Kong/8/73. Matching between vaccine and circulating strains is unknown
OutcomesRespiratory illness and pneumonia without definition, deaths from pneumonia
NotesVery poor description of methods; groups were roughly comparable as age and general health. None information about flu activity and laboratory confirmation
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Isaacs 1997

MethodsAuthors investigated an outbreak in a nursing home, in Ontario, Canada during the 1996 to 1997 influenza season. Follow-up period was 1 January 1997 to 11 January 1997. Nasal swabs were obtained from 3 ill residents
Participants172 nursing home residents (149 treated and 23 controls, all included in the analysis)
InterventionsParenteral influenza vaccine. Vaccine strains probably matched circulating strains (other studies)
OutcomesClinically defined ILI (fever 38 °C or greater, cough, sore throat, nasal congestion, muscle ache, lethargy, lasting 2 days or more)
NotesAmantadine was used in all residents. One positive result was obtained by rapid testing. Poor reporting
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Jordan 2007

MethodsCase-control study nested within a cohort of older people registered with 79 participating general practices in central England. Patients were included in the identified cohort if aged 65 to 89 years and if they consulted their GP (or other emergency medical services) for an acute episode of respiratory infection or acute exacerbation of pre-existing respiratory disease, between 1 October 2003 and 31 March 2004. Patients with simple upper respiratory tract infections were excluded
Participants

Description of cases

Cases were defined as all patients admitted to hospital with acute respiratory disease. The first admission during the study period only was included. Surviving cases were invited for interview.

Description of controls

Controls were defined as patients presenting with acute respiratory disease but who were managed in the community. 6 controls were invited per case to mitigate for a potential low uptake, in order to achieve four controls interviewed per case. Controls were matched to cases for age (within ± 5 years where possible), sex and consultation date (within ±7 days where possible)

There were 3970 eligible patients identified. 500 patients were admitted to hospital. Altogether 44.1% of invited cases and 54.5% of controls agreed to interview: 157 cases and 639 controls were finally interviewed. The proportion of cases vaccinated against influenza before entry to the study was 74.5% and in controls was 74.2%

InterventionsInfluenza vaccination and admissions to hospital for acute respiratory disease
Outcomes
NotesThe authors conclude that in a winter typical of the current levels of circulating influenza, they were unable to demonstrate that influenza vaccination had a specific effect on preventing hospitalisation among elderly patients clinically ill with acute respiratory disease, although there was a possible effect during the peak weeks of influenza activity. Solely relying on the influenza vaccine to control the annual winter bed pressures in hospitals is unlikely to be a sufficiently effective yearly strategy and that continuing attention to other factors (e.g. the effective vaccination of healthcare workers, treatment of comorbidities, indoor housing conditions) is essential

Kaplan 1982

MethodsSurveillance population-based study conducted in USA, during the 1979 to 1980 and 1980 to 1981 influenza season. Case report from for each case was obtained from neurologists. All case reports were included. Follow-up period was 1 September 1979 to 31 March 1980 and 1 September 1980 to 31 March 1981
ParticipantsUSA (minus Maryland) adult population, 18 years or older
InterventionsSeasonal trivalent vaccine
OutcomesCases of Guillain-Barré syndrome. Vaccine associated cases were defined as those with onset within the 8-week period after influenza vaccination
NotesVaccination rates in population were obtained from national immunisation survey
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Kaway 2003

MethodsProspective cohort study conducted in Japan, during the 2001 to 2002 period in the community. Data sources were: the general practitioner database; self-administered questionnaire. Follow-up period was 31 December 2001 to 31 May 2002. Unvaccinated subjects were matched for sex and age, as closely as possible, to the vaccinated subjects. Laboratory confirmation was performed on 60% of cases
Participants4423 mostly community-dwelling (3520 treated and 903 controls were included in the analysis), 65 to 104 years old
InterventionsParenteral influenza vaccine: A/New Caledonia/20/99; A/Panama/2007/99; B/Johannesburg/5/99. Vaccine strains matched the circulating strain
OutcomesClinically defined ILI (all of the following symptoms: sudden onset, fever 38°C or more, cough)
NotesThe influenza season was mild. The study controls for age, sex and previous vaccinations in analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Keitel 1996

MethodsExperimental study conducted in USA, Texas, during the 1994 to 1995 influenza season, randomised, placebo-controlled trial; randomisation method and allocation concealment were not described. Subjects were allocated to receive ascending doses (15 ug/45 ug/135 ug) of antigen. Only 15 ug vaccine was included in analysis. Follow-up period was 48 hours after vaccination
Participants21 ambulatory, medically stable persons, 65 years or older
InterventionsParenteral monovalent subvirion 15 ug (9 participants) and purified HA 15 ug (12 participants) influenza vaccine: A/Singapore/6/86
OutcomesDiscomfort, erythema/induration, headache, malaise without further description
NotesDifferent vaccines (HA and SV) were analysed as a single "treatment group"
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Lasky 1998

MethodsSurveillance population-based study conducted in the USA (4 states: Illinois, Maryland, North Carolina, Washington), during the 1992 to 1993 and 1993 to 1994 influenza season. Discharge diagnoses database were used to identify cases. Hospital charts were reviewed to confirm diagnosis. Follow-up period was 1 September 1992 to 28 February 1993 and 1 September 1993 to 28 February 1994
ParticipantsAbout 21 million people, 18 years or older
InterventionsSeasonal trivalent vaccine
OutcomesCases of Guillain-Barré syndrome. Vaccine associated cases were defined a priori as those with onset within the 6-week period after influenza vaccination
NotesResults were stratified by age and adjusted by season and sex. Vaccination rates in population were estimated from a random-digit dialing telephone survey
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Leung 2007

MethodsRetrospective cohort study conducted in 46 elderly homes in Hong Kong, Chinato assess the effectiveness of influenza vaccination on influenza, pneumonia, hospitalisation for influenza and death. Subjects were eligible if they aged 65 years or above. The exposed group comprised subjects who had  not received influenza vaccination while the control group comprised subjects who had received influenza vaccination from the department of health or other health care providers in 2004. Information regarding vaccination was based on its documentation in the elderly home records. For resident having unknown history of influenza vaccination in the preceding calendar year he was regarded as being not vaccinated. A standardised questionnaire was used to collect data from the elderly homes once an influenza outbreak was defined in the elderly home. The occurrence of influenza was identified by the self-administered questionnaires. The occurrence of pneumonia, hospitalisation and death were identified from the hospital records.
Participants3177 residents participated in the study. The mean age was 83 years, 2133 were females and 1044 males. There were 2943 vaccinated (92.6%) and 234 (7.4%) unvaccinated subjects. More females were vaccinated (67.7%) compared with males (59.8%).
InterventionsInfluenza vaccination versus no vaccination
OutcomesInfluenza, pneumonia, hospitalisation and death
NotesThe authors conclude that this study failed to demonstrate the protective effect of influenza vaccine against influenza and its complications during outbreaks

Lopez Hernandez 1994

MethodsRetrospective cohort study conducted in Spain, during the 1991 to 1992 influenza season in the community. Data sources were: the health centre register, death certificate archives, hospital records. Follow-up period was 7 months after vaccination. Patients were excluded if they did not approach the centre in the last 3 years
Participants1965 community-dwelling elderly enrolled in a health centre (779 treated and 1186 controls, all included in the analysis), 65 years or older, mean age 73.5 years
InterventionsParenteral influenza vaccine. Vaccine strains probably matched the circulating strain
OutcomesHospitalisation from cardio-respiratory causes; death from all causes. Only deaths for all causes are included in analysis
NotesThe study controls for confounders in analysis (age, health status, home care). The season had low epidemic levels
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Mangtani 2004a

MethodsRetrospective cohort study conducted in UK, during the 1990 to 1998 influenza season, in the community. Data sources were: managed care organisation database. Follow-up period was the epidemic period (period with consultation rate for ILI more than 50/100000 person-weeks). Patients were identified and included in the study if they were registered on the first day of the week that included 1 September each year
Participants692,819 person-years in vaccine recipients and 1,534,280 person-years in vaccine non-recipients, 65 years or older
InterventionsParenteral influenza vaccine
OutcomesHospitalisation for acute respiratory illness (ICD 466, 480-487); respiratory related deaths
NotesMost of the seasons were epidemic, with vaccine strains matching the circulating strains. Data were presented by health status; other strata: year, flu activity, age. Data by health status were extracted by rates reported in tables
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004b

MethodsSee Mangtani. Influenza season 1990 to 1991
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004c

MethodsSee Mangtani. Influenza season 1991 to 1992
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004d

MethodsSee Mangtani. Influenza season 1992 to 1993
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Non-epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004e

MethodsSee Mangtani. Influenza season 1993 to 1994
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004f

MethodsSee Mangtani. Influenza season 1994 to 1995
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Non-epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004g

MethodsSee Mangtani. Influenza season 1995 to 1996
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004h

MethodsSee Mangtani. Influenza season 1996 to 1997
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004i

MethodsSee Mangtani. Influenza season 1997 to 1998
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine did not match the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Non-epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mangtani 2004j

MethodsSee Mangtani. Influenza season 1998 to 1999
ParticipantsSee Mangtani
InterventionsSee Mangtani. Vaccine matched the epidemic strain
OutcomesSee Mangtani
NotesSee Mangtani. Epidemic year
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Margolis 1990a

MethodsExperimental study conducted in Minneapolis, USA during the 1988 to 1989 influenza season, randomised, double-blind, placebo-controlled cross-over trial; randomisation method and allocation concealment were not described. Follow-up period was 7 days after vaccination. Symptoms were assessed by phone interview
Participants672 outpatients (336 treated and 336 controls were included in the analysis), 65 years or older
InterventionsParenteral influenza recommended vaccine: A/Taiwan/1/86; A/Sichuan/2/87; B/Victoria/2/87
OutcomesCough, coryza, fatigue, malaise, myalgia, headache, nausea, sore arm, disability, feverish without further description
NotesPlacebo was saline injection
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Meiklejohn 1987

MethodsAuthors investigated an outbreak in a nursing home, in Wyoming, USA during the 1984 to 1985 influenza season. Follow-up period was 2 January 1985 to 3 March 1985. Throat washing and convalescent sera were obtained from some residents
Participants55 nursing home residents (36 treated and 19 controls, all included in the analysis) 60 to 98 years old
InterventionsParenteral influenza vaccine: A/Philippines/82; A/Chile/83; B/URSS/84. Vaccine strains probably matched circulating strains
OutcomesClinically defined URI (upper respiratory illness: fever, chills, myalgia, respiratory symptoms); radiologically confirmed pneumonia; hospitalisation and death without further specification
NotesAmantadine was used in cases. The circulating strain that year was of A/Philippine type. No virus strain was isolated from patients but serologic tests confirmed influenza A virus infections. Poor description of methods
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Monto 2001

MethodsProspective cohort study conducted in Michigan, USA during the 1991 to 1992 influenza season. Authors investigated 26 skilled nursing homes with evidence of flu activity; nursing homes with high rates of immunisation (herd immunity) were excluded from the study; data on ILI or pneumonia were recorded prospectively under supervision of a nurse coordinator. Follow-up period was 1 November 1991 to 29 February 1992.
Participants2351 residents in 26 nursing homes (1728 treated and 623 controls, all included in the analysis), 65 years or older, for whom vaccination status was known
InterventionsParenteral influenza vaccine. Vaccine strains matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater + cough, sore throat or nasal congestion) clinical pneumonia, deaths occurred within 3 months of the onset of respiratory illness. Influenza was considered have been introduced into a nursing home when a least 2% of residents developed ILI within a 7-day period during community documented virus circulation or when virus was isolated from cases
NotesBoth influenza A (H3N2) and A (H1N1) co-circulated with influenza A (H3N2) predominantly. The circulating strains were closely related to the vaccine strain. Rate ratio estimates were adjusted by sex, age, home size and presented by "peak period". Groups were comparable as age and chronic conditions
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Morens 1995

MethodsAuthors investigated an outbreak in a nursing home, in Honolulu, USA during the 1989 to 1990 influenza season; vaccination records, hospital records, residents records were reviewed. Follow-up period was 15 December 1989 to 28 January 1990. Specimens for virus isolation were obtained from 9 ill patients and paired sera specimens were obtained from 34 case and non-case residents
Participants39 nursing home residents with multiple chronic conditions (36 treated and 3 controls, all included in the analysis); 36 to 102 years (mean age 80 years)
InterventionsParenteral influenza vaccine; pneumococcal vaccine was also used. Vaccine strains matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater + cough, coryza or sore throat), laboratory confirmed influenza, pneumonia, deaths from ILI or pneumonia
NotesAmantadine was administered to all patients over a 1-week period (January 4 to 12, 1990). The circulating strain was indistinguishable from the vaccine strain A/England/4/27/88. Lack of serologic evidence for other respiratory agents
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Mukerjee 1994

MethodsAuthors investigated outbreaks in 14 nursing homes, in Wales, UK during the 1991 to 1992 influenza season. Follow-up period was 15 December 1991 to 28 February 1992. Paired sera specimens were collected from 7 cases in 2 homes
Participants466 residents in 14 nursing homes (104 treated and 362 controls, all included in the analysis)
InterventionsParenteral influenza vaccine. Vaccine strains probably matched circulating strains
OutcomesClinically defined URI (upper respiratory illness: fever, chills, myalgia, cough)
NotesVery poor reporting. Vaccine strain was assumed to match the circulating strain according to literature data
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Mullooly 1994

MethodsCase-controlled study conducted in USA, during the 1981 to 1989 period, in the community. Data sources were: managed care organisation database . Follow-up period was the epidemic period according to surveillance data. Cases were admitted to services with pneumonia or influenza or died in hospital from pneumonia or influenza; community controls were matched for high risk status
Participants251,034 members of a medical care programme, 65 years or older
InterventionsParenteral influenza vaccine; patients received pneumococcal vaccination too. Vaccine strains matched the circulating strain
OutcomesPneumonia and influenza without hospitalisation, hospitalisation from pneumonia and influenza (ICD 480-487), hospitalised death
NotesMost of the seasons were epidemic, and vaccine strains did not match the circulating strains. The study controls for confounders in analysis (age, sex, pneumococcal vaccination). Data are stratified by health status, but allow only quantitative analysis. The OR adjusted by risk status was obtained pooling the data reported in the paper using Wolf method
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Murayama 1999

MethodsAuthors investigated 2 consecutive outbreaks in the same nursing home in Japan, during the 1996 to 1997 influenza season; patients records were reviewed. Follow-up period was 25 December 1996 to 14 January 1997 and 19 February 1997 to 26 February 1997. Throat swab and paired sera specimens were obtained from ill residents
Participants128 nursing home residents (60 treated and 68 controls, all included in the analysis) 70 years or older. None of the residents was previously vaccinated
InterventionsTwo doses of parenteral influenza vaccine: A/Yamagata/32/89; A/Wuhan/359/95; B/Mie/1/93 . Vaccine strains matched circulating strains
OutcomesICHPP-2 defined ILI (laboratory evidence or epidemiological criteria or 6 of the following symptoms: sudden onset, fever, cough, prostration, chills, weakness, myalgia, widespread aches); hospitalisations and deaths without definition
NotesEpidemic reoccurrence of influenza A outbreak was observed. Both the outbreaks were investigated; vaccinated and control groups were comparable as age or risk status. The circulating strain was A/Wuhan/359/95. Amantadine was not used. Other respiratory virus were not isolated
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Nichol 1994a

MethodsProspective cohort study conducted in Minneapolis, USA during the 1990 to 1991 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 1 October 1990 to 31 March 1991. The rate was adjusted for age, sex, health status, pneumococcal vaccination
Participants25,532 members of a medical care programme continuously enrolled for the 1-year period (11,483 treated and 14,049 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. 3% of vaccinees and 1% of unvaccinated received pneumococcal vaccination. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions (ICD 460, 462, 465-466, 480-487, 490-96, 500-518), hospitalisation from congestive heart failure (ICD 428), death from all causes (not reported)
NotesThe season was an epidemic one. Data are extracted by rates reported in tables. Quantitative analysis with adjusted rates is not performed because data reported and statistical model used are not homogeneous to those reported in the other studies
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nichol 1994b

MethodsProspective cohort study conducted in Minneapolis, USA during the 1991 to 1992 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 1 October 1991 to 31 March 1992. The rate was adjusted for age, sex, health status, pneumococcal vaccination
Participants26,369 members of a medical care programme continuously enrolled for the 1-year period (15,288 treated and 11,081 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. 5% of vaccinees and 2% of unvaccinated received pneumococcal vaccination. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions (ICD 460, 462, 465-466, 480-487, 490-96, 500-518), hospitalisation from congestive heart failure (ICD 428), death from all causes (not reported)
NotesThe season was an epidemic one. Data are extracted by rates reported in tables. Quantitative analysis with adjusted rates is not performed because data reported and statistical model used are not homogeneous to those reported in the other studies
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nichol 1994c

MethodsProspective cohort study conducted in Minneapolis, USA during the 1992 to 1993 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 1 October 1992 to 31 March 1993. The rate was adjusted for age, sex, health status, pneumococcal vaccination
Participants26,626 members of a medical care programme continuously enrolled for the 1-year period (14,647 treated and 11,979 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. 6% of vaccinees and 3% of unvaccinees received pneumococcal vaccination. Vaccine strains did not match the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions (ICD 460, 462, 465-466, 480-487, 490-96, 500-518), hospitalisation from congestive heart failure (ICD 428), death from all causes (not reported)
NotesThe season was an epidemic one. Data are extracted by rates reported in tables. Quantitative analysis with adjusted rates is not performed because data reported and statistical model used are not homogeneous to those reported in the other studies
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nichol 1998a

MethodsProspective cohort study conducted in Minneapolis, USA during the 1990 to 1995 period, in the community. Data source was the managed care organisation database. Follow-up period was 15 November to 31 February. A subgroup analysis by health status was performed. The rate was adjusted for age, sex, health status, vaccination status
Participants147,551 members of a medical care programme continuously enrolled for the 1-year period (87,898 treated and 59,653 controls included in the analysis), 64 years or older
InterventionsParenteral influenza vaccine. 11.3% of vaccinees and 4.5% of unvaccinees received pneumococcal vaccination, on average
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions), hospitalisation from congestive heart failure, death from all causes (deaths were not reported)
NotesMost of the seasons were epidemic, with vaccine strains matching the circulating strains. Data were extracted by rates reported in tables. Only data stratified by health status were included in the analysis. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Nichol 1998b

MethodsProspective cohort study conducted in Minneapolis, USA during the 1993 to 1995 period, in the community. Data source was the managed care organisation database. Follow-up period was 15 November to 31 March. The rate was adjusted for age, sex, health status, vaccination status
Participants69,024 members of a medical care programme continuously enrolled for the 1-year period (46,480 treated and 22,544 controls included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. 11.3% of vaccinees and 4.5% of unvaccinees received pneumococcal vaccination, on average
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from all respiratory conditions), hospitalisation from congestive heart failure, death from all causes (deaths were not reported)
NotesAll the seasons were epidemic, with vaccine strains matching the circulating strains. Data were extracted by rates reported in tables and calculated by difference with data reported in previous studies
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nichol 2003a

MethodsProspective cohort study conducted in USA, during the 1998 to 1999 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 15 November to 31 February. The rate was adjusted for age, sex, health status
Participants140,055 members of a medical care programme continuously enrolled for the 1-year period (77,738 treated and 62,317 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from cerebrovascular disease (ICD 431-437), hospitalisation from heart disease (ICD 410-414, 428), death from all causes
NotesThe season probably was an epidemic one. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nichol 2003b

MethodsProspective cohort study conducted in USA, during the 1999 to 2000 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 15 November to 31 March. The rate was adjusted for age, sex, health status
Participants146,328 members of a medical care programme continuously enrolled for the 1-year period (87,357 treated and 58,971 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487), hospitalisation from cerebrovascular disease (ICD 431-437), hospitalisation from heart disease (ICD 410-414, 428), death from all causes
NotesThe season probably was an epidemic one. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nicholson 1999

MethodsProspective cohort study conducted in Leicester, UK during the 1993 to 1994 influenza season, in the community. Data sources were: weekly phone interviews. Follow-up period was 18 October 1993 to 19 December 1993. The sample was randomly selected. Symptomatic subjects were checked for laboratory confirmation
Participants427 community-dwelling elderly (223 treated and 216 controls, 218 and 209 included in the analysis respectively), 63 to 89 years old
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesLaboratory confirmed influenza (4-fold increase in antibody titre)
NotesThe study was conducted throughout an outbreak of influenza. The study controls for age, health status and smoking habits in analysis. Data are presented by smoking habits
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Nordin 2001a

MethodsProspective cohort study conducted in USA, during the 1996 to 1997 influenza season, in the community. Data source was a 3 managed care organisation database. Follow-up period was 5 October 1996 to 3 May 1997
Participants122,974 members of a medical care programme continuously enrolled for the 1-year period (71,005 treated and 51,969 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine matched the circulating strain
OutcomesHospitalisation from influenza and pneumonia (ICD 480-487), death from all causes
NotesIdentical to Hak 1. Odds Ratios adjusted for age, sex, site, health status were presented. Frequencies data were not available. To perform quantitative analysis adjusted data were used
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Nordin 2001b

MethodsProspective cohort study conducted in USA, during the 1997 to 1998 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 23 November 1997 to 4 April 1998
Participants158,454 members of a medical care programme continuously enrolled for the 1 year period (92,001 treated and 66,453 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine did not match the circulating strain
OutcomesHospitalisation from influenza and pneumonia (ICD 480-487), death from all causes
NotesIdentical to Hak 2. Odds Ratios adjusted for age, sex, site, health status were presented. Frequencies data were not available. To perform quantitative analysis adjusted data were used
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Ohmit 1995a

MethodsCase-controlled study conducted in Michigan, USA during the 1990 to 1991 influenza season in the community. Data sources were: database discharge diagnoses, mailed questionnaire. Follow-up period was 1 November 1990 to 30 April 1991. Cases were resident discharged from hospital with pneumonia or influenza; community controls were matched for age, sex and residence
Participants2197 non-institutionalised elderly (860 cases and 1828 controls, were identified; 667 and 1530 were included in analysis respectively), 65 years or older
InterventionsParenteral influenza vaccine, subjects were also offered pneumococcal vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487)
Notes41% of cases and 28% of controls received pneumococcal vaccination. The season had probably low epidemic levels. The study controls for confounders in analysis: influenza activity, health status age, sex, region. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Ohmit 1995b

MethodsCase-control study conducted in Michigan, USA during the 1991 to 1992 influenza season, in the community. Data sources were: database discharge diagnoses, mailed questionnaire. Follow-up period was 1 November 1991 to 30 April 1992. Cases were resident discharged from hospital with pneumonia or influenza; community controls were matched for age, sex and residence
Participants2761 non-institutionalised elderly (1186 cases and 2345 controls, were identified; 890 and 1871 were included in analysis respectively), 65 years or older
InterventionsParenteral influenza vaccine, subjects were also offered pneumococcal vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation from pneumonia and influenza (ICD 480-487)
Notes44% of cases and 32% of controls received pneumococcal vaccination. The season was probably an epidemic one. The study controls for confounders in analysis: influenza activity, health status age, sex, region. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Ohmit 1999

MethodsCase-controlled study conducted in Michigan, USA during the 1989 to 1990 influenza season, in 23 nursing homes. Data sources were: patients specific logs, vaccination records. Follow-up period was the epidemic period according to surveillance data. Cases developed ILI during the period of laboratory confirmed community influenza activity; controls resided in the same facility and were matched for age
Participants1198 residents in 23 nursing homes that experienced outbreaks or with virus isolation (361 cases and 837 controls, all included in analysis), 65 years or older
InterventionsParenteral influenza vaccine; 17% of cases and 17% of controls received pneumococcal vaccination. Vaccine strains matched the circulating strain
OutcomesClinically defined ILI (fever 37.8 °C or greater and on or more of the following: cough, sore throat, or coryza)
NotesCirculating strain: A/Shanghai/11/87. The season was an epidemic one. The study controls for confounders in analysis: home size, vaccination level, sex and age. Quantitative analysis was not performed as the logistic model used by the authors does not control by health status
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Patriarca 1985a

MethodsRetrospective cohort study conducted in Michigan, USA during the 1982 to 1983 influenza season. Authors investigated 7 nursing homes with evidence of flu activity. Throat swab and paired sera specimens were obtained from some residents; medical records. Follow-up period was 10 December 1982 to 4 March 1983
Participants1018 residents in 7 nursing homes with outbreak (548 treated and 470 controls, all included in the analysis)
InterventionsParenteral influenza vaccine: A/Bangkok/79; A/Brazil/78; B/Singapore/79. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater + cough, coryza or sore throat), Rx confirmed pneumonia, hospitalisation for ILI, deaths occurred within 2 weeks of onset of ILI. An outbreak was defined by a number of ILI per week exceeded 10% of the residents
NotesCohorts were comparable as age and level of nursing care. Amantadine was not used. The circulating strain was A/Bangkok/1/79-like. Laboratory confirmation of influenza A infection was obtained in 3 homes
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Patriarca 1985b

MethodsRetrospective cohort study conducted in Michigan, USA during the 1982 to 1983 influenza season, in 6 nursing homes. Throat swab and paired sera specimens were obtained from some residents; medical records were reviewed. Follow-up period was 10 December 1982 to 4 March 1983
Participants458 residents in 6 nursing homes without outbreak (339 treated and 119 controls, all included in the analysis)
InterventionsParenteral influenza vaccine: A/Bangkok/79; A/Brazil/78; B/Singapore/79. Vaccine strains matched circulating strains
OutcomesClinically defined ILI (fever 37.8 °C or greater + cough, coryza or sore throat), deaths occurred within 2 weeks of onset of ILI
NotesCohorts were comparable as age and level of nursing care. Amantadine was not used. The circulating strain in the community was A/Bangkok/1/79-like, but laboratory confirmation was not available in the homes
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Pregliasco 2002

MethodsProspective cohort study conducted in Milan, Italy during the 2000 to 2001 influenza season, in the community. Data sources were: monthly phone interviews and self-administered questionnaires. Follow-up period was 30 November 2000 to 31 March 2001
Participants363 community-dwelling elderly (264 treated and 99 controls, 184 and 79 included in the analysis respectively), mean age 75 years
InterventionsAdjuvant virosomal vaccine. Vaccine strains probably matched the circulating strain
OutcomesClinically defined ILI (fever + at least 1 systemic symptom: headache, myalgia, chills, weakness + at least 1 respiratory symptom: cough, sore throat, congestion); acute respiratory infection (respiratory symptoms without immediate fever); hospitalisation for pulmonary infections
NotesLow viral circulation. Cohorts were not significantly different as co-morbidity
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?High riskC - Inadequate

Puig-Barbera 2007

MethodsThree case-control studies were performed in the elderly (> 64 years of age) population from 3 health districts in the Valencia Autonomous Region, Spain (total number of elderly residents in these districts: n = 105,454 at 31 December 2004), where MF59-adjuvanted subunit influenza vaccine was used. The risk of hospitalisation for ACS, CVA or pneumonia was evaluated for patients who had received influenza vaccine and for those who had not been vaccinated against influenza
Participants

Description of cases

Incident cases for each disease were identified from all consecutive emergency hospitalisations following their admission between 15 November 2004 and 31 March 2005. Diagnoses were made according to the International Classification of Diseases, 9th version, Clinical Modification for ACS (410-411.89 and 413), CVA (431-436) or pneumonia (480-487). Only non-institutionalised patients who were > 64 years of age, had lived in the hospital catchment area for the previous 6 months, were able to give informed consent, and remained in hospital for at least 72 hours were included in the study. After consideration of the exclusion criteria, 144 cases admitted for ACS, 134 for CVA and 198 for pneumonia were included in the study

Description of controls

Each case was paired with 1 or 2 controls, matched for hospital and gender. Controls were recruited according to the same inclusion criteria as cases, following emergency hospitalisations for an acute surgical process or trauma. The admission date for controls was matched to the case admission date, preferably being the same day, and with a maximum interval of 10 days. 258 controls were admitted for ACS, 246 for CVA and 321 for pneumonia

A total of 75.2% and 78.1% of vaccinated cases and controls, respectively (P = 0.314), were vaccinated and on the population register. Of these, all cases and 99.73% of controls had received MF59-adjuvanted subunit influenza vaccine

InterventionsInfluenza vaccination and hospitalisation for ACS, CVA and pneumonia
Outcomes
NotesThe authors conclude that the results suggest that MF59TM-adjuvanted influenza vaccination is associated with a significant reduction in the risk of hospitalisation for ACS, CVA and pneumonia during the period of influenza virus circulation

Puig-Barberà 1997

MethodsCase-controlled study conducted in Spain, during the 1994 to 1995 influenza season, in the community. Data sources were: hospital emergency logs and records; structured interview. Follow-up period was 15 November 1994 to 31 March 1995. Cases were residents admitted to hospital for pneumonia; controls were admitted to hospital in the same week for acute abdominal surgical condition or trauma
Participants249 non-institutionalised persons (94 cases and 166 controls, were identified; 83 and 166 were included in analysis respectively), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strains matched the circulating strain
OutcomesHospitalisation for pneumonia; pneumonia was clinically defined and radiologically confirmed
NotesThe study controls for confounders in analysis: health status, age, socio-economic factors. The season had probably low epidemic levels. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Puig-Barberà 2004

MethodsCase-control study conducted in Spain, Valencia, during the 2002 to 2003 influenza season in the community. Data sources were: hospital records; structured interview by trained field investigator. Follow-up period was 15 November 2002 to 31 March 2003. Cases were residents admitted to hospital for pneumonia; controls were admitted to hospital in the same week for acute abdominal surgical condition or trauma
Participants815 non-institutionalised persons: (325 cases and 525 controls, were identified; 290 and 525 were included in analysis respectively), 65 years or older
InterventionsParenteral influenza MF59 adjuvant vaccine. 42% of cases and 34% of controls received pneumococcal vaccination. Vaccine strains matched the circulating strain
OutcomesHospitalisation for pneumonia (ICDIX code 480-487); pneumonia was clinically defined and radiologically confirmed
NotesThe study controls for confounders in analysis: health status, smoking habits, pneumococcal vaccination. The season had low epidemic levels. Quantitative analysis was also performed
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Ruben 1974

MethodsAuthors investigated an outbreak in a nursing home, in California, USA during the 1972 to 1973 influenza season; independent blind assessment was conducted. Follow-up period was 20 December 1972 to 28 January 1973. Throat swabs were obtained from ill residents
Participants392 nursing home residents (204 treated and 192 controls, all included in the analysis). Patients were both ambulatory and bed ridden
InterventionsParenteral influenza vaccine: A/Aichi/2/62; B/Mass/1/71. Vaccine strains did not matched circulating strains
OutcomesClinically defined ILI (fever 37.7 °C + upper respiratory symptoms), laboratory confirmed ILI (positive swab culture), deaths from outbreak related respiratory illness
NotesData stratified by nurse floor. The circulating strain was A/ENG/42/72
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Rudenko 2001

MethodsExperimental study conducted in Russia, during the 1996 to 1997 influenza season, randomised, double-blind, placebo-controlled; random sample stratified by age and underlying health conditions. Follow-up period was 20 January 1997 to 2 March 1997
Participants602 nursing home residents (93 vaccinated with parenteral vaccine, 111 vaccinated with aerosol vaccine and 109 controls); severely debilitated and immunosuppressed subjects were excluded, 41 to 95, median 73 years
InterventionsLive cold adapted vaccine aerosol administered: A/Leningrad/134/17/57; B/Ann Arbor/60/69 parenteral vaccine: A/Texas/36/91; A/Nanchang/933/95; B/Harbin/7/94 . Vaccine strains matched the circulating strains
OutcomesLaboratory confirmed ILI: positive swab or 4-fold increase in antibody titre
NotesNo description of methods; 1 or 2 doses' efficacy was tested; data are extracted irrespective of the number of doses administered
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Saah 1986a

MethodsProspective cohort study conducted in New York, USA during the 1979 to 1980 influenza season. Authors investigated a nursing home with evidence of flu activity; medical records were reviewed. Comparability between cohorts was assessed by analysis of the underlying conditions of a sample of the population; 62 patients with severe organic brain syndrome were excluded. Follow-up period was 1 November 1979 to 30 April 1980
Participants453 residents in nursing home for healthy and ill elderly (219 treated and 234 controls, all included in the analysis); most patients required skilled nursing home care
InterventionsParenteral influenza vaccine: A/Brazil/78; A/Texas/77; B/Hong Kong/72. Matching between vaccine and circulating strains is unknown
OutcomesSymptoms defined and radiologically confirmed pneumonia; death from pneumonia within 60 days from the onset of pneumonia
NotesVaccinated subjects had very slight excess of underlying conditions; smokers were rare; pneumococcal vaccine was rarely used. Specific viral diagnosis was not attempted, but the circulating strain in the community was B/Singapore/79-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Saah 1986b

MethodsProspective cohort study conducted in New York, USA during the 1980 to 1981 influenza season. Authors investigated a nursing home with evidence of flu activity; medical record were reviewed. Comparability between cohorts was assessed by analysis of the underlying conditions of a sample of the population; 62 patients with severe organic brain syndrome were excluded. Follow-up period was 1 November 1980 to 30 April 1981
Participants458 residents in nursing home for healthy and ill elderly (244 treated and 214 controls, all included in the analysis); most patients required skilled nursing home care
InterventionsParenteral influenza vaccine: A/Brazil/78; A/Bangkok/79; B/Singapore/79. Vaccine strains matched circulating strains
OutcomesSymptoms defined and radiologically confirmed pneumonia; death from pneumonia within 60 days from the onset of pneumonia
NotesVaccinated subjects had very slight excess of underlying conditions; smokers were rare; pneumococcal vaccine was rarely used. Specific viral diagnosis was not attempted, but the circulating strain in the community was A/Bangkok/79-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Saah 1986c

MethodsProspective cohort study conducted in New York, USA during the 1981 to 1982 influenza season in 26 nursing homes. Comparability between cohorts was assessed by analysis of the underlying conditions of a sample of the population; 62 patients with severe organic brain syndrome were excluded; medical records were reviewed. Follow-up period was 1 November 1981 to 30 April 1982
Participants451 residents in nursing home for healthy and ill elderly (225 treated and 226 controls, all included in the analysis); most patients required skilled nursing home care
InterventionsParenteral influenza vaccine: A/Brazil/78; A/Bangkok/79; B/Singapore/80. Matching between vaccine and circulating strains is unknown
OutcomesSymptoms defined and radiologically confirmed pneumonia; death from pneumonia within 60 days from the onset of pneumonia
NotesVaccinated subjects had very slight excess of underlying conditions; smokers were rare; pneumococcal vaccine was rarely used. The circulating strain was not identified
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Saito 2002a

MethodsProspective cohort study conducted in Japan during the 1998 to 1999 influenza season in 9 nursing homes. Follow-up period was the epidemic period. Efficacy assessment was also performed by vaccination rate in residents and HCWs, physical impairment, sex, age and health status of residents. Throat swabs were obtained from ill individuals; medical charts were reviewed
Participants699 residents in 9 nursing homes (331 treated and 368 controls, all included in the analysis). The vaccinated group had more underlying diseases
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sidney/5/97; B/Mie/1/93. Vaccine strains matched circulating strains (good match)
OutcomesClinically defined ILI (fever + cough or coryza or sore throat) occurring during the epidemic period
NotesThe circulating strain was A/Sydney. Influenza virus exposure was confirmed in all 9 facilities. Outbreaks were demonstrated only in 4 homes. No other respiratory viruses were isolated. Data were extracted by RRs reported in tables
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Saito 2002b

MethodsProspective cohort study conducted in Japan during the 1999 to 2000 influenza season in 11 nursing homes. Follow-up period was the epidemic period. Efficacy assessment was also performed by vaccination rate in residents and HCWs, physical impairment, sex, age and health status of residents. Throat swabs were obtained from ill individuals; medical charts were reviewed
Participants930 residents in 11 nursing homes (743 treated and 187 controls, all included in the analysis). The vaccinated group had more physical impairment of daily living
InterventionsParenteral influenza vaccine: A/Beijing/262/95; A/Sidney/5/97; B/Shandon/7/97. Vaccine strains matched circulating strains (good match)
OutcomesClinically defined ILI (fever + cough or coryza or sore throat) occurring during the epidemic period
NotesThe circulating strain was A/Sydney. Influenza virus exposure was confirmed in only 4/11 facilities. No outbreaks were detected. No other respiratory viruses were isolated. Data were extracted by RRs reported in tables
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Schonberger 1979

MethodsSurveillance population-based study conducted in USA, during the 1976 to 1977 influenza season. Neurologists were directly contacted; physician and hospital records were reviewed. Suspected cases reported to CDC directly by patients or medical personnel were included only if accepted by a state health department. Follow-up period was 1 October 1976 to 31 January 1977
ParticipantsUSA population
InterventionsMonovalent A/New Jersey/76 or bivalent A/New Jersey/76 and A/Victoria/75 parenteral vaccine
OutcomesCases of Guillain-Barré syndrome
NotesResults were stratified by age group and vaccine type. Vaccination rates in population were obtained from national immunisation survey
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Shapiro 2003

MethodsRetrospective cohort study conducted in Israel, during the 2000 to 2001 influenza season, in the community. Data source was: managed care organisation database. Follow-up period was the entire influenza season
Participants84,640 community-dwelling elderly (36,596 treated and 48,044 controls included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strain probably matched the circulating strain (literature)
OutcomesHospitalisation for any reason; deaths from all causes
NotesVery poor description of methods; no information about flu activity: probably not epidemic year. Data were presented by health status. Only deaths were included in the analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskB - Unclear

Strassburg 1986

MethodsAuthors investigated an outbreak in a nursing home, in Los Angeles, USA during the 1982 to 1983 influenza season; patients records were reviewed. Follow-up period was 1 February 1983 to 31 March 1983. Virus circulation was confirmed with throat swab from ill persons
Participants87 nursing home residents, 59 to 94 years old, most of them suffering from dementia (65 treated and 19 controls were included in the analysis; for 3 residents vaccination status could not be determined)
InterventionsParenteral influenza vaccine: A/Bangkok/79; A/Brazil/78; B/Singapore/79. Vaccine strains probably matched circulating strains
OutcomesClinically defined ILI (fever or fever + respiratory symptoms) occurring during the epidemic period, deaths from ILI
NotesAge, sex ratio and health status were similar in vaccinated and unvaccinated persons. The circulating strain was A/Bangkok/79-like. No other positive laboratory findings were found. Amantadine was not used
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Stuart 1969

MethodsExperimental study conducted in California, USA during the 1965 to 1966 influenza season, the control group received influenza B vaccine, placebo or no vaccine; laboratory samples were obtained from ill persons to confirm the infection active surveillance. Follow-up period was 1 February 1966 to 30 April 1966
Participants4180 residents in the house, healthy (1561 treated and 2619 controls were included in the analysis), 52 years or older
InterventionsMonovalent A2 parenteral influenza vaccine: A2/Taiwan/1/64. Vaccine strains matched the circulating strains
OutcomesClinically defined febrile illness (fever + cough or malaise or coryza or myalgia, or headache), clinically defined afebrile illness, hospitalisation and deaths without definition
Side effects were reported but they were excluded from analysis as they refer to an old oil adjuvant vaccine
NotesSubjects randomised the previous year but not vaccinated (reason not explained) in the current year were added in the control group; the study year was an epidemic one
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Taylor 1992

MethodsAuthors investigated an outbreak in a nursing home, in Washington, USA during the 1988 to 1989 influenza season; patients records and hospital charts were reviewed. Follow-up period was 29 January 1989 to 1 March 1989. Throat swabs were obtained from a sample of acutely ill residents; paired sera were obtained from 63% of both ill and well residents
Participants109 nursing home residents (48 treated and 61 controls, 45 and 52 included in the analysis respectively) 58 to 105 years old. Groups were similar in age, gender or level of care required
InterventionsParenteral influenza vaccine: A/Taiwan; A/Sichuan; B/Victoria. Vaccine strains probably matched circulating strains
OutcomesOutbreak associated cases: clinically defined ILI (fever + cough) or laboratory confirmed influenza (4-fold increase in antibody titre); pneumonia, hospitalisation from ILI or pneumonia, deaths from ILI or pneumonia
NotesVaccination was not offered to staff. Positive specimens showed a diagnostic titre rise to A/Sichuan, but no virus was isolated: matching was only hypothetic. Amantadine was not used. Laboratory confirmed cases were analysed by intention-to-treat
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Treanor 1994

MethodsExperimental study conducted in New York, USA during the 1990 to 1991 influenza season, randomised, double-blind, placebo-controlled study; randomisation method and allocation concealment were not described. 34 patients received live vaccine; 30 patients received trivalent vaccine; 11 patients received placebo. Follow-up period was for 7 days after vaccination. Self-administered diary card was filled by participants
Participants75 outpatients with chronic disease or elderly, mostly 65 years or older
InterventionsLive cold adapted influenza B virus vaccine, aerosol administered; parenteral trivalent influenza vaccine
OutcomesUpper respiratory symptoms (coryza or sore throat), lower respiratory symptoms (cough, hoarseness or dyspnoea), systemic symptoms (malaise and myalgia), sore arm, fever
NotesSubjects experiencing symptoms within 1 week of vaccination were considered
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Unclear riskD - Not used

Voordouw 2003

  1. a

    ACS = acute coronary syndromes
    CAP = community-acquired pneumonia
    CVA = cerebro-vascular accident
    HCWs = health care workers
    ICD = ischaemic cardiac disease
    ILI = influenza-like illness
    NI = neurominadase inhibitor
    OR = odds ratio
    Rx = X-ray
    URI = upper respiratory infection
    RR = risk ratio

MethodsRetrospective cohort study conducted in Netherlands, during the 1996 to 1997 influenza season, in the community. Data source was the managed care organisation database. Follow-up period was 1 September 1996 to 1 June 1997. For every individual who had received an influenza vaccination, 1 age-sex matched unvaccinated control subject was randomly selected
Participants17,822 community-dwelling elderly with a permanent status in one of the practices (8911 treated and 8911 controls, all included in the analysis), 65 years or older
InterventionsParenteral influenza vaccine. Vaccine strain matched the circulating strain
OutcomesInfluenza as defined by International Classification for primary care (R80: proven influenza without pneumonia), pneumonia, deaths from all causes
NotesThe influenza season was relatively mild. Data were stratified by age and health status. Quantitative analysis was also performed only for the outcome "deaths from all causes"
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    GP = general practice

Allsup 2001Elderly denominator 19 and no breakdown of cases by age groups is given
Allsup 2003See Allsup 2004
Anonymous 1995Comment
Anonymous 2004bNo data presented
Ansaldi 2002Cross-sectional study
Arden 1986Review
Armstrong 2004Data presented cannot be used in the analysis. The statistical model is not comparable with that used in the other studies
Arroyo 1988Description of epidemic
Arya 2003No data presented
Ayala-Montiel 2004No placebo/do nothing comparator: influenza + pneumococcus versus influenza vaccine
Baldo 1999Lack of a control group
Barker 1980Cross-sectional study
Bektimirov 1993No original data presented
Belshe 2004Children and adults
Ben-Yehuda 2003No placebo/do nothing comparator
Berg 2004The study does not investigate the vaccine efficacy
Buxton 2001Lack of a control group
Carman 2000Data are not presented by vaccine condition
Castilla 2006Retrospective paper looking at vaccination cover in > 65 and relations with effectiveness claimed as efficacy. 60 ILI cases only were tested out of a total of 2300
Chen 2004The study does not investigate the vaccine efficacy
Chlibek 2002This could be a cohort study to be considered for the adult's review
Christenson 2002Same cohorts of Christenson 2001
Chumakov 1992High-risk groups
Cohen 2004Does not present original data
Conne 1997Lack of a control group
Cruijff 1999Same cohorts of Govaert 1994
D'Alessandro 2004Both arms have influenza vaccines, no placebo/do nothing comparator
de Bernardi 2002Healthy adults; lack of a control group
de Bruijn 2004Serological outcome only
De Serres 2004Same data set as Skowronski - high-risk group
Deguchi 2000Same cohorts of Deguchi 2001
Deguchi 2000aSame cohorts of Deguchi 2001
Deguchi 2000bSame cohorts of Deguchi 2001
Deibel 1970The study does not investigate the vaccine efficacy
Elder 1996Healthy adults
Ender 2001Assessment of vitamins before vaccination as immunomodulators
Erofeeva 2001Frequency data are not reported; outcome is not clearly defined
Fedson 1992The study does not investigate the vaccine efficacy
Fedson 1993Comment
Fitzner 2001Economic study without original data
Fukumi 1969The study does not investigate the vaccine efficacy
Fukushima 1999Serological outcome only
Galanti 1976Data presented cannot be estimated for the analysis
Galasso 1977Healthy adults
Garcia Garcia 2009Only 16% of participants are over the age of 60
Garcia-Doval 2001Case report
Gasparini 2002Economic study; data source not described
Gavira 1990Economic evaluation
Gendon 1988No original data presented
Giglio 1994Unclear study design: probably retrospective cohort based only on individual recall of disease
Glass 1978The study does not investigate the vaccine efficacy
Glezen 1987The study does not investigate the vaccine efficacy
Gomez de Caso 1996The study does not investigate the vaccine efficacy
Govaert 1994 2Antibody outcomes only
Gowda 1979The study does not investigate the vaccine efficacy
Grigor'eva 1994Study population is children
Grigor'eva 2002Study population is children
Gross 1977Study population is children
Gross 1995Review
Guarino 1977Serological survey
Guillevin 1983The study does not investigate the vaccine efficacy
Gutierrez 2001Unclear study design, probably retrospective cohort based only on individual recall of disease; 1-year follow up
Hak 1998High-risk groups
Hall 1981The study does not investigate the vaccine efficacy
Hampson 1997Economic review
Hara 2008Redundant publication of Hara 2006
Harling 2004NI used
Harper 1985Comment
Hedlund 2003Same cohorts of Christenson 2001
Helliwell 1988Economic evaluation
Hennessen 1978Cross-sectional study
Herzog 2003The study does not investigate the vaccine efficacy
Heymann 2004Same cohorts of Shapiro 2003
Hirota 1997Healthy adults
Hoberman 2003Study population is children
Hope-Simpson 1970The study does not investigate the vaccine efficacy
Howell 1967Not elderly
Hurwitz 1983Non-comparative data
Icardi 2002Unclear study design: probably cross-sectional
Ikematsu 1998Poorly described study. ILI was defined only as "fever". Deaths from all causes were referred to a too long period (from January to September)
Ikematsu 2000Poorly described study. ILI was defined only as "fever". Asymptomatic infections were undistinguishable from symptomatic ones
Isahak 2007Inadequate comparator
Jackson 1999High-risk groups
Jackson 2002High-risk groups
Jahnz-Rozyk 2003Economic evaluation
Jani 1994Case report
Jarstrand 1974The study does not investigate the vaccine efficacy
Jovanovic 1977Lack of a control group; high-risk groups
Kaplan 1983Non-comparative design
Keavey 1999No data
King 1997Comment
Knight 1984Case report
Knottnerus 1996Cost of illness study
Kurland 1984Non-comparative study
Landi 2003One-year follow up in a population with important diseases
Landi 2006Same dataset as Landi 2003
Lavergne 1980No placebo/do nothing comparator, serological responses and age group?
Lawson 2000Frequency data not reported
Lindahl 1999Case report
Lohse 1999Case report
Luce 2001Economic evaluation
Mair 1974Lack of a control group
Mandal 1973Descriptive
Manzano 2000Case report
Manzoli 2007Feasibility study of GP reporting method to assess vaccine effectiveness
Margolis 1990bNo placebo/do nothing comparator
Marine 1973Serological outcome only
Marinich 1997Serological outcome only
Martin 1997Lack of a control group
Marwick 1995Comment
Masurel 1979Antibody only
Maxim 1998No data presented
Mayon-White 1994No data presented
McCall 1996No data presented
McCarthy 1978No data presented
McElhaney 2002No data presented
McGuffey 1993No data presented
Meiklejohn 1989Interruption study
Mendelman 2001Study population is children and adults
Meynaar 1991Comment
Mignogna 2000Case report
Miller 1975Lack of a control group
Modlin 1977Children
Monto 1994No data presented
Moreno 2009Non-systematic review and meta-analysis with metaviews back to front
Mostow 1969Lack of a control group
Mostow 1988No data presented
Nguyen-van-Tam 1992Unclear study design
Nichol 1996Same cohorts of Nichol 1994
Nichol 1999aNo original effectiveness data presented
Nichol 1999bSame cohorts of Nichol 1994
Nichol 1999cHigh-risk groups
Nichol 1999dAdult population
Nichol 2002Same cohorts of Nichol 1998
Nichol 2007Data already in review from other publication by the same author
Nicholson 1979No placebo/do nothing comparator
Nicholson 1983Lack of a control group
Nicholson 1990aUnclear study design: symptomatic subjects only
Nicholson 1990bNo data presented
Nicholson 1992Unclear study design: symptomatic subjects only
Nielsen 1996No data presented
Nygaard 1999No data presented
Odelin 1993Lack of a control group
Odelin 2003Lack of a control group
Ohmit 1995Same population of Ohmit 1995 included
Ortqvist 2007Data already included in the 2005 review. Re-analysis of the same dataset
Oshitani 2000Ecological study
Parkin 1978Case series
Parsons 1997No data
Patel 1988Case report
Patriarca 1985The study does not investigate the vaccine efficacy
Patriarca 1994Comment
Pena-Rey 2003The study does not investigate the vaccine efficacy
Perez 2000Case report
Perez-Tirse 1992Review of economic evaluations
Perucchini 2004Lack of a control group
Peters 1988Serological outcomes
Philip 1969Data by age are not presented
Phillips 1970Lack of a control group
Phillips 1971Comment
Piedra 2002Study population is children
Poe 1977Not about vaccine effectiveness
Poland 2002Review
Potter 1997Data are not presented by vaccine condition
Powers 1991Serological outcome only
Pregliasco 1997Not about vaccine effectiveness
Pregliasco 1999The study does not investigate the vaccine efficacy
Profeta 1987Serological outcome only
Provinciali 1994Unclear study design
Puig Barberà 1995Review
Puretz 1979Review
Pyhala 1997Guideline
Quinlisk 1990Not about vaccines
Quinnan 1983Does not report safety outcomes by age groups
Rao 1982Not about vaccines
Read 2000No outcome data by vaccine status, uncertain denominators
Reedy 2000Review
Ruben 1973Serological outcome only
Rubin 1973No data
Rudenko 1981Review
Rudenko 1993Children
Ruel 2002Only one subject was unvaccinated
Ruf 2004Antibody titres and no placebo/do nothing comparator
Runehagen 2002Not about vaccines
Russell 2001Not about vaccines
Ryan 1984No placebo/do nothing comparator
Sadler 2000Not about vaccines
Sandrini 1997Data only in graphs
Saslaw 1966Antibody responses
Satsuta 1985Not about vaccines
Schoenbaum 1969Poor description; data do not fit the comparison of this review
Schwartz 1995Comment
Selvaraj 1998Case report
Serie 1977Very poor description; absence of definitions, incoherence between data reported in text and data reported in tables
Sethi 2002Not about vaccines
Sharbaugh 1997Descriptive study
Shinkawa 2002No data
Shoji 2003Comment
Siewert 1988The study does not investigate the vaccine efficacy
Simonsen 2005Ecological study
Skowronski 2003High-risk groups
Skull 2009Study assessing risk factors for CAP. Insufficient data presented for evaluation of influenza vaccine effectiveness.
Slepuskin 1967Ecological study
Sloan 1993Comment
Socan 2004Lack of a control group
Solomon 1984Case report
Solomon 1996Case report
Solomon 1999Case report
Spencer 1979Healthy adults
Sprenger 1990The study does not investigate the vaccine efficacy
Squarcione 2003No placebo/do nothing comparator
Stamboulian 1999Unclear study design
Stott 2001Letter with no data
Tamblyn 1997Comment
Thompson 1988Review
Treanor 1992Lack of a control group
Treanor 1998Lack of a control group
Tsai 2007Model based on aspecific outcomes
Upshur 2000Descriptive study
Urquhart 1974Antibody titres
Uyeki 2003The study does not investigate the vaccine efficacy
Vallee 2000No data presented
Van Horren 1976Not about effectiveness
van Vuuren 2009Insufficient data
Verde 1973Serological outcomes
Verweij 2002Ethical study
Vila-Corcoles 2005Insufficient data reported
Visconti 1973Serological outcomes
Voordouw 2004Lack of a control group
Voordouw 2006Insufficient data reported (denominators are not reported)
Vu 2002Review
Wagner 1993Lacks controls
Wagner 1994Comment
Wakefield 1990The study does not investigate the vaccine efficacy
Wang 1986Comment
Wang 20021-year follow up
Warburton 1972Ecological study
Wareing 2001Review
Watson 1997Review
Weaver 2001The study does not investigate the vaccine efficacy
Wiehl 2001Comment
Williams 1980Comment
Wilson 1994Comment
Winer 1984Survey of cases
Wise 1977Healthy adults
Wood 2000Review
Woratz 1984Methodological paper
Yassi 1993Vaccine and amantadine were used to control outbreak: amantadine acts as confounder
Zambon 2001The study does not investigate the vaccine efficacy
Zimmerman 2004Not about vaccine effectiveness
Zoffmann 1977Not about vaccine effectiveness
Zourbas 1973Serological outcome only
Zuckerman 1990Serological outcome only
Zuckerman 1992Serological outcome only
Zuckerman 1993Serological outcome only