Vaccines for preventing influenza in healthy adults

  • Comment
  • Review
  • Intervention

Authors


Abstract

Background

Different types of influenza vaccines are currently produced worldwide. Healthy adults are presently targeted mainly in North America.

Objectives

Identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2), MEDLINE (January 1966 to June 2010) and EMBASE (1990 to June 2010).

Selection criteria

Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally-occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data.

Main results

We included 50 reports. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barré Syndrome per million vaccinations. The harms evidence base is limited.

Authors' conclusions

Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission.

WARNING:
This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.

摘要

健康成人預防流感的疫苗

背景

目前全世界生產了不同類型的流感疫苗,主要標的於北美的健康成人。

目標

找出、追溯及評估所有評值疫苗於健康成人流感預防效果的研究。

搜尋策略

我們搜尋了Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library,2010年第2期)、MEDLINE (1966年1月年到2010年6月)與EMBASE (1990年到2010年6月)。

選擇標準

隨機控制試驗(RCTs)或類隨機控制試驗16到65歲健康成人自然發生的流感情形,比較流感疫苗與安慰劑或是無介入措施的預防效果。我們也納入評估嚴重與不常見危害的比較性研究。

資料收集與分析

兩位作者獨立評估試驗品質並擷取資料。

主要結論

我們採用50個報告,其中40個(59個子研究)為臨床試驗,共計有超過70000名民眾。共計8個為可比較性的非隨機控制試驗評估嚴重的危害。兩個是危害報告,無法進行資料分析。在疫苗對應病毒株與高流行相對不普遍的情形中,有4%未接種疫苗民眾對比1%接種疫苗民眾產生流感症狀 (危險差(Risk Difference, RD) 3%, 95%信賴區間(CI) 2% to 5%)。不良疫苗相符性的對應數字為2% 與1% (RD 1, 95% CI 0% to 3%)。這些差異不太可能是因為機會造成。在請假期間,接種疫苗具有一些效果;而在住院期間及合併症比率則無影響。未活化疫苗造成局部傷害,此外,估計每百萬人有1.6個Guillain-Barré症狀的情形。疫苗危害的相關證據基礎有限。

作者結論

流感疫苗在降低流感症狀與減少請假天數上有一些效果,但沒有證據顯示流感疫苗影響併發症,如: 肺炎或傳染。

請留意:
此文獻回顧所包含36個試驗中,有15個是由企業出資(有4個未聲明資金來源)。一項較早期的系統文獻回顧截至2007年的274個流感疫苗研究的結果發現,企業出資的研究在許多有聲望的期刊中發表,這些研究在方法的品質與研究’樣本大小上,較其他獨立的(非企業出資)研究被引用的為多。相反地,由公共資源出資的研究明顯的較不傾向於呈現疫苗有效的結論。本文獻回顧顯示: 流感疫苗效果上,可靠的證據較為薄弱,但有證據顯示研究結論已被人為操弄及散播。本文獻回顧的內容及結論應以此文回顧的結果進行詮釋根據。

Résumé

Vaccins pour la prévention de la grippe chez l'adulte en bonne santé

Contexte

Différents types de vaccins contre la grippe sont aujourd'hui produits dans le monde. Actuellement, les adultes en bonne santé sont principalement ciblés en Amérique du Nord.

Objectifs

Identifier, extraire et évaluer toutes les études étudiant les effets des vaccins antigrippaux chez les adultes en bonne santé.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) (Bibliothèque Cochrane, 2010, numéro 2), MEDLINE (janvier 1966 à juin 2010) et EMBASE (1990 à juin 2010).

Critères de sélection

Les essais contrôlés randomisés (ECR) ou quasi-ECR comparant des vaccins antigrippaux à un placebo ou à l'absence d'intervention pour la grippe contractée naturellement chez des individus en bonne santé, âgés de 16 à 65 ans. Nous avons aussi inclus toutes les études comparatives évaluant les effets nocifs rares et graves.

Recueil et analyse des données

Deux auteurs de revue ont évalué la qualité de l'essai individuellement et ont extrait les données.

Résultats Principaux

Nous avons inclus 50 rapports. Quarante (59 sous-études) étaient des essais cliniques comprenant plus de 70 000 personnes. Huit étaient des essais contrôlés non randomisés comparatifs évaluant les effets délétères graves. Deux étaient des rapports d'effets délétères ne pouvant être inclus dans l'analyse des données. Dans les cas relativement rares où la circulation était élevée et où le vaccin correspondait à la souche virale en circulation, 4 % des personnes non vaccinées, contre 1 % des personnes vaccinées, développaient des symptômes grippaux (différence de risques (DR) 3 %, intervalle de confiance (IC) à 95 % entre 2 % et 5%). Les chiffres pour une faible correspondance du vaccin sont de 2 % et de 1 % (DR 1, IC à 95 % entre 0 % et 3 %). Ces différences n'étaient probablement pas dues au hasard. La vaccination avait un effet modeste sur la durée d'absence au travail et elle n'avait aucun effet sur le nombre d'admissions à l'hôpital ou sur le taux de complications. Les vaccins inactivés provoquaient des effets délétères locaux et environ 1,6 cas supplémentaire de syndrome de Guillain-Barré pour chaque million de vaccinations. La base de preuves relatives aux effets délétères est limitée.

Conclusions des auteurs

Les vaccins antigrippaux avaient un effet modeste sur la réduction des symptômes grippaux et le nombre de jours de travail perdus. Aucune preuve ne montrait une incidence de ces vaccins sur les complications, telles que la pneumonie, ou la transmission.

AVERTISSEMENT :
Sur les 36 essais de cette revue, 15 étaient financés par des fabricants et 4 n'avaient pas de déclaration de financement. Une précédente revue systématique de 274 études portant sur des vaccins antigrippaux, publiée jusqu'en 2007, révélait que les études financées par l'industrie étaient publiées dans des revues plus prestigieuses et qu'elles étaient plus citées que les autres études et ce, sans tenir compte de la taille et de la qualité méthodologique. Les études financées par des fonds publics étaient significativement moins susceptibles de rapporter des conclusions favorables aux vaccins. La revue a montré que les preuves solides sur les vaccins contre la grippe sont minces mais qu'il existe des preuves d'une manipulation répandue des conclusions, ainsi que de la réputation infondée des études. Le contenu et les conclusions de cette revue devraient être interprétés en tenant compte de ces constatations.

Plain language summary

Vaccines to prevent influenza in healthy adults

Over 200 viruses cause influenza and influenza-like illness which produce the same symptoms (fever, headache, aches and pains, cough and runny noses). Without laboratory tests, doctors cannot tell the two illnesses apart. Both last for days and rarely lead to death or serious illness. At best, vaccines might be effective against only influenza A and B, which represent about 10% of all circulating viruses. Each year, the World Health Organization recommends which viral strains should be included in vaccinations for the forthcoming season.

Authors of this review assessed all trials that compared vaccinated people with unvaccinated people. The combined results of these trials showed that under ideal conditions (vaccine completely matching circulating viral configuration) 33 healthy adults need to be vaccinated to avoid one set of influenza symptoms. In average conditions (partially matching vaccine) 100 people need to be vaccinated to avoid one set of influenza symptoms. Vaccine use did not affect the number of people hospitalised or working days lost but caused one case of Guillian-Barré syndrome (a major neurological condition leading to paralysis) for every one million vaccinations. Fifteen of the 36 trials were funded by vaccine companies and four had no funding declaration. Our results may be an optimistic estimate because company-sponsored influenza vaccines trials tend to produce results favorable to their products and some of the evidence comes from trials carried out in ideal viral circulation and matching conditions and because the harms evidence base is limited..

總結

健康成人預防流感的疫苗

健康成人預防流感的疫苗

超過200種病毒造成流感以及類流感疾病,其產生了相同的症狀(發燒、頭痛、疼痛、咳嗽與流鼻水)。沒有實驗室測試,醫師無法分辨兩種疾病,兩者都會持續數天並少有導致死亡或嚴重的疾病。頂多,疫苗可有效的扺抗的只有A型流感與B型流感,其代表了所有流行病毒中的10%左右。每一年,世界衛生組織建議那些病毒株應包含進接種疫苗內以待即將到來的季節。

本審閱作者評估所有比較接種民眾與未接種民眾的效果。這些試驗結合的結果顯示,在理想條件(疫苗完全符合流行病毒結構)下,33位健康成人需進行接種以避免一組流感症狀。在平均條件下(部分相符的疫苗),100位民眾需要接種疫苗以避免一組流感症狀。疫苗使用不會影響民眾住院治療或請假天數,但會造成格林巴利綜合症的情形(主要的神經系統疾病,會導致癱瘓),於每一百萬個接種中會產生一個。36個試驗中有15個由疫苗公司出資而4個無聲明資金來源。我們的結果可能是樂觀的估計,因為公司贊助的流感疫苗試驗傾向於產生支持他們產品的結果,且某些試驗產生的證據是在理想的病毒流行及符合環境下執行,危害的證據基礎因此而受限制。

譯註

East Asian Cochrane Alliance 翻譯
翻譯由 台灣衛生福利部/台北醫學大學實證醫學研究中心 資助

Résumé simplifié

Vaccins pour la prévention de la grippe chez l'adulte en bonne santé

Vaccins pour prévenir la grippe chez l'adulte en bonne santé

Plus de 200 virus sont à l'origine de la grippe et du syndrome d'allure grippale, qui produisent les mêmes symptômes (fièvre, maux de tête, douleurs, toux et gouttes au nez). Sans analyses effectuées en laboratoire, les médecins ne peuvent pas distinguer les deux maladies. Elles durent pendant des jours et conduisent rarement à un décès ou à une maladie grave. Au mieux, les vaccins pourraient seulement être efficaces contre la grippe A et B, qui représentent près de 10 % de tous les virus en circulation. Tous les ans, l'Organisation mondiale de la santé recommande les souches virales à inclure dans les vaccins pour la saison à venir.

Les auteurs de cette revue ont évalué tous les essais comparant des personnes vaccinées avec des personnes non vaccinées. Les résultats combinés de ces études ont montré que dans des conditions idéales (le vaccin correspond tout à fait à la configuration du virus en circulation), 33 adultes en bonne santé doivent être vaccinés pour éviter un ensemble de virus grippaux. Dans des conditions moyennes (le vaccin correspond partiellement), cent personnes doivent être vaccinées pour éviter un ensemble de symptômes grippaux. La vaccination n'affectait pas le nombre de personnes hospitalisées ou le nombre de jours de travail perdus. Elle était toutefois à l'origine d'un cas de syndrome de Guillain-Barré (une maladie neurologique entraînant la paralysie) pour chaque million de vaccinations. Quinze des 36 essais étaient financés par des fabricants de vaccins et quatre n'avaient pas de déclaration de financement. Nos résultats peuvent être une estimation optimiste, car les essais de vaccins financés par des fabricants ont tendance à obtenir des résultats favorables à leurs produits et certaines preuves proviennent d'essais réalisés dans des conditions de correspondance et de circulation du virus idéales, et parce que la base de preuves en matière d'effets délétères est limitée.

Notes de traduction

Traduit par: French Cochrane Centre 4th June, 2013
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

Plain language summary

Cjepivo za sprječavanje gripe u zdravih odraslih osoba

Cjepivo za sprječavanje gripe u zdravih odraslih osoba

Preko 200 virusa uzrokuje gripu i bolest koja nalikuje na gripu, koje imaju iste simptome – vrućicu, glavobolju, bolove, kašalj i curenje iz nosa. Bez laboratorijskih testove liječnici ne mogu razlikovati ove dvije bolesti. Obje traju danima i rijetko uzrokuju smrt ili ozbiljnu bolest. U najboljem slučaju cjepiva mogu biti korisna za gripu tipa A ili B, što predstavlja svega oko 10% svih virusa koji cirkuliraju. Svake godine Svjetska zdravstvena organizacija preporučuje koji soj virusa treba biti uključen u cjepivo za nadolazeću sezonu.

Autori Cochrane sustavnog pregleda analizirali su sva klinička ispitivanja koja su usporedila cijepljene ljude s onima koji se nisu cijepili. Kombinirani rezultati svih tih istraživanja pokazuju da se u idealnim uvjetima (kada cjepivo savršeno odgovara soju virusa koji trenutno cirkulira) 33 zdrave odrasle osobe trebaju cijepiti da bi se izbjegla pojava gripe kod 1 osobe. U prosječnim uvjetima (djelomična podudarnost cjepiva), 100 ljudi treba se cijepiti da bi se pojava gripe izbjegla kod 1 osobe. Cijepljenje nije utjecalo na broj osoba koje su hospitalizirane ili broj izgubljenih radnih dana, ali je uzrokovalo jedan slučaj Guillian-Barreovog sindroma (teškog neurološkog stanja koje uzrokuje paralizu) na svakih milijun cijepljenja. Petnaest od 36 kliničkih ispitivanja financirale su tvrtke koje proizvode cjepiva, a u 4 studije nije bio naveden izvor financiranja. Autori naglašavaju da ovi rezultati mogu biti vrlo optimistična procjena, budući su rezultati istraživanja koje su sponzorirale tvrtke koje proizvode cjepiva pokazali povoljnije rezultate u korist cjepiva, dio dokaza dolazi iz istraživanja provedenih u idealnim uvjetima s potpunim podudaranjem cjepiva i virusa, a isto tako i zbog toga što su ograničeni dokazi o mogućim štetama cjepiva.

Translation notes

Translated by: Croatian Branch of the Italian Cochrane Centre

Background

Description of the condition

Viral respiratory disease imposes a heavy burden on society. The majority of viral respiratory disease (influenza-like illness (ILI)) is caused by many different agents which are not clinically distinguishable from one another. A variable proportion of ILI (7% to 15% on average) is caused by influenza viruses and is known as influenza (Jefferson 2009b).

Influenza is an acute respiratory infection caused by a virus of the Orthomyxoviridae family. Three serotypes are known (A, B and C). Influenza causes an acute febrile illness with myalgia, headache and cough. Although the median duration of the acute illness is three days, cough and malaise can persist for weeks. Complications of influenza include otitis media, pneumonia, secondary bacterial pneumonia, exacerbations of chronic respiratory disease and bronchiolitis in children. Additionally, influenza can cause a range of non-respiratory complications including febrile convulsions, Reye's syndrome and myocarditis (Wiselka 1994). Efforts to prevent or minimise the impact of seasonal influenza in the second part of the 20th century centred on the use of vaccines. Due to the yearly changes in viral antigenic configuration and the lack of carry-over protection from year to year, vaccination campaigns annually require a huge scientific and logistic effort to ensure production and delivery of that year's vaccines for high population coverage.

Description of the intervention

Currently there are three types of influenza vaccines: (1) whole virion vaccines which consist of complete viruses which have been 'killed' or inactivated, so that they are not infectious but retain their strain-specific antigenic properties; (2) subunit virion vaccines which are made of surface antigens (H and N) only; (3) split virion vaccines in which the viral structure is broken up by a disrupting agent. These vaccines contain both surface and internal antigens. In addition a variety of non-European manufacturers produce live attenuated vaccines. Traditionally whole virion vaccines are thought to be the less well-tolerated because of the presence of a lipid stratum on the surface of the viral particles (a remnant of the host cell membrane coating the virion, when budding from the host cell). Influenza vaccines are produced worldwide. Periodic antigenic drifts and shifts pose problems for vaccine production and procurement, as a new vaccine closely matching circulating antigenic configuration must be produced and procured for the beginning of each new influenza 'season'. To achieve this, the World Health Organization (WHO) has established a worldwide surveillance system allowing identification and isolation of viral strains circulating the different parts of the globe. Sentinel practices recover viral particles from the naso-pharynx of patients with influenza-like symptoms and the samples are swiftly sent to the laboratories of the national influenza centres (110 laboratories in 79 countries). When new strains are detected the samples are sent to one of the four WHO reference centres (London, Atlanta, Tokyo and Melbourne) for antigenic analysis. Information on the circulating strain is then sent to the WHO, who in February of each year recommends, through a committee, the strains to be included in the vaccine for the forthcoming 'season'. Individual governments may or may not follow the WHO recommendations. Australia, New Zealand and more recently South Africa, follow their own recommendations for vaccine content. Surveillance and early identification thus play a central part in the composition of the vaccine.

How the intervention might work

Every vaccination campaign has stated aims against which the effects of the campaign must be measured. Perhaps the most detailed document presenting the rationale for a comprehensive preventive programme was that by the US Advisory Committee on Immunization Practices (ACIP) published in 2006 (ACIP 2006). The document identified 11 categories at high risk of complications from influenza, among which are healthy adults 50 to 65 years of age and healthcare workers. The rationale for policy choices rests on the heavy burden which influenza imposes on the populations and on the benefits accruing from vaccinating them. Reductions in cases and complications (such as excess hospitalisations, absence from work, mortality and healthcare contacts) and the interruption of transmission, are the principal arguments for extending vaccination to healthy adults aged 50 to 65 years (ACIP 2006).

The 2009 ACIP document update recommends vaccination for three categories of healthy adults: “Annual vaccination against influenza is recommended for any adult who wants to reduce the risk of becoming ill with influenza or of transmitting it to others. Vaccination is recommended for all adults without contraindications in the following groups, because these persons either are at higher risk for influenza complications, or are close contacts of persons at higher risk:
persons aged > 50 years;
women who will be pregnant during the influenza season;
health-care personnel;
household contacts and caregivers of children aged below five years and adults aged > 50 years, with particular emphasis on vaccinating contacts of children aged under six months; and household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza” (ACIP 2009).

Why it is important to do this review

Given the very high cost of yearly vaccination for large parts of the population and the extreme variability of influenza incidence during each 'season', we carried out a systematic review of the evidence. To enhance relevance for decision-makers in the 2007 update of the review (Jefferson 2007) we included comparative non-randomised studies reporting evidence of serious and/or rare harms.

Objectives

To identify, retrieve and assess all studies evaluating the effects (efficacy, effectiveness and harm) of vaccines against influenza in healthy adults we defined:

  1. efficacy as the capacity of the vaccines to prevent influenza A or B and its complications;

  2. effectiveness as the capacity of the vaccines to prevent influenza-like illness and its consequences; and

  3. harm as any harmful event potentially associated with exposure to influenza vaccines.

Methods

Criteria for considering studies for this review

Types of studies

Any randomised controlled trial (RCT) or quasi-RCT comparing influenza vaccines in humans with placebo or no intervention or comparing types, doses or schedules of influenza vaccine. Only studies assessing protection from exposure to naturally occurring influenza were considered.

Comparative non-randomised studies were included if they reported evidence on the association between influenza vaccines and serious adverse effects (such as Guillain-Barré or oculo-respiratory syndromes).

We defined as RCTs as studies in which it appears that 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 healthcare using random allocation. A study is quasi-randomised when it appears that 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 healthcare using some quasi-random method of allocation (such as alternation, by date of birth, or by case record number).

Types of participants

Healthy individuals aged 16 to 65 years, irrespective of influenza immune status. Studies considering more than 25% of individuals outside this age range were excluded from the review.

Types of interventions

Live, attenuated or killed vaccines or fractions thereof administered by any route, irrespective of antigenic configuration.

Types of outcome measures

Primary outcomes
Clinical

Numbers and seriousness (complications and working days lost) of symptomatic influenza and influenza-like illness (ILI) cases occurring in vaccine and placebo groups.

Harms

Number and seriousness of adverse effects (systemic and severe). Systemic adverse effects include cases of malaise, nausea, fever, arthralgia, rash, headache and more generalised and serious signs such as neurological harms.

Secondary outcomes

Local adverse effects include induration, soreness and redness at the site of inoculation.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, issue 2) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (PubMed) (January 1966 to June 2010) and EMBASE.com (1990 to June 2010).

See Appendix 1 for the MEDLINE search strategy used in 2004, Appendix 2 and Appendix 3 for the 2009 strategies. There were no language or publication restrictions.

Searching other resources

To identify further trials, we read the bibliographies of retrieved articles and handsearched the journal Vaccine from its first issue to the end of 2009. Results of handsearches are included in CENTRAL. In order to locate unpublished trials for the first edition of this review, we wrote to the following: manufacturers; first or corresponding trial authors of studies in the review.

Data collection and analysis

Review authors TJ and DR for the 2007 update and TJ, GB and LAA for the 2010 update independently applied inclusion criteria to all identified and retrieved articles. Four review authors (TJ, GB, LAA, EF) then extracted data from included studies on standard Cochrane Vaccines Field forms. The procedure was supervised and arbitrated by another review authors (CDP).

Selection of studies

One review author (AR) carried out an initial screening of retrieved citations. Subsequently two review authors (TJ, LAA) independently applied inclusion criteria to all identified and retrieved articles.

Data extraction and management

Four review authors (TJ, GB, LAA, EF) extracted data from included studies on standard Cochrane Vaccines Field forms. The procedure was supervised and arbitrated by another review author (CDP).

Assessment of risk of bias in included studies

Assessment of methodological quality for RCTs was carried out using criteria from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We assessed studies according to randomisation, generation of the allocation sequence, allocation concealment, blinding and follow up. We assessed quality of non-randomised studies in relation to the presence of potential confounders using the appropriate Newcastle-Ottawa Scales (NOS) (Wells 2004). We used quality at the analysis stage as a means of interpreting the results. We assigned risk of bias categories on the basis of the number of NOS items judged inadequate in each study: low risk of bias - up to one inadequate item; medium risk of bias - up to three inadequate items; high risk of bias - more than three inadequate items; very high risk of bias - when there was no description of methods.

Measures of treatment effect

Efficacy (against influenza) and effectiveness (against ILI) (effects) estimates were summarised as risk ratios (RR) and for the main findings risk difference (RD) within 95% confidence intervals (CIs) (in brackets after the summary estimate). Absolute vaccine efficacy (VE) was expressed as a percentage using the formula: VE = 1-RR whenever statistically significant.

Similar analyses were undertaken for other events, such as complications, hospital admissions and harms.

As the data on average time off work were reported as a continuous measurement, these results were expressed as differences in means and combined using the mean difference method. Caution should be exercised in interpreting these results as the data are very skewed.

Unit of analysis issues

Four different definitions of 'epidemic period' were found.

  1. The interval between the first and the last virus isolation in the community.

  2. The interval during which influenza virus was recovered from more than a stated percentage of ill subjects.

  3. The period during which an increase of respiratory illness more than a stated % was recorded.

  4. The winter period taken as a proxy for epidemic period.

The data were included regardless of the definition of epidemic period used in the primary study. When data were presented for the epidemic period and the entire follow up period, those which occurred during the former were considered.

An ILI case (specific definition) was assumed to be the same as a 'flu-like illness' according to a predefined list of symptoms (including the Centers for Disease Control and Prevention (CDC) case definition for surveillance), or 'upper respiratory illness' according to a predefined list of symptoms. When more than one definition was given for the same trial, data related to the more specific definition were included.
The laboratory confirmation of influenza cases found were:

  1. virus isolation from culture;

  2. four-fold antibody increase (haemagglutinin) in acute or convalescent phase sera; and

  3. four-fold antibody increase (haemagglutinin) in post-vaccination or post-epidemic phase sera.

When more than one definition was given for the same trial, data related to the more sensitive definition (for example, influenza) were included.

Dealing with missing data

For the initial version of the review we wrote to first authors and manufacturers to identify possible unpublished studies and missing data. The response was disappointing and we desisted from any further attempts.

Assessment of heterogeneity

The I2 statistic was calculated for each pooled estimate, in order to assess the impact on statistical heterogeneity. The I2 statistic may 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 I2 statistic < 30% there is little concern about statistical heterogeneity (Higgins 2002; Higgins 2003). We used random-effects models throughout to take account of the between-study variance in our findings (DerSimonian 1986). Variance is to be expected in influenza vaccine trials as there are unpredictable systematic differences between trials regarding the circulating strains, degree of antigenic matching of the vaccine, type of vaccine, and the levels of immunity presented by different population in different settings. Not all studies reported sufficient details to enable a full analysis of the sources of heterogeneity, but we were able to take into account vaccine matching and circulating strain.

Assessment of reporting biases

The main problem with influenza vaccines studies is their poor quality and discrepancies between data presented, conclusions and authors' recommendations. For example, an earlier review of 274 influenza vaccines studies in all age groups (including the studies in this review) showed an inverse relationship between risk of bias and direction of study conclusions. Conclusions favorable to the use of influenza vaccines were associated with higher risk of bias. In these studies the authors made claims and drew conclusions unsupported by the data they presented. In addition, industry funded studies are more likely to have favorable conclusions and be published in significantly higher impact factor journals and have higher citation rates than non-industry funded studies. This difference is not explained by either their size or methodological quality (Jefferson 2009a). The review found no evidence of publication bias.

Any interpretation of the body of evidence in this review should be made with these findings in mind.

Data synthesis

We carried out a random-effects meta-analysis of efficacy and effectiveness data (Higgins 2009) but we did not perform a quantitative analysis of non-randomised studies.

The data and analyses tables were constructed according to the following criteria.

  1. Inactivated parenteral (intramuscular or subcutaneous) influenza vaccines versus placebo or no intervention (Analysis 01).

  2. Live aerosol vaccines (Analysis 02).

  3. Inactivated aerosol vaccines (Analysis 03).

For all three major comparisons, subgroup analyses were carried out according to the degree of matching with that year's WHO recommended content and with circulating viruses ("WHO recommended and matching" when known). WHO recommendations on content of vaccines have been published since 1973. Different dosages and schedules of the vaccine and the presence of different adjuvants were not compared and data from arms of trials comparing only vaccine composition or dosage were pooled in the analysis. Compliance of the study vaccine with the official antigenic content and potency recommendations was checked by reviewing WHO records when possible. In case of uncertainty due to ambiguity of wording used (in the oldest trials), the opinion stated by authors was taken into account. The compliance of a live attenuated vaccine with the recommendation was classified according to the antigenic comparability of the wild strains.

The following outcomes were included in the comparisons.

  1. Cases of influenza (defined on the basis of a specific list of symptoms and/or signs backed up by laboratory confirmation of infection with influenza A or B viruses).

  2. Cases of ILI (clinically defined on the basis of a specific list of symptoms and/or signs).

  3. Hospital admissions.

  4. Complications.

  5. Working days lost.

  6. Local harms.

  7. Systemic harms.

  8. Severe/rare harms.

Hospital admissions rates were calculated as proportion of cases hospitalised for respiratory causes. Complications were considered as proportion of cases complicated by bronchitis, pneumonia or otitis. Working days lost in episodes of sickness absence regardless of cause were also considered. Only five trials used working days lost as an outcome measure and four of them measured the work absence in terms of difference of the average number of days lost in the two arms of the trial (Analysis 1.7). These studies presented a value of standard error measured accordingly. The remainder (Nichol 1999a) expressed the work absence in terms of rate ratio and this does not allow the recalculation of the correct estimate of the standard error. Therefore this study was excluded from the pooled analysis.

Local symptoms are presented separately from systemic symptoms. Individual harms have been considered in the analysis, as well as a combined endpoint (any or highest symptom). All the data included in the analysis were used as presented by the authors in the primary study regardless of the number of drop-outs. This approach (complete case scenario) was decided because the majority of the studies did not present any attempt at using an intention to treat analysis nor mentioned the reasons for the loss to follow up and did not contain detailed information to allow estimations of the real number of participants.

Subgroup analysis and investigation of heterogeneity

Several trials included more than one active vaccine arm. Where several active arms from the same trial were included in the same analysis, the placebo group was split equally between the different arms, so that the total number of subjects in any one analysis did not exceed the actual number in the trials. As it was not possible to identify all sources of heterogeneity, we decided to carry out a sensitivity analysis on the results applying fixed-effect and a random-effects model to assess the impact of heterogeneity on our results. Finally, we carried out a separate analysis of trials carried out during the 1968 to 1969 (H3N2) pandemic.

Sensitivity analysis

Future updates of this review may include sensitivity analysis by funding source.

Results

Description of studies

Results of the search

The first version of the review contained 20 studies (Demicheli 1999). The 2004 version added five more studies (Demicheli 2004). In 2007 we included 48 studies in all (Jefferson 2007). Some of them had more than two arms, comparing different vaccines, routes of administration, schedules or dosages and reported data from different settings and epidemic seasons. We split these studies into sub-studies (data sets). For the remainder of this review, the term 'study report' refers to the original study report, while the word 'dataset' refers to the sub-study. Details of the division of the reports of studies into data sets are given in the table of included studies. In this 2010 update we included two new trials (Beran 2009a; Beran 2009b). We excluded three new studies (Belongia 2009; Chou 2007; Khazeni 2009).

Overall, 25 data sets contributed data on efficacy/effectiveness (16 on inactivated parenteral vaccines, seven on live aerosol vaccines and two on inactivated aerosol vaccines), 12 on all effects (seven on inactivated parenteral vaccines, three on live aerosol vaccines and two on inactivated aerosol vaccines) and 20 on harms only (nine on inactivated parenteral vaccines, nine on live aerosol vaccines and two on inactivated aerosol vaccines) (Table 1).

Table 1. Study datasets by type of vaccine and outcomes
Vaccine typeEfficacy onlyEfficacy and safetySafety onlyTotal
Inactivated parenteral167932
Live aerosol73919
Inactivated aerosol2226
Total25122057

Included studies

Included trials assessed three types of vaccine: inactivated parenteral, live attenuated aerosol and inactivated aerosol.

Thirty-four data sets of inactivated parenteral vaccine were included. Eigtheen data sets (12 study reports) provided data about efficacy or effectiveness (Beran 2009a; Beran 2009b; Eddy 1970; Hammond 1978; Keitel 1988a; Keitel 1988b; Keitel 1997a; Keitel 1997b; Keitel 1997c; Leibovitz 1971; Mixéu 2002; Mogabgab 1970a; Mogabgab 1970b; Powers 1995b; Powers 1995c; Waldman 1969a; Waldman 1969b; Weingarten 1988). They involved 34,573 participants: 18,557 in the vaccines arm and 16,016 in the placebo arms.

Seven data sets (five study reports) reported both effectiveness and harms data (Bridges 2000a; Bridges 2000b; Mesa Duque 2001; Nichol 1995; Powers 1995a; Waldman 1972b; Waldman 1972d). The population sample of these consisted of 4227 participants: 2251 received the vaccine and 1976 received the placebo.

The remaining nine data sets (nine studies) with inactivated parenteral vaccines assessed harms outcomes only and were carried out on 2931 participants (Caplan 1977; El'shina 1996; Forsyth 1967; Goodeve 1983; Phyroenen 1981; Rocchi 1979a; Saxen 1999; Scheifele 2003; Tannock 1984). In this last group, 1560 participants were immunised and 1371 received the placebo.

Live aerosol vaccines were tested in 19 data sets.
Seven data sets (three studies) reported efficacy/effectiveness outcomes (Edwards 1994a; Edwards 1994b; Edwards 1994c; Edwards 1994d; Sumarokow 1971; Zhilova 1986a; Zhilova 1986b). Altogether 29,955 participants were involved: 15,651 in vaccines and 14,304 in the placebo arms. Three data sets (three studies) provided effectiveness and harms data (Monto 1982; Nichol 1999a; Rytel 1977), 5010 individuals in all; 3290 in vaccines arms and 1720 in placebo. Nine data sets (eight studies) reported harms data only (Atmar 1990; Betts 1977a; Evans 1976; Hrabar 1977; Keitel 1993a; Keitel 1993b; Lauteria 1974; Miller 1977; Rocchi 1979b): 630 in the vaccinated and 344 in the placebo arms; 974 observations in total.

Six data sets with inactivated aerosol vaccine were included.
Two data sets provided data on efficacy or effectiveness only (Waldman 1969c; Waldman 1969d). The total number of subjects was 1187: with 950 who were vaccinated and 237 who received placebo.
Two data sets (one study) evaluated efficacy/effectiveness and harms (Waldman 1972a; Waldman 1972c) with a total population of 487: 389 in the vaccine arms 389 and 98 in the placebo arms.
Two trials (two studies) reported data on harms outcomes only (Boyce 2000; Langley 2005), with a total population of 151,120 in the vaccine arms and 31 in the placebo arms).

Two studies with live aerosol vaccine (Reeve 1982; Spencer 1977) each one data set) could not be introduced in the harms analysis (secondary effects) because data did not allow quantitative analysis (systemic and local harms were reported as given cumulative in Spencer 1977 and data were not clearly reported in Reeve 1982).

Ten studies (eight of which were comparative non-randomised studies) investigated possible associations between influenza vaccines and serious harms.
Atmar 1990 (respiratory function), DeStefano 2003 (multiple sclerosis and optic neuritis), Kaplan 1982 (Guillan Barrè Syndrome (GBS)), Lasky 1998 (GBS) Mastrangelo 2000 (cutaneous melanoma), Mutsch 2004 (Bell's palsy), Payne 2006 (optic neuritis), Scheifele 2003 (oculo respiratory syndrome), Shoenberger 1979 (GBS), Siscovick 2000 (cardiac arrest).

Included studies are described in the relevant table.

Excluded studies

We excluded 92 studies (see Characteristics of excluded studies table).

Risk of bias in included studies

Thirty-three studies were properly randomised, seven stated that the allocation method was quasi-random and two studies were field trials. Three non-randomised studies were at high risk of bias (Kaplan 1982; Mastrangelo 2000; Siscovick 2000), one was at medium risk of bias (Mutsch 2004) and two were at low risk of bias (Atmar 1990; Lasky 1998).

Allocation

In the included trials, allocation concealment was adequate in 10, inadequate in four, unclear in 26 and not relevant in two.

Blinding

Assessment was double-blinded in 23 studies. Five studies were single blind and twelve did not mention blinding. Thirty-three studies were properly randomised, seven stated that the allocation method was quasi-random and two studies were field trials.

Incomplete outcome data

Few studies reported information on influenza circulation in the surrounding community, making interpretation of the results and assessment of their generalisability difficult

Selective reporting

The harms dataset from randomised studies is small. The trial authors appear to regard harms as less important than effectiveness assessment. For example, in the trials by Beran et al (Beran 2009a; Beran 2009b) data collection on harms began at the receipt of the vaccine or placebo and continued until the end of the study.  However, harms data were solicited from a subset of subjects and no mention of method used to select them and no justification for not collecting harms data from all participants were reported.

Other potential sources of bias

It is now known that industry funding of influenza vaccines studies determines publication in high prestige journals and higher citation rates than other types of funding. In addition industry funding is associated with optimistic conclusions, but the quality of the majority of influenza vaccines studies is low, irrespective of funding. A previously cited review showed a complex web of interrelationships between these variables (Jefferson 2009a), but how this impacts on policy making is unknown.

Effects of interventions

Inactivated parenteral vaccines (Analysis 01)

Inactivated parenteral vaccines were 30% effective (95% CI 17% to 41%) against the symptoms of ILI if content matched WHO recommendations and circulating strain, but were not effective (RR 0.93, 95% CI 0.79 to 1.09) when these were unknown (Analysis 1.1.2)

Against influenza symptoms vaccines were 73% efficacious (54% to 84%) when content matched WHO recommendations and circulating strain but decreased to 44% (95% CI 23% to 59%) when it did not (Analysis 1.2).

An alternative to the use of risk ratio based formula 1-RR expressed as percentage is the use of risk difference (RD). In this case 30% of unvaccinated people versus 24% of people vaccinated with inactivated parenteral vaccines developed symptoms of ILI. This is the equivalent to saying that 70% of the unvaccinated study participants did not get ILI symptoms compared to 76% of the vaccinated study participants who did not get ILI symptoms (effectiveness). When the vaccine matched the viral circulating strain and circulation was high, 4% (2% to 5%) of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (efficacy). These differences were not likely to be due to chance. When the vaccine content did not match the circulating influenza viruses 1% of vaccinated people developed symptoms compared to 2% of unvaccinated people.

Efficacy was lower (74%, 95% CI 45% to 87%) when the studies carried out during the 1968 to 1969 pandemic were excluded. Based on one study, 42% less (95% CI 9% to 63%) physician visits are carried out in those vaccinated with WHO recommended vaccines matching circulating viruses, but not in those not matching (RR 1.28, 95% CI 0.90 to 1.83) (Analysis 1.3.2). A similar result is seen in the effect on days of illness (Analysis 1.4), but there seems to be no effect on times an antibiotic or a drug were prescribed (Analysis 1.5 and 1.6). Five trials evaluated time off work, estimating that vaccination saved on average around 0.13 working days. This result was not statistically significant. Hospital admissions (evaluated in four trials) were also lower in vaccinated arms, but the difference was not statistically significant. There was little difference in complication rates between vaccinated and unvaccinated groups (Analyses 1.7 to 1.10). The conclusions of this comparison were unaffected by analysis using either random- or fixed-effect models

Harms

Local tenderness and soreness was more than three times as common among parenteral vaccine recipients than those in the placebo group (RR 3.11, 95% CI 2.08 to 4.66) (Analysis 1.11.1). There were also increases in erythema (RR 4.01, 95% CI 1.91 to 8.41) (Analysis 1.11.2), but not induration or arm stiffness. The combined local effects endpoint was significantly higher for those receiving the vaccine (RR 2.87, 95% CI 2.02 to 4.06) (Analysis 1.11.5). Myalgia was significantly associated with vaccination (RR 1.54, 95% CI 1.12 to 2.11) (Analysis 1.12.1). None other of the systemic effects were individually more common in parenteral vaccine recipients than in placebo recipients. However, the combined endpoint was increased (RR 1.29, 95% CI 1.01 to 1.64) (Analysis 1.12.6).

Live aerosol vaccines (Analysis 02)

Live aerosol vaccines have an effectiveness of 10% (95% CI 4% to 16%) and content and matching appear not to affect their performance significantly. However, overall their efficacy is 62% (95% CI 45% to 73%). Again, neither content nor matching appear to affect their performance significantly. The effectiveness of the aerosol vaccines against ILI (with no clear definition) was significant only for WHO recommended vaccine matching absent or unknown (11%, 95% CI 3% to 18%). The conclusions of this comparison were unaffected by analysis using either random- or fixed-effect models.

Harms

Significantly more recipients experienced symptoms of upper respiratory infection, sore throats and coryza after vaccine administration than placebo administration (upper respiratory infection RR 1.66, 95% CI 1.22 to 2.27; coryza RR 1.56, 95% CI 1.26 to 1.94; sore throat 1.73, 95% CI 1.44 to 2.08)). There was no significant increase in systemic harms, although rates of fever fatigue and myalgia were higher in vaccine than placebo groups.

Inactivated aerosol vaccines (Analysis 03)

Inactivated aerosol vaccines had effectiveness of 42% (95% CI 17% to 60%) although this observations is based on four data sets from two studies. The conclusions of this comparison were substantially unaffected by analysis using either random- or fixed-effect models although effectiveness against ILI - WHO recommended content and matching vaccine went from a fixed-effect RR 0.59 (95% CI 0.43 to 0.81) to a random-effects RR of 0.47 (95% CI 0.19 to 1.13) (Analysis 3.1.1) and the subcomparison ILI - WHO recommended but with content and matching unknown went from a fixed-effect RR 0.69 (95% CI 0.51 to 0.93) to a random-effects RR 0.63 (95% CI 0.37 to 1.07) (Analysis 3.1.2).

We conclude that the presence of heterogeneity does not materially alter our conclusions. Sensitivity analysis by methodological study quality did not affect our findings.

Harms

None of the trials on inactivated aerosol vaccines reported significant harms.

Serious and rare harms
Oculo-respiratory syndrome (ORS)

On the basis of one randomised trial (Scheifele 2003) on 651 healthy adults aged around 45, trivalent split inactivated vaccine (TIV) causes mild oculo-respiratory syndrome in people with no previous history of ORS. ORS was defined as bilateral conjunctivitis, facial swelling (lip, lid or mouth), difficulty in breathing and chest discomfort (including cough, wheeze, dysphagia or sore throat). ORS (attributable risk 2.9%, 95% CI 0.6 to 5.2), hoarseness (1.3%, 95% CI 0.3 to 1.3) and coughing (1.2%, 95% CI 0.2 to 1.6) occurred within six days of vaccination. The association did not appear to be specific for any type of TIV.

Guillain-Barré Syndrome (GBS)

Three studies assessed the association between influenza vaccination and Guillain-Barré Syndrome (GBS) (rapidly progressing symmetric paralysis with usually spontaneous resolution). The first study compared GBS cases by vaccination status and the national incidence in vaccinated and unvaccinated national cohorts. The attributable risk from vaccination was just below 1 case of GBS every 100,000 vaccinations (Shoenberger 1979). The rise in GBS following rapid immunisation of millions of Americans in 1976 to 1977 led to the halting of the campaign. The second study (Kaplan 1982) was a retrospective cohort model comparing incidence of GBS in vaccinated and unvaccinated adults in the USA (minus the state of Maryland) within eight weeks from vaccination. The study reported a lack of evidence of association (RR of 0.6 and 1.4 for the two seasons included in the study; described as non-significant but with no confidence intervals reported). The study is a poor quality model with poor case ascertainment, no case definition and assumptions of the size of the exposed and non-exposed denominators. A similar design but with more sophistication was used in the Lasky et al study for the 1992 to 1993 and 1993 to 1994 seasons (Lasky 1998). Lasky et al. assessed the risk of GBS within six weeks from vaccination. Assessment of exposure was based on a random digit phone sample validated through state data on vaccine coverage and provider-sources data on vaccination timings. Two hundred and seventy three cases of GBS were identified through the CDC VAERS surveillance database and histories validated using hospital documentation. Only 180 cases were available for interview. Nineteen cases were assessed by the authors as being vaccine-associated (received vaccine in the previous six weeks (RR 1.8, 95% CI 1.0 to 3.5) adjusted for age, sex and season). The cases had a mean age of 66 years. The authors estimated the incidence of vaccine-induced GBS as 0.145 cases per million persons per week or 1.6 extra cases per million vaccinations. Despite its many limitations (mainly due to case attrition and variable reliability of exposure data) the study is well conducted and its conclusions credible, if conservative. We conclude that there may be a small additional risk of GBS. The studies demonstrate the danger of commencing a large vaccination campaign without adequate harms assessment.

Demyelinating diseases

Based on two case-control studies there is no evidence of an association between influenza vaccine and demyelinating disease (DeStefano 2003; Payne 2006).

Bell's palsy

One case-control study and case-series based in the German-speaking regions of Switzerland assessed association between an intranasal inactivated virosomal influenza vaccine and Bell's palsy (Mutsch 2004). Two hundred and fifty cases that could be evaluated (from an original 773 cases identified) were matched to 722 controls. All were aged around 50. The study reports a massive increase in risk (adjusted OR 84, 95% CI 20.1 to 351.9) within 1 to 91 days since vaccination. Despite its many limitations (case attrition - 187 cases could not be identified - and ascertainment bias - physicians picked controls for their own cases - confounding by indication - different vaccine exposure rate between controls and the reference population) it is unlikely that such a large OR could have been affected significantly by systematic error. The authors called for larger pre-licence harms trials, given the rarity of Bell's palsy. On the basis of this study the vaccine was withdrawn from commerce.

Cutaneous melanoma

The association between influenza vaccines and cutaneous melanoma was assessed by a case-control study on 99 cases and 104 controls (Mastrangelo 2000). The authors report a protective effect of repeated influenza vaccination on the risk cutaneous melanoma (OR 0.43, 95% CI 0.19 to 1.00). The study is at high risk of bias because of the selective nature of cases (all patients in the authors' hospital), attrition bias (four cases and four controls eliminated because of "failure to collaborate", recall bias (up to five years exposure data were based on patients' recollection) and ascertainment bias (non-blinded exposure survey).

Primary cardiac arrest

The association between influenza vaccination the previous year and the risk of primary (i.e. occurring in people with no previous history of cardiac disease) cardiac arrest was assessed by a case-control study on 360 cases and 418 controls (Siscovick 2000). The authors concluded that vaccination is protective against primary cardiac arrest (OR 0.51, 95% CI 0.33 to 0.79). The difficulty of case ascertainment (77% of potential cases had no medical examiner report and/or autopsy), recall bias (spouses provided exposure data for 304 cases, while 56 survivor cases provided data jointly with their spouses) make the conclusions of this study unreliable. It is impossible to judge the reliability of this study because of a lack of details on the circulation of influenza in the study areas in the 12 months preceding cardiac arrest (the causal hypothesis is based on the effects of influenza infection on the oxygen supply to the myocardium through lung infection and inflammation).

Pulmonary function

The effects of different types of live attenuated cold recombinant influenza vaccination on pulmonary function were assessed by a double-blind placebo-controlled randomised trial on 72 healthy volunteers aged around 26 (Atmar 1990) (data on 17 asthmatics were not extracted). The authors report several non-significant drops in lung function up to seven days post-inoculation and a higher incidence of influenza like illness (17/46 versus 4/26) in the vaccinated arms.

Vaccines for the 1968 to 1969 (H3N2) influenza pandemic (Comparisons 04 to 08)

Five studies yielded 12 data sets (Eddy 1970; Mogabgab 1970a; Mogabgab 1970b; Sumarokow 1971; Waldman 1969a; Waldman 1969b; Waldman 1969c; Waldman 1969d; Waldman 1972a; Waldman 1972b; Waldman 1972c; Waldman 1972d). As one would expect, vaccine performance was poor when content did not match the pandemic strain (Analysis 4). However, one-dose or two-dose monovalent whole-virion (i.e. containing dead complete viruses) vaccines achieved 65% (95% CI 52% to 75%) protection against ILI and 93% (95% CI 69% to 98%) protection against influenza, and 65% (95% CI 6% to 87%) against hospitalisations (Analysis 5). Approximately half a working day lost and half a day of illness were saved but no effect was observed against pneumonia. All comparisons except for influenza-like illness are based on a single study (Analysis 5). The large effect on ILI is coherent with the high proportion of these illnesses caused by influenza viruses in a pandemic (i.e. the gap between efficacy and effectiveness of the vaccines is narrow). Aerosol polyvalent or monovalent vaccines had modest performance (Analyses 6 to 8).

Discussion

Although this review presents a large number of comparisons and outcomes based on a number of different groupings of studies and trials, most of the discussion was based on the results of the analysis of a WHO recommended vaccine against placebo. Parenterally administered influenza vaccines appear significantly better than their comparators and can reduce the risk of developing influenza symptoms by around 4%, if the WHO recommendations are adhered to and the match is right. However, whilst the vaccines do prevent influenza symptoms, this is only one part of the spectrum of "clinical effectiveness" as they reduce the risk of total "clinical" seasonal influenza (i.e. influenza-like illness) symptoms by around 1%. When the results of our analysis are expressed as RD the effect appears minimal. This is remarkable as healthy adults are the population in which inactivated vaccines perform best. We found no evidence that vaccines prevent viral transmission or complications.

It is not possible to give a definite indication on the practical use of live aerosol vaccines, because the assessment of their effectiveness is based on a limited number of studies presenting conflicting results. The effectiveness, according to WHO criteria, appears relatively low. Results regarding inactivated aerosol vaccine are based on the analysis of a few trials reporting only clinical outcomes not directly comparable, owing to non-homogeneous definitions. It does not seem wise to draw conclusions from these data. Rates of complications caused by influenza in these trials were very low and analysis of the few trials which contained this outcome, did not reveal a significant reduction with the influenza vaccine. This result appears to contrast with assertions of policy makers (ACIP 2006) and may be due to the general rarity of complications caused by respiratory infection in healthy adults. Hospitalisation was assessed in four trials and did not show a significant benefit from vaccination. Working days lost in placebo recipient and vaccine recipients were significantly reduced in the vaccinated group, but by less than half a day on average.

Inactivated vaccines cause local (redness, induration) and systemic harms (myalgia, possibly fatigue). In rare cases there may be an increased risk of GBS, of ORS and Bell's palsy but this may be product-specific. Given the low effectiveness of the aerosol vaccines, the effects classified as harms (sore throat and cough) may be caused by influenza. Although the possibility of causing serious harm may be rare, it must be born in mind when proposing the inception of a mass campaign of immunisation to a whole population, i.e. when exposure to the vaccines is increased.

While the parenteral vaccine efficacy against seasonal (i.e. non-pandemic) influenza is around 75% for the WHO recommended and matched strain, its impact on the global incidence of clinical cases of influenza (i.e. ILI) is limited (around 16% in best case scenario). The universal immunisation of healthy adults should achieve a number of specific goals: reducing the spread of the disease, reducing the economic loss due to working days lost and reducing morbidity and hospitalization. None of the studies included in the review presented results evaluating the ability of this vaccination to interrupt the spread of the disease. Some studies presented data on reduction of working days lost and showed a very limited effect. Similarly a very limited effect was found on morbidity and no effect was found on hospitalization. Given the limited availability of resources for mass immunisation, the use of influenza vaccines should be primarily directed where there is clear evidence of benefit.

Whole-virion monovalent inactivated vaccines may help control a pandemic, if the antigenic match between virus and vaccine is right. Although this observation is based on a limited number of old trials, the high effectiveness of the vaccine (i.e. against ILI) would seem to confirm its potential for use. Efforts to update and enhance these vaccines should have priority.

A number of problems should be taken into consideration when interpreting the results of this review.

  1. None of the live aerosol vaccines included in the review were registered.

  2. Methods of vaccine standardisation have changed significantly.

  3. Recent vaccines present significant differences in purity when compared with older ones.

  4. Different doses and schedules were pooled in the analysis

The content and results of previous versions of this review have been extensively misquoted especially in public policy documents (Jefferson 2009c). Two types of common misquotes are the generalisation of evidence from this review to all age and risk groups and the generalisation of estimates of effect to all outcomes (especially complications and deaths). The misquotes then assume that the performance of influenza vaccines is uniform across all age groups and from symptom prevention to all outcomes. Both generalisations are not supported by any evidence and seem to originate from the desire to use our review to support decisions already taken. The misquotes appear to be based on both the abstract and Plain language summary (which is what you would expect from a superficial reading of the review by people with a specific agenda). It is for these reasons that in this 2010 update we have tried to minimise the risk of being misquoted by presenting effects on major outcomes both in RR and RD format and have inserted a general warning on the quality of evidence in the field of influenza vaccines. Recent examples of misquotes of this review come from page 11 of the 2009 ACIP document (ACIP 2009). The 2007 version of the review is indicated as reference 121: “When the vaccine and circulating viruses are antigenically similar, TIV prevents laboratory-confirmed influenza illness among approximately 70% to 90% of healthy adults aged < 65 years in randomised controlled trials (121, 124). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when the vaccine and circulating viruses are well-matched (121, 123). Efficacy or effectiveness against laboratory-confirmed influenza illness was 47% - 77% in studies conducted during different influenza seasons when the vaccine strains were antigenically dissimilar to the majority of circulating strains (117,119,121,124). However, effectiveness among healthy adults against influenza-related hospitalization, measured in the most recent of these studies, was 90% (125)”. There are three subtle manipulations in the text. First, the review is cited with single study references. Second, the impression reading the text is that vaccines have effect against all outcomes when the evidence quoted refers to cases (or symptoms as we call them in this latest update of the review). Third, our review (which only includes RCT evidence of effectiveness) shows no effect on hospitalisations, CDC quote reference 125 which is a 2007 observational study. The CDC authors clearly do not weight interpretation by quality of the evidence, but quote anything that supports their theory.

Summary of main results

Inactivated influenza vaccines decrease the risk of symptoms of influenza and time off work, but their effects are minimal, especially if the vaccines and the circulating viruses are mismatched. There is no evidence that they affect complications or transmission.

Overall completeness and applicability of evidence

Taken alone, the review shows that according to randomised evidence, inactivated vaccines have a small effect in preventing symptoms of influenza and getting workers back to work quicker.

Quality of the evidence

We found evidence from more than 80,000 people in 50 randomised studies. Regardless of quality, all studies fail to report any evidence of effect on complications. The safety evidence base from randomised trials of inactivated vaccines is very small, probably indicating less concern with harms. Inactivated vaccines cause rare major harms which appear to be mostly linked to specific products or lots.

Potential biases in the review process

The review conclusions are uncertain about the safety profile of inactivated vaccines which is a reflection of the size of the evidence base.

Agreements and disagreements with other studies or reviews

We are not aware of other systematic reviews on this topic.

Authors' conclusions

Implications for practice

The results of this review seem to discourage the utilisation of vaccination against influenza in healthy adults as a routine public health measure. As healthy adults have a low risk of complications due to respiratory disease, the use of the vaccine may be only advised as an individual protection measure against symptoms in specific cases.

Implications for research

The major differences in effect size between outcomes highlight the need for careful consideration of the best study design to assess the effects of public health measures such as vaccines. Large studies encompassing several influenza seasons are required to allow assessment of the effect of the vaccines on seemingly rare outcomes such as complications and death.

Acknowledgements

The authors gratefully acknowledge the help received from Drs Brian Hutchison, Alan Hampson, James Irlam, Andy Oxman, Barbara Treacy, Gabriella Morandi, Kathie Clark, Hans van der Wouden, Nelcy Rodriguez, Leonard Leibovici, Mark Jones, Jeanne Lenzer, Janet Wale, Clare Jeffrey, Robert Ware, Roger Damoiseaux, and Maryann Napoli. The original review was funded by the UK Ministry of Defence, the 2004 update was supported by the two Italian Local Health Authorities in which two of the review authors were employed, the 2007 update was funded by the same Local Health Authorities and the UK's Department of Health Cochrane Incentive Scheme. The 2010 update was not funded. Professor Jon Deeks designed and carried out statistical analyses in earlier versions of the review. Finally, the review authors wish to acknowledge Daniela Rivetti and Vittorio Demicheli as previous authors.

Data and analyses

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Comparison 1. Inactivated parenteral vaccine versus placebo or do-nothing
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness2119139Risk Ratio (M-H, Random, 95% CI)0.80 [0.71, 0.89]
1.1 WHO recommended - matching vaccine106984Risk Ratio (M-H, Random, 95% CI)0.70 [0.59, 0.83]
1.2 WHO recommended - vaccine matching absent or unknown912062Risk Ratio (M-H, Random, 95% CI)0.93 [0.79, 1.09]
1.3 Monovalent not WHO recommended - vaccine matching159Risk Ratio (M-H, Random, 95% CI)1.02 [0.28, 3.70]
1.4 Monovalent not WHO recommended - vaccine matching - high dose134Risk Ratio (M-H, Random, 95% CI)0.46 [0.09, 2.30]
2 Influenza1731325Risk Ratio (M-H, Random, 95% CI)0.39 [0.30, 0.52]
2.1 WHO recommended - matching vaccine811285Risk Ratio (M-H, Random, 95% CI)0.27 [0.16, 0.46]
2.2 WHO recommended - vaccine matching absent or unknown610331Risk Ratio (M-H, Random, 95% CI)0.56 [0.41, 0.77]
2.3 Monovalent not WHO recommended - vaccine matching29675Risk Ratio (M-H, Random, 95% CI)0.22 [0.10, 0.52]
2.4 Monovalent not WHO recommended - vaccine matching - high dose134Risk Ratio (M-H, Random, 95% CI)0.11 [0.00, 2.49]
3 Physician visits22308Risk Ratio (M-H, Random, 95% CI)0.87 [0.40, 1.89]
3.1 WHO recommended - matching vaccine11178Risk Ratio (M-H, Random, 95% CI)0.58 [0.37, 0.91]
3.2 WHO recommended - vaccine matching absent or unknown11130Risk Ratio (M-H, Random, 95% CI)1.28 [0.90, 1.83]
4 Days ill44800Mean Difference (IV, Random, 95% CI)-0.29 [-0.72, 0.15]
4.1 WHO recommended - matching vaccine33670Mean Difference (IV, Random, 95% CI)-0.48 [-0.62, -0.34]
4.2 WHO recommended - matching absent or unknown11130Mean Difference (IV, Random, 95% CI)0.66 [0.16, 1.16]
5 Times any drugs were prescribed22308Mean Difference (IV, Random, 95% CI)-0.01 [-0.03, 0.01]
5.1 WHO recommended - matching vaccine11178Mean Difference (IV, Random, 95% CI)-0.02 [-0.04, -0.00]
5.2 WHO recommended - matching absent or unknown11130Mean Difference (IV, Random, 95% CI)0.0 [-0.00, 0.00]
6 Times antibiotic was prescribed22308Mean Difference (IV, Random, 95% CI)-0.02 [-0.03, -0.01]
6.1 WHO recommended - matching vaccine11178Mean Difference (IV, Random, 95% CI)-0.02 [-0.03, -0.01]
6.2 WHO recommended - matching absent or unknown11130Mean Difference (IV, Random, 95% CI)-0.01 [-0.03, 0.01]
7 Working days lost55393Mean Difference (IV, Random, 95% CI)-0.13 [-0.25, -0.00]
7.1 WHO recommended - matching vaccine44263Mean Difference (IV, Random, 95% CI)-0.21 [-0.36, -0.05]
7.2 WHO recommended - matching absent or unknown11130Mean Difference (IV, Random, 95% CI)0.09 [0.00, 0.18]
8 Hospitalisations514877Risk Ratio (M-H, Random, 95% CI)0.89 [0.65, 1.20]
8.1 WHO recommended - matching vaccine22580Risk Ratio (M-H, Random, 95% CI)0.37 [0.12, 1.12]
8.2 WHO recommended - vaccine matching absent or unknown22681Risk Ratio (M-H, Random, 95% CI)0.85 [0.38, 1.91]
8.3 Monovalent not WHO recommended - vaccine matching19616Risk Ratio (M-H, Random, 95% CI)0.96 [0.85, 1.08]
9 Pneumonia22953Risk Ratio (M-H, Random, 95% CI)0.80 [0.13, 4.93]
9.1 WHO recommended - matching vaccine11402Risk Ratio (M-H, Random, 95% CI)0.59 [0.04, 9.43]
9.2 WHO recommended - vaccine matching absent or unknown11551Risk Ratio (M-H, Random, 95% CI)1.01 [0.09, 11.13]
10 Clinical cases (clinically defined without clear definition)45926Risk Ratio (M-H, Random, 95% CI)0.63 [0.41, 0.99]
10.1 WHO recommended - matching vaccine33723Risk Ratio (M-H, Random, 95% CI)0.56 [0.27, 1.16]
10.2 WHO recommended - vaccine matching absent or unknown12203Risk Ratio (M-H, Random, 95% CI)0.83 [0.69, 0.99]
11 Local harms16 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 Local - tenderness/soreness146833Risk Ratio (M-H, Random, 95% CI)3.11 [2.08, 4.66]
11.2 Local - erythema63388Risk Ratio (M-H, Random, 95% CI)4.01 [1.91, 8.41]
11.3 Local - induration2543Risk Ratio (M-H, Random, 95% CI)2.24 [0.48, 10.59]
11.4 Local - arm stiffness150Risk Ratio (M-H, Random, 95% CI)1.62 [0.54, 4.83]
11.5 Local - combined endpoint (any or highest symptom)125171Risk Ratio (M-H, Random, 95% CI)2.87 [2.02, 4.06]
12 Systemic harms13 Risk Ratio (M-H, Random, 95% CI)Subtotals only
12.1 Systemic - myalgia52676Risk Ratio (M-H, Random, 95% CI)1.54 [1.12, 2.11]
12.2 Systemic - fever82775Risk Ratio (M-H, Random, 95% CI)1.17 [0.80, 1.72]
12.3 Systemic - headache83667Risk Ratio (M-H, Random, 95% CI)1.30 [0.84, 2.03]
12.4 Systemic - fatigue or indisposition63456Risk Ratio (M-H, Random, 95% CI)1.37 [0.94, 2.02]
12.5 Systemic - nausea/vomiting31667Risk Ratio (M-H, Random, 95% CI)2.68 [0.55, 13.08]
12.6 Systemic - combined endpoint (any or highest symptom)82603Risk Ratio (M-H, Random, 95% CI)1.29 [1.01, 1.64]
Analysis 1.1.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 1 Influenza-like illness.

Analysis 1.2.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 2 Influenza.

Analysis 1.3.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 3 Physician visits.

Analysis 1.4.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 4 Days ill.

Analysis 1.5.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 5 Times any drugs were prescribed.

Analysis 1.6.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 6 Times antibiotic was prescribed.

Analysis 1.7.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 7 Working days lost.

Analysis 1.8.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 8 Hospitalisations.

Analysis 1.9.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 9 Pneumonia.

Analysis 1.10.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 10 Clinical cases (clinically defined without clear definition).

Analysis 1.11.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 11 Local harms.

Analysis 1.12.

Comparison 1 Inactivated parenteral vaccine versus placebo or do-nothing, Outcome 12 Systemic harms.

Comparison 2. Live aerosol vaccine versus placebo or do-nothing
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness612688Risk Ratio (M-H, Random, 95% CI)0.90 [0.84, 0.96]
1.1 WHO recommended - matching vaccine24254Risk Ratio (M-H, Random, 95% CI)0.92 [0.76, 1.12]
1.2 WHO recommended - vaccine matching absent or unknown38150Risk Ratio (M-H, Random, 95% CI)0.89 [0.82, 0.97]
1.3 Non WHO recommended - vaccine matching absent or unknown1284Risk Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.16]
2 Influenza68524Risk Ratio (M-H, Random, 95% CI)0.38 [0.27, 0.55]
2.1 WHO recommended - matching vaccine24254Risk Ratio (M-H, Random, 95% CI)0.44 [0.24, 0.81]
2.2 WHO recommended - vaccine matching absent or unknown23843Risk Ratio (M-H, Random, 95% CI)0.36 [0.16, 0.82]
2.3 Non WHO recommended - vaccine matching absent or unknown2427Risk Ratio (M-H, Random, 95% CI)0.21 [0.08, 0.56]
3 Complications (bronchitis, otitis, pneumonia)119887Risk Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.24]
3.1 Non WHO recommended - vaccine matching absent or unknown119887Risk Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.24]
4 Influenza cases (clinically defined without clear definition)323900Risk Ratio (M-H, Random, 95% CI)0.89 [0.71, 1.11]
4.1 WHO recommended - matching vaccine11931Risk Ratio (M-H, Random, 95% CI)0.63 [0.49, 0.80]
4.2 WHO recommended - vaccine matching absent or unknown12082Risk Ratio (M-H, Random, 95% CI)1.05 [0.88, 1.25]
4.3 Non WHO recommended - vaccine matching absent or unknown119887Risk Ratio (M-H, Random, 95% CI)0.98 [0.92, 1.05]
5 Local harms11 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Local - upper respiratory infection symptoms6496Risk Ratio (M-H, Random, 95% CI)1.66 [1.22, 2.27]
5.2 Local - cough4852Risk Ratio (M-H, Random, 95% CI)1.24 [0.69, 2.22]
5.3 Local - coryza24782Risk Ratio (M-H, Random, 95% CI)1.56 [1.26, 1.94]
5.4 Local - sore throat55391Risk Ratio (M-H, Random, 95% CI)1.73 [1.44, 2.08]
5.5 Local - hoarseness1306Risk Ratio (M-H, Random, 95% CI)1.21 [0.51, 2.83]
5.6 Local - combined endpoint (any or highest symptom)34921Risk Ratio (M-H, Random, 95% CI)1.56 [1.31, 1.87]
6 Systemic harms6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Systemic - myalgia3713Risk Ratio (M-H, Random, 95% CI)2.28 [0.81, 6.45]
6.2 Systemic - fever3713Risk Ratio (M-H, Random, 95% CI)1.28 [0.43, 3.79]
6.3 Systemic - fatigue or indisposition2413Risk Ratio (M-H, Random, 95% CI)1.52 [0.66, 3.49]
6.4 Systemic - headache1370Risk Ratio (M-H, Random, 95% CI)2.33 [0.52, 10.33]
6.5 Systemic - combined endpoint (any or highest symptom)51018Risk Ratio (M-H, Random, 95% CI)1.40 [0.82, 2.38]
Analysis 2.1.

Comparison 2 Live aerosol vaccine versus placebo or do-nothing, Outcome 1 Influenza-like illness.

Analysis 2.2.

Comparison 2 Live aerosol vaccine versus placebo or do-nothing, Outcome 2 Influenza.

Analysis 2.3.

Comparison 2 Live aerosol vaccine versus placebo or do-nothing, Outcome 3 Complications (bronchitis, otitis, pneumonia).

Analysis 2.4.

Comparison 2 Live aerosol vaccine versus placebo or do-nothing, Outcome 4 Influenza cases (clinically defined without clear definition).

Analysis 2.5.

Comparison 2 Live aerosol vaccine versus placebo or do-nothing, Outcome 5 Local harms.

Analysis 2.6.

Comparison 2 Live aerosol vaccine versus placebo or do-nothing, Outcome 6 Systemic harms.

Comparison 3. Inactivated aerosol vaccine versus placebo or do-nothing
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness41674Risk Ratio (M-H, Random, 95% CI)0.58 [0.40, 0.83]
1.1 WHO recommended - matching vaccine2841Risk Ratio (M-H, Random, 95% CI)0.47 [0.19, 1.13]
1.2 WHO recommended - vaccine matching absent or unknown2833Risk Ratio (M-H, Random, 95% CI)0.63 [0.37, 1.07]
2 Local harms4716Risk Ratio (M-H, Random, 95% CI)1.09 [0.85, 1.40]
2.1 Local - sore throat2151Risk Ratio (M-H, Random, 95% CI)0.82 [0.43, 1.56]
2.2 Local - combined endpoint (any or highest symptom)3565Risk Ratio (M-H, Random, 95% CI)1.15 [0.88, 1.50]
3 Systemic harms41018Risk Ratio (M-H, Random, 95% CI)1.00 [0.77, 1.31]
3.1 Systemic - myalgia2151Risk Ratio (M-H, Random, 95% CI)0.90 [0.36, 2.25]
3.2 Systemic - fatigue or indisposition2151Risk Ratio (M-H, Random, 95% CI)1.40 [0.52, 3.75]
3.3 Systemic - headache2151Risk Ratio (M-H, Random, 95% CI)1.52 [0.85, 2.72]
3.4 Systemic - combined endpoint (any or highest symptom)3565Risk Ratio (M-H, Random, 95% CI)0.83 [0.54, 1.27]
Analysis 3.1.

Comparison 3 Inactivated aerosol vaccine versus placebo or do-nothing, Outcome 1 Influenza-like illness.

Analysis 3.2.

Comparison 3 Inactivated aerosol vaccine versus placebo or do-nothing, Outcome 2 Local harms.

Analysis 3.3.

Comparison 3 Inactivated aerosol vaccine versus placebo or do-nothing, Outcome 3 Systemic harms.

Comparison 4. 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness33065Risk Ratio (M-H, Random, 95% CI)0.71 [0.57, 0.88]
1.1 Standard recommended parenteral - non matching - 1 dose32715Risk Ratio (M-H, Random, 95% CI)0.74 [0.57, 0.95]
1.2 Standard recommended parenteral - non matching - 2 doses1350Risk Ratio (M-H, Random, 95% CI)0.66 [0.44, 0.98]
2 Influenza12072Risk Ratio (M-H, Random, 95% CI)0.47 [0.26, 0.87]
2.1 Standard recommended parenteral - non matching12072Risk Ratio (M-H, Random, 95% CI)0.47 [0.26, 0.87]
3 Hospitalisations12072Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.68]
3.1 Standard recommended parenteral - non matching12072Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.68]
4 Pneumonia12072Risk Ratio (M-H, Random, 95% CI)1.01 [0.14, 7.17]
4.1 Standard recommended parenteral - non matching12072Risk Ratio (M-H, Random, 95% CI)1.01 [0.14, 7.17]
Analysis 4.1.

Comparison 4 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 1 Influenza-like illness.

Analysis 4.2.

Comparison 4 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 2 Influenza.

Analysis 4.3.

Comparison 4 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 3 Hospitalisations.

Analysis 4.4.

Comparison 4 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 4 Pneumonia.

Comparison 5. 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness44580Risk Ratio (M-H, Random, 95% CI)0.35 [0.25, 0.48]
1.1 WHO recommended parenteral - matching vaccine - 1 dose44226Risk Ratio (M-H, Random, 95% CI)0.35 [0.23, 0.53]
1.2 WHO recommended parenteral - matching vaccine - 2 doses1354Risk Ratio (M-H, Random, 95% CI)0.35 [0.22, 0.57]
2 Influenza11923Risk Ratio (M-H, Random, 95% CI)0.07 [0.02, 0.31]
2.1 WHO recommended parenteral - matching vaccine11923Risk Ratio (M-H, Random, 95% CI)0.07 [0.02, 0.31]
3 Hospitalisations11923Risk Ratio (M-H, Random, 95% CI)0.35 [0.13, 0.94]
3.1 WHO recommended parenteral - matching vaccine11923Risk Ratio (M-H, Random, 95% CI)0.35 [0.13, 0.94]
4 Pneumonia11923Risk Ratio (M-H, Random, 95% CI)0.59 [0.05, 6.51]
4.1 WHO recommended parenteral - matching vaccine11923Risk Ratio (M-H, Random, 95% CI)0.59 [0.05, 6.51]
5 Working days lost11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]
5.1 WHO recommended parenteral - matching vaccine11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]
6 Days ill11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]
6.1 WHO recommended - matching vaccine11667Mean Difference (IV, Random, 95% CI)-0.45 [-0.60, -0.30]
Analysis 5.1.

Comparison 5 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 1 Influenza-like illness.

Analysis 5.2.

Comparison 5 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 2 Influenza.

Analysis 5.3.

Comparison 5 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 3 Hospitalisations.

Analysis 5.4.

Comparison 5 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 4 Pneumonia.

Analysis 5.5.

Comparison 5 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 5 Working days lost.

Analysis 5.6.

Comparison 5 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 6 Days ill.

Comparison 6. 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness21000Risk Ratio (M-H, Random, 95% CI)0.66 [0.46, 0.95]
1.1 Inactivated polyvalent aerosol vaccine versus placebo - non matching - 1 dose2644Risk Ratio (M-H, Random, 95% CI)0.64 [0.32, 1.27]
1.2 Inactivated polyvalent aerosol vaccine versus placebo - non matching - 2 doses1356Risk Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.97]
Analysis 6.1.

Comparison 6 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo, Outcome 1 Influenza-like illness.

Comparison 7. 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza-like illness21009Risk Ratio (M-H, Random, 95% CI)0.54 [0.32, 0.91]
1.1 Inactivated monovalent aerosol vaccine versus placebo - matching - 1 dose2650Risk Ratio (M-H, Random, 95% CI)0.49 [0.17, 1.41]
1.2 Inactivated monovalent aerosol vaccine versus placebo - matching - 2 doses1359Risk Ratio (M-H, Random, 95% CI)0.57 [0.38, 0.86]
Analysis 7.1.

Comparison 7 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo, Outcome 1 Influenza-like illness.

Comparison 8. 1968 to 1969 pandemic: live aerosol vaccine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Influenza cases (clinically defined without clear definition)119887Risk Ratio (M-H, Random, 95% CI)0.98 [0.92, 1.05]
1.1 Non-matching119887Risk Ratio (M-H, Random, 95% CI)0.98 [0.92, 1.05]
2 Complications (bronchitis, otitis, pneumonia)119887Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.24]
2.1 Non-matching119887Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.24]
Analysis 8.1.

Comparison 8 1968 to 1969 pandemic: live aerosol vaccine versus placebo, Outcome 1 Influenza cases (clinically defined without clear definition).

Analysis 8.2.

Comparison 8 1968 to 1969 pandemic: live aerosol vaccine versus placebo, Outcome 2 Complications (bronchitis, otitis, pneumonia).

Appendices

Appendix 1. MEDLINE search strategy for 2004 update

MEDLINE
#1 ("Influenza Vaccine/administration and dosage"[MeSH] OR "Influenza Vaccine/adverse effects"[MeSH] OR "Influenza Vaccine/contraindications"[MeSH] OR "Influenza Vaccine/immunology"[MeSH] OR "Influenza Vaccine/metabolism"[MeSH] OR "Influenza Vaccine/radiation effects"[MeSH] OR "Influenza Vaccine/therapeutic use"[MeSH] OR "Influenza Vaccine/toxicity"[MeSH]) OR ("Influenza/epidemiology"[MeSH] OR "Influenza/immunology"[MeSH] OR "Influenza/mortality"[MeSH] OR "Influenza/prevention and control"[MeSH] OR "Influenza/transmission"[MeSH])
#2 (influenza vaccin*[Title/Abstract]) OR ((influenza [Title/Abstract] OR flu[Title/Abstract]) AND (vaccin*[Title/Abstract] OR immuni*[Title/Abstract] OR inoculati*[Title/Abstract] OR efficacy[Title/Abstract] OR effectiveness[Title/Abstract])
#3 #1 OR #2
# 4 "Randomized Controlled Trial"[Publication Type] OR "Randomized Controlled Trials"[MeSH] OR "Controlled Clinical Trial"[Publication Type] OR "Controlled Clinical Trials"[MeSH] OR "Random Allocation"[MeSH] OR "Double-Blind Method"[MeSH] OR "Single-Blind Method"[MeSH]
#5 controlled clinical trial*[Title/Abstract] OR randomised controlled trial*[Title/Abstract] OR clinical trial*[Title/Abstract] OR random allocation[Title/Abstract] OR random*[Title/Abstract] OR placebo[Title/Abstract] OR double - blind[Title/Abstract] OR single - blind[Title/Abstract] OR RCT[Title/Abstract] OR CCT[Title/Abstract] OR allocation[Title/Abstract] OR follow - up[Title/Abstract]
#6 #4 OR #5
#7 #3 AND #6

Appendix 2. MEDLINE (PubMed) search strategies for 2010 update

#1   "Influenza Vaccines"[MeSH] OR ("Influenza, Human/complications"[MeSH] OR "Influenza, Human/epidemiology"[MeSH] OR "Influenza, Human/immunology"[MeSH] OR "Influenza, Human/mortality"[MeSH] OR "Influenza, Human/prevention and control"[MeSH] OR "Influenza, Human/transmission"[MeSH])

#2 ((influenza vaccin*[Text Word]) OR ((influenza [Text Word] OR flu[Text Word]) AND (vaccin*[Text Word] OR immuni*[Text Word] OR inoculation*[Text Word] OR efficacy[Text Word] OR effectiveness[Text Word])))

#3   #1 OR #2

#4   randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) AND humans [mh]

#5   ("cross over" OR "crossover" OR "Follow Up") OR ("Cross-Over Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR "Prospective Studies"[MeSH]) OR ("time series" OR "interrupted time series") OR (placebo* OR random* OR "double blind" OR "single blind" OR clinical trial* OR trial design) OR ("Case-Control Studies"[MeSH] OR (cases[Title/Abstract] AND controls[Title/Abstract])) OR ("Cohort Studies"[MeSH] OR cohort*) OR ("Comparative Study"[Publication Type]) OR ("before after"[Title/Abstract] OR "before-after"[Title/Abstract] OR "before/after"[Title/Abstract] OR "before and after"[Title/Abstract]) OR (volunteer*[Title/Abstract]) OR (control*[Text Word] AND evaluation[Text Word])

#6   #4 OR #5

#7  #3 AND #6

Appendix 3. EMBASE.com search strategy for 2010 update

#1 'influenza vaccine' /exp OR 'influenza vaccine' OR ( influenza OR flu AND ( vaccin* OR immuni* OR inoculat* )) OR 'influenza vaccine' /syn OR ( 'influenza' /exp AND 'vaccine' /exp)

#2 'case control study' /syn OR 'case control' :de,ab,ti OR ( cases :ab,ti AND controls :ab,ti) OR 'cohort analysis' /syn OR 'cohort study' :de,ab,ti OR 'study cohort' :de,ab,ti OR prospectiv* :ab,ti OR volunteer* :ab,ti OR observational :ab,ti OR 'clinical trial' :it OR 'randomized controlled trial' :it OR 'drug therapy' /exp OR 'drug therapy' :de OR randomized :ab,ti OR randomised :ab,ti OR placebo :ab,ti OR randomly :ab,ti OR trial :ab,ti OR groups :ab,ti

#3 'clinical trial' :it OR 'randomized controlled trial' :it OR 'drug therapy' /exp OR 'drug therapy' :de OR randomized :ab,ti OR randomised :ab,ti OR placebo :ab,ti OR randomly :ab,ti OR trial :ab,ti OR groups :ab,ti

#4 'clinical trial' :it OR 'randomized controlled trial' :it OR 'randomized controlled trial' /exp OR 'randomization' /exp OR 'single blind procedure' /exp OR 'double blind procedure' /exp OR 'clinical trial' /exp OR 'clinical' NEAR/0 'trial' OR 'clinical trial' OR ( singl* OR doubl* OR trebl* OR tripl* AND ( mask* OR blind* )) OR 'placebo' /exp OR placebo* OR random* OR 'control group' /exp OR 'experimental design' /exp OR 'comparative study' /exp OR 'evaluation study' OR 'evaluation studies' /exp OR 'follow up' /exp OR 'prospective study' /exp OR control* OR prospectiv* OR volunteer* AND [humans]/lim

#5 #2 OR #3 OR #4

#6 #1 AND #5

#7 #1 AND #5 AND [humans]/lim AND [embase]/lim

Appendix 4. Glossary

Efficacy

the impact of an intervention (drug, vaccines etc) on a problem or disease in ideal conditions - in this case the capacity of vaccines to prevent or treat influenza and its complications.

Effectiveness

the impact of an intervention (drug, vaccines etc) on a problem or disease in field conditions - in this case the capacity of vaccines to prevent or treat ILI and its complications.

Influenza

an acute respiratory infection caused by a virus of the Orthomyxoviridae family. Three serotypes are known (A, B and C). Influenza causes an acute febrile illness with myalgia, headache and cough. Although the median duration of the acute illness is three days, cough and malaise can persist for weeks. Complications of influenza include otitis media, pneumonia, secondary bacterial pneumonia, exacerbations of chronic respiratory disease and bronchiolitis in children. These illnesses may require treatment in a hospital and can be life-threatening especially in 'high-risk' people e.g. the elderly and people suffering from chronic heart disease. Additionally, influenza can cause a range of non-respiratory complications including febrile convulsions, Reye's syndrome and myocarditis. The influenza virus is composed of a protein envelope around an RNA core. On the envelope are two antigens: neuraminidase (N antigen) and hemagglutinin (H antigen). Hemagglutinin is an enzyme that facilitates the entry of the virus into cells of the respiratory epithelium, while neuraminidase facilitates the release of newly produced viral particles from infected cells. The influenza virus has a marked propensity to mutate its external antigenic composition to escape the hosts' immune defences. Given this extreme mutability, a classification of viral subtype A based on H and N typing has been introduced. Additionally, strains are classified on the basis of antigenic type of the nucleoprotein core (A, B ), geographical location of first isolation, strain serial number and year of isolation. Every item is separated by a slash mark (e.g. A/Wuhan/359/95 (H3N2)). Unless otherwise specified such strains are of human origin. The production of antibodies against influenza beyond a conventional quantitative threshold is called seroconversion. Seroconversion in the absence of symptoms is called asymptomatic influenza.

Influenza-like illness (ILI)

an acute respiratory illness caused by scores of different viruses (including influenza A and B) presenting with symptoms and signs which are not distinguishable from those of influenza. ILI does not have documented laboratory isolation of the causative agent and is what commonly presents to physicians and patients (also known as the flu").

Feedback

Inconsistency between results and abstract

Summary

We feel there is some inconsistency between results and abstract of this review regarding off work time.

In the results it states that 0.4 days are saved, but that this result is not statistically significant. In the abstract, however, this difference is labelled significant. Can you help us in understanding this?

I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms.
JC van der Wouden
Feedback added 16/04/07

Reply

The difference is statistically significat as it says in the abstract. In the results the word "statistical" has been used instead of "clinical". Indeed the meaning of the comment was to underline that, although statistically significant, a difference of 0.4 day is clinically inconsistent.

Contributors

Vittorio Demicheli

Comments regarding the conclusion

Summary

Your conclusion is confusing. You write: "Universal immunization of healthy adults is not supported by the results of this review." If so, why the first sentence? You wrote in the Discussion that "serologically confirmed cases of influenza are only part of the spectum of clinical effectiveness." Furthermore, it would be helpful if you had explained the difference between influenza and influenza-like illness in the abstract. Also, the title of the synopsis is inaccurate. Why say "not enough evidence" when there are so many trials in your review? It should read: Clinical trials do not support the universal recommendation, etc. And "by a quarter" is not going to be understood by the general public. Please put in absolute terms.

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.

Maryann Napoli
Feedback added 05/04/06

Reply

This comment has been superseded and addressed by the 2006 latest update.

Contributors

The review authors

Vaccines for preventing influenza in healthy adults, 13 May 2013

Summary

There seems to be an inconsistency in the presentation of the Cochrane Summary: "Vaccines to prevent influenza in healthy adults". The Plain language summary states that "Vaccine use did not affect the number of people hospitalised or working days lost", but under Main Results we read that "Vaccination had a modest effect on time off work and had no effect on hospital admissions". These two claims seem to be at odds regarding working days/time lost.

I agree with the conflict of interest statement below:
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.

Robyn Kath

What's new

DateEventDescription
24 May 2013Feedback has been incorporatedFeedback comment added to the review. The review authors will address the comment when they update the review.

History

Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1999

DateEventDescription
3 June 2010New search has been performedSearches conducted. For this update we screened 3729 titles and identified 44 studies for possible inclusion. We included two new trials (Beran 2009a; Beran 2009b) and excluded three new trials (Belongia 2009; Chou 2007; Khazeni 2009).
11 March 2010New citation required but conclusions have not changedFor this update Eliana Ferroni (EF), Lubna Al Ansari and Ghada Bawazeer joined as new authors. Carlo Di Pietrantonj (CDP), Alessandro Rivetti (AR) and Tom Jefferson (TJ) remained.
10 May 2009AmendedContact details updated.
26 April 2008AmendedConverted to new review format.
15 April 2007Feedback has been incorporatedFeedback comment added to review.
20 November 2006New citation required and conclusions have changedSubstantive amendment. For the 2006 update we included 30 new studies but tightened up our inclusion criteria, excluding studies with influenza B vaccine as a control. These do not come within our comparator rules of placebo or do-nothing. Twenty two of the new included studies were clinical trials evaluating efficacy and / or safety of different type of influenza vaccines.
We also carried out a subanalysis of the five 1968 to 1969 pandemic trials (with numerous subtrials) in our dataset. Finally, we included more data (ten studies) on potential serious or rare harms, looking also at non-randomised evidence.
4 April 2006Feedback has been incorporatedFeedback commented added to review.
10 January 2006New search has been performedSearches conducted.
1 December 2003New search has been performedSearches conducted. In the 2004 update we included five more studies which were not identified by the original searches and we updated text and references. We also assessed and excluded 25 more studies. The random-effects model was used for analysing all the comparisons and outcomes. The updated results and conclusions of our review do not change much.
27 December 1997New search has been performedSearches conducted. Review first published Issue 4, 1999.

Contributions of authors

For the 2010 update Tom Jefferson (TJ) and Eliana Ferroni (EF) designed the update.
Alessandro Rivetti (AR) carried out the searches and preliminary screening of references.
TJ and LAA applied inclusion criteria.
TJ, LAA, EF and GB extracted data.
Carlo Di Pietrantonj (CDP) arbitrated and checked the data extraction.
CDP performed the meta-analysis and carried out statistical testing.
TJ and AR wrote the final report.
All review authors contributed to both the protocol and final report.

Statistical support to previous review versions was provided by JJ Deeks.

Declarations of interest

TJ owned shares in GlaxoSmithKline and has received consultancy fees from Sanofi-Synthelabo (2002) and Roche (1997 to 1999). All other review authors have no conflicts to declare.

Sources of support

Internal sources

  • ASL 19 and 20, Piemonte, Italy.

External sources

  • Ministry of Defence, UK.

  • NHS Dept of Health Cochrane Incentive Scheme, UK.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Atmar 1990

MethodsDouble-blind placebo-controlled randomised trial
Participants74 healthy volunteers aged 18 to 40 years (data on 17 asthmatics were not extracted)
InterventionsCold - recombinant vacc. A (H1N1); n = 16
versus
Cold - recombinant vacc. A (H3N2); n = 13
versus
Cold - recombinant vacc. B; n = 17
versus
Placebo; n = 26
Intranasal
OutcomesPulmonary function tests (performed on day 0, 3 to 4, 7 after vaccination):
- Forced respiratory volume in 1 second (FEV1)
- Forced expiratory vital capacity (FVC)
- FEV1/FVC
- Forced expiratory flow rate 25 to 75% (FEF 25 to 75)
NotesThe authors report several non-significant drops in FEV and FVC up to 7 days post inoculation and a higher incidence of ILI (17/46 versus 4/26) in the vaccinated arms. Safety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Beran 2009a

MethodsRandomised double blind, placebo controlled study conducted in Czech Republic during the 2005 to 2006 influenza season. This was defined retrospectively as starting the first week with two culture-confirmed cases in the study area and ending the last week with one culture-confirmed case in the study area. Randomisation was generated by GSK (sponsor) using SAS program, in 2:1 blocking scheme using a minimisation procedure (no explanation of why to use such method or ratio). Allocation concealment method was not explicitly mentioned. However, authors mentioned that placebo and vaccine treatments were indistinguishable in appearance and that blinding to treatment assignment was maintained until study analysis
ParticipantsSelf-referred healthy adults (n = 6203), predominately Caucasian (99.8%), aged between 18 and 64 years (mean 35 + 13 years) of both genders (TIV group: F 55.3%, placebo group: F 54.2%) and with no history of influenza vaccination within the last 3 influenza seasons. A subset of participants who were randomly selected for vaccine safety and reactogenicity were given a calibrated thermometer and a diary card to record symptoms. The method of selection of this subset was not explained. Use of antimicrobial/influenza antiviral therapy seem to be allowed but was not quantified
Interventions

TIV vaccine: 0.5 ml single dose by IM injection or placebo (normal saline) administered intramuscularly. Use of more than one lot was not reported.

TIV contain hemagglutinin antigens of

  • A/New Caledonia/20/99 (H1N1) IVR-116 virus as an A/New Caledonia/20/99-like strain

  • A/New York/55/2004 (H3N2) X-157 virus as an A/California/7/2004-like strain

  • B/Jiangsu/10/2003 virus as a B/Shanghai/361/2002-like strain.

Two modes of surveillance were used.
Passive: started on the day of vaccination, participants self report through a toll free number of ILI symptoms
Active: started 2 weeks after vaccination day: a biweekly telephone contact of the subjects by someone (not clear who) for ILI symptoms

It is not clear if the surveillance included the entire cohort or just a subset, or why the authors did carry out harms surveillance using the 2 surveillance methods already in-place

Outcomes

Serological

Blood samples were collected for the specified subset and were tested/analyzed at GSK Biologicals SSW Dresden, Germany

Blood sample obtained prior to vaccination and at 21 days following vaccination. Serum samples were stored at -20°C until blinded analyses were conducted

Hemagglutination-inhibition test was done using chicken red blood cells with the three virus strains present in the TIV used as antigens. The serum titre was expressed as the reciprocal of the highest dilution that showed complete inhibition of hemagglutination

Serology was not a primary outcome in this study

Effectiveness

Incidence of culture-confirmed ILI (primary outcome, reported as the attack rate in the efficacy cohort)

Nasal and throat swab collected by a nurse on the same day

swab samples were stored at 28°C and transferred within 5 days of the onset of ILI symptoms

Sample sent to the National Reference Laboratory for Influenza (NRL, Prague, Czech Republic) for conventional influenza virus culture using Madin Darby Canine Kidney (MDCK) cells

Confirmation of influenza A or B was determined using the following:

  • hemagglutination assay with turkey and guinea pig erythrocytes

  • hemagglutination inhibition was used to identify virus type, subtype and drift variant

  • direct immunoperoxidase assay using anti-influenza A and anti-influenza B nucleoprotein antibodies

There were 814 reported ILI episodes, only 46 gave positive culture 

Clinical

Incidence of ILI symptoms (secondary outcome, reported as attack rate in the ATP cohort)

IL was defined as fever (oral temperature greater or equal to 37.8°C) plus cough and/or sore throat. An ILI episode was defined as the period from the first day of ILI symptoms until the last day of ILI symptoms. A new episode was taken into account only after the complete resolution of the previous one. To count as a separate episode at least 7 days free of any symptoms should pass

Number of events was 370 reported events (254 in TIV and 120 in placebo)

Number of subjects reporting at least one event (240 in TIV and 113 in placebo) was used to calculate the attack rate

Reasons to exclude from the ATP cohort include:

  • protocol violation (inclusion/exclusion criteria): seems that the selected subset have certain criteria but not mentioned by the authors

  • underlying medical condition: not specified what? Or why not excluded from the efficacy cohort as well since participants are reported to be healthy

  • forbidden by the protocol: protocol not clear

  • subjects not exposed during the influenza season: not understood what it meant (did the patient travel after getting the study treatment?)

Immunogenicity: blood sample obtained prior to vaccination and at 21 days following vaccination. Performed only for a subset of patient not all efficacy cohort

Safety

Data on serious adverse events (SAEs) began at the receipt of vaccine/placebo and continued until the end of the study.  However safety was solicited from a subset of subjects (no mention of method used to randomly select them, no justification for not collecting SAEs from all participants, especially with the presence of two surveillance methods)

Reactogenicity:  defined as the presence and intensity of the following symptoms within 4 days of vaccination: pain, redness and swelling (found to occur more in the TIV group) other general symptoms of fatigue, fever, headache, muscle aches, shivering and joint pain (found to occur more in the TIV group)

The intensities of adverse events were recorded according to a standard 0 to 3 grade scale: "absent", "easily tolerated", "interferes with normal activity" and "prevents normal activity"

NotesThe authors report that due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear risk

Generation of allocation schedule

b) computer random-number generator                     

Concealment of treatment allocation

No explicit description of the method of concealment, authors only mentioned that treatments were numbered and that they were indistinguishable in appearance)

Exclusion of allocated participants from the analysis of the trial

a) Did the report mention explicitly the exclusion of allocated

participants from the analysis of trial results? Yes

b) If so did the report mention the reason(s) for exclusion?

yes, details were reported in the study flow chart. Of the 6213 enrolees, 10 were excluded because the identification number assigned to the same 4 subjects who were

Measures to implement double blinding 

a) Did the report mention explicitly measures to implement and protect double blinding? No, authors reported that the blinding assignment was maintained until study analysis 

b) Did the author(s) report on the physical aspect of compound administration - (i.e. appearances, colour, route administration). Authors mentioned the treatments were indistinguishable in appearance 

Medium risk of bias. Basis for selection of follow up and allocation concealment not described

Beran 2009b

Methods

A randomised, double-blind, placebo-controlled study conducted during the 2006 to 2007 influenza season at 15 centres located in the Czech Republic and Finland. The protocols and study documents were approved by the ethics committee of each country. Participants were randomised to receive 1 dose of TIV (lot 1 or lot 2 of Fluarix) or placebo (normal saline solution) at the first study visit (day 0) by intramuscular injection. Each 0.5 mL dose of TIV contained 15 mg of each of the hemagglutinin antigens of strains A/New Caledonia/20/99(H1N1) IVR-116, A/Wisconsin/67/2005(H3N2), and B/Malaysia/2506/2004 (from the Victoria lineage). 

From the day of vaccination, passive and active surveillance (biweekly contact) to detect ILI cases. For each case of suspected ILI, a nasal and throat swab specimen (composed of a swab of both nasal sinuses and a second swab of the throat) was collected for culture (as much as possible on the same day as the ILI report and, at the latest, 5 days after the ILI onset). Each subject was provided with a calibrated thermometer to measure temperature and a diary card to record temperatures and symptoms during the ILI episode. Blinded analysis was carried out at GSK biologicals in Dresden, Germany.

Blood samples for the evaluation of influenza vaccine immunogenicity were obtained from  the randomly selected, planned subset of ?500 participants just prior to vaccination and 21-28 days later. Frozen aliquots of culture supernatants from positive viral cultures were sent to J. Treanor’s laboratory  University of Rochester Vaccine Evaluation Unit Influenza Serology Laboratory, Rochester, New York) for identification of virus-matching isolates by  conventional hemagglutination-inhibition testing (using H1 and H3 antisera from the CDC and B/Malaysia antiserum from the WHO)

Participants

Eligible participants were:

  • self-referred women or men who were

  • between 18 and 64 years of age

  • who had no significant clinical disease at the time of vaccination

Who provided written informed consent

Interventions

Intervention 1 dose of TIV (lot 1 or lot 2 of Fluarix), IM injection, at the first day of the study (Day 0).
Each 0.5 mL dose of TIV contained 15 mg of each of the hemagglutinin antigens of strains A/New/Caledonia/20/99(H1N1) IVR-116, A/Wisconsin/67/2005(H3N2), and B/Malaysia/2506/2004 (from the Victoria lineage).

Comparator placebo (normal saline solution), IM injection, at the first day of the study (Day 0)

Outcomes

Serological  (only carried out for the TIV group)

Effectiveness 

Evaluate efficacy of TIV versus placebo in the prevention of culture-confirmed influenza A and/or B due to strains antigenically matched to the vaccine (their primary objective) .

Secondary objectives

  • Evaluation of TIV in the prevention of culture-confirmed influenza due to strains antigenically matched to the vaccine for  each of the 2 vaccine lots

  • Evaluation of TIV in the prevention of culture-confirmed Influenza A and/or B attributable to any influenza A or B strain

  • Evaluation of TIV in the prevention of ILI which was less-stringently- defined as at least 1 systemic symptom (fever and/or myalgia) and 1 respiratory symptom (cough and/or sore throat).

Safety vaccine reactogenicity and immunogenicity in a random subset of subjects by obtaining blood samples prior to vaccination and 21-28 days later. However, no harms data are reported

NotesThe authors conclude that TIV is efficacious against culture-confirmed influenza in healthy adults
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear risk

No details provided of either randomisation or allocation concealment. There is no mention of appearance of the injection content.

Attrition reasons for the whole cohort are as follows

  • Administration of vaccines forbidden in the protocol

  • Administration of medication forbidden in the protocol

  • Underlying medical condition forbidden by the protocol

  • Subjects not exposed during the influenza season

  • Randomisation code broken at the investigation site

  • Protocol violation (inclusion/exclusion criteria)

The additional stated reasons for the 'Safety' subset study:

  • Non compliance with blood sampling

Essential serological data missing

Betts 1977a

MethodsRandomised controlled trial carried out from April 1976 at Rochester University. Vaccine and placebo were randomly administered in double blind manner, thus any description of allocation procedure is given. Thirty-six days after immunisation all subjects were challenged with wild type virus (A/Victoria/3/75, H3N2) and antibody response determined in serum and nasal secretions (before vaccination, 36 later and 21 days after challenge, not for analysis).
Participants47 healthy male and female university students with absent or low HAI titre (i.e. little or no immunity) to both A/Scotland/74 and A/Victoria/3/75
InterventionsLive attenuated A/Scotland/74 (H3N2) versus placebo, one 0.5 ml-dose intranasal. On day 37 after immunisation subjects were challenged with A/Victoria/3/75
OutcomesA physician examined the subjects 1 day and 4 days after the received vaccine or placebo. Temperature was observed only one day after. Observed symptoms were: Mild sore throat and rhinorrhea : Vacc 4/23 ; placebo 3 /24 ; Fever (Temp > 37.50 °C); none had it
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Boyce 2000

MethodsOpen label/single blind randomised controlled trial to assess safety and immunogenicity of adjuvanted and unadjuvanted subunit influenza vaccine, prepared with the strains recommended for and isolated in the 1997 to 1998 season
Participants74 healthy adults aged between 10 and 40 years, who did not receive influenza immunisation during the 6 months preceding the trial
Interventions1) M-59 adjuvanted subunit trivalent flu vaccine (prepared with A/Bayern/795 H1N1, A/Wuhan/359/95 H3N2, B/Beijing/184/93 -like strains, each 15 mcg/ 0.5 ml-dose)
2) Unadjuvated vaccine (prepared with the same strains at the same concentrations as the adjuvanted preparation)
3) Placebo (consisting of 0.5 ml sterile saline)
All preparation were intranasal administered in two doses 28 days apart. 24 individuals received their first dose of adjuvanted (n = 12) or unadjuvanted (n = 12) subunit vaccine in open label manner. After it was stated that they tolerated the first dose, the randomised phase of the trial (n = 50) was begun. In this phase 18 subjects received two doses of unadjuvanted vaccine, 19 adjuvanted and 13 placebo
OutcomesAfter each immunisation, subjects were observed for 30 minutes, were examined after 2 days and then completed a diary card reporting symptoms occurred within 7 days after. Local reactions: nasal symptoms, unpleasant taste, bloody nasal discharge, sneezing. Systemic reactions: chills, pulmonary, nausea, malaise, myalgia or arthralgia, urticarial rash, headache, Oral temperature >= 38°C, stay at home, due to use of analgesic or antipyretic. Data were not given separately for randomised and open-label phase of the study
NotesIt is not possible to consider separately safety data for the two study phases. Safety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Bridges 2000a

MethodsRandomised controlled trial, double blind conducted in USA during the 1997 to 1998 influenza season. Follow up lasted from November to March. Influenza period was defined as the period during which clinical specimens collected from ill subjects yielded influenza viruses: Dec 8 1997 through Mar 2, 1998 and lasted 12 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random number. Pharyngeal swab and paired sera were collected from ill people
Participants1184 healthy factory employees: 595 treated and 589 placebo. Age of participants was 18 to 64
InterventionsCommercial trivalent, inactivated, intramuscular vaccine. Schedule and dose were not indicated. Vaccine composition was: A/Johannesburg/82/96, A/Nanchang/933/95 and B/Harbin/7/94. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness, influenza, days ill, physician visits, times any drug was prescribed, times antibiotic was prescribed, working days lost, admissions, adverse effects. They were defined as follow: Influenza-like illness: fever = 37.7 °C with cough or sore throat); upper respiratory illness: cough with sore throat or fever = 37.7 °C. Local adverse effects were arm soreness and redness. Systemic adverse effect were: fever, sore throat, coryza, myalgia, headache and fatigue, but authors reported no data. Surveillance was passive
NotesFor analysis we chose the Influenza-like illness definition. ITT was performed. Systemic adverse effects were not reported. Circulating strain was A/Sidney/5/97-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Bridges 2000b

MethodsRandomised controlled trial, double blind conducted in USA during 1998 to 1999 influenza season. Follow up lasted from November to March. The influenza period was defined as the period during which clinical specimens collected from ill subjects yielded influenza viruses: Jan 4, 1998 through Mar 14, 1999 and lasted 10 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random number. Pharyngeal swab and paired sera were collected from ill people
Participants1191 healthy factory employees: 587 treated and 604 placebo. Age of participants was 19 to 64
InterventionsCommercial trivalent, inactivated, intramuscular vaccine. Schedule and dose were not indicated. Vaccine composition was: A/Beijing/262/95, A/Sydney/5/97 and B/Harbin/7/94. Placebo was sterile saline for injection. Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness, influenza, days ill, physician visits, times any drug was prescribed, times antibiotic was prescribed, working days lost, admissions, adverse effects. They were defined as follow: Influenza-like illness: fever = 37.7 °C with cough or sore throat); upper respiratory illness: cough with sore throat or fever = 37.7 °C. Local adverse effects were arm soreness and redness. Systemic adverse effect were: fever, sore throat, coryza, myalgia, headache and fatigue, but authors reported no data. Surveillance was passive
NotesFor analysis we chose the influenza-like illness definition. ITT was performed. Systemic adverse effects were not reported. Circulating strain was A/Sidney/5/97-like and B/Beijing/184/93-like
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Caplan 1977

MethodsRandomised controlled trial to assess reactogenicity and safety of monovalent whole virus- and split virus vaccines prepared with strain A/Victoria/3/75 from different U.S. manufacturer
Participants208 healthy adult volunteers aged between 18 and 64 years, recruited from the University of Maryland, USA
InterventionsMonovalent whole-virus vaccine (Merck Sharp & Dohme, Merrell-National Laboratories) or monovalent split virus vaccine (Parke, Davis and Company ; Wyeth Laboratories) administered in different antigen concentrations (200, 400 or 800 CCA) versus placebo. All from A/Victoria75. One dose intramuscular
OutcomesTemperature >= 100°F (37.8°C) ; feverishness; pain or burning; tenderness; malaise or myalgia; nausea or vomiting; headache; other. 21-day follow up. Safety outcomes are also given in cumulative % for each category : Local, systemic, bothersome; febrile; or scores for systemic reactions
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

DeStefano 2003

MethodsCase control study
ParticipantsData from Vaccine Safety Datalink (large database of cases of disease following vaccination) in the USA
InterventionsImmunisation with influenza and other vaccines assessed by means of medical records
OutcomesCases: Physician diagnosis of multiple sclerosis or optic neuritis in medical record
Controls: Up to 3 controls per case were selected from automated HMO member files, at least 1 year of HMO enrolment, matched on age (within 1 year) and gender
NotesRare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Eddy 1970

MethodsControlled clinical trial, single blind conducted in South Africa during the 1969 influenza season. Follow up lasted from May to July. The first clinical case of influenza appeared on May 21 1969, and the last 6 weeks later. The epidemic period lasted 6 weeks. The control subjects were selected by drawing a 1-in-4 systematic sample from a ranked list of the personnel numbers
Participants1758 healthy male black African employees: 1254 treated and 413 placebo. Age of participants was 18 to 65
InterventionsMonovalent inactivated parenteral vaccine. Schedule and dose were single injection, 1 ml. Vaccine composition was: A2/Aichi/2/68 (Hong Kong variant). Placebo was sterile water. Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness, working days lost, days ill. Influenza-like illness was not defined; case features were generically described in results section. All ill persons were admitted to hospital until recovery. Surveillance was passive
NotesThe word "double blinding" was not used, but the control group received an injection of "dummy vaccine". Poor reporting, poor quality study. Circulating strain was A2/Hong Kong/68 virus
Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskC - Inadequate

Edwards 1994a

MethodsRandomised controlled trial, double blind conducted in USA during 1986 to 1987 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 8 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people
Participants1311 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 872 treated and 439 placebo. Age of participants was 1 to 65
InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107,6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: cold adapted: Texas/1/85 H1N1 and Bethesda/1/85 H3N2; inactivated: Chile/1/83 H1N1 and Mississippi/1/85 H3N2 . Placebo was allantoic fluid. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (only patients who presented for culture were considered); throat culture. Surveillance was passive
NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Taiwan/1/86. Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Edwards 1994b

MethodsRandomised controlled trial, double blind conducted in USA during 1987 to 1988 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 14 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people
Participants1561 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 1029 treated and 532 placebo. Age of participants was 1 to 65
InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107.6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: cold adapted: Kawasaki/9/86 H1N1 and Bethesda/1/85 H3N2; inactivated: Taiwan/1/86 H1N1 and Leningrad/360/86 H3N2. Placebo was allantoic fluid. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (ILI retrospectively reported were considered); fourfold antibody rise between post-vaccination and spring sera. Surveillance was passive
NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Sichuan/2/87 (H3N2) (antigen drift from vaccine strain) and B/Victoria/2/87
Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Edwards 1994c

MethodsRandomised controlled trial, double blind conducted in USA during 1988 to 1989 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 11 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people
Participants1676 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 1114 treated and 562 placebo. Age of participants was 1 to 65
InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107,6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: cold adapted: Kawasaki/9/86 H1N1 and Los Angeles/2/87 H3N2; inactivated: Taiwan/1/86 H1N1 and Sichuan/2/87 H3N2. Placebo was allantoic fluid. Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (ILI retrospectively reported were considered); fourfold antibody rise between postvaccination and spring sera. Surveillance was passive
NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Taiwan/1/86 (H1N1) and B/Yamata/16/88. Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Edwards 1994d

MethodsRandomised controlled trial, double blind conducted in USA during 1989 to 1990 influenza season. Follow up lasted the whole epidemic period. The epidemic period in any study year started on the day that the first influenza A virus isolate was obtained in Nashville and ended on the day that the last isolate was obtained and lasted 11 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Pharyngeal swab and paired sera were collected from ill people
Participants1507 healthy children and adults of metropolitan Nashville. 85% of people were older than 16: 999 treated and 508 placebo. Age of participants was 1 to 65
InterventionsBivalent, live cold adapted, aerosol administered influenza A vaccine and the commercial inactivated intramuscularly administered influenza vaccine. Schedule and dose were: single dose; cold adapted 107-107,6 pfu/ml; inactivated 15 micrograms each strain. Vaccine composition was: Kawasaki/9/86 H1N1 and Los Angeles/2/87 H3N2; inactivated: Taiwan/1/86 H1N1 and Shanghai/11/87 H3N2 . Placebo was allantoic fluid. Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness, influenza. They were defined as follows: fever of abrupt onset with at least one of the following: chills, headache, malaise, myalgia, cough, pharyngitis or other respiratory complaints (ILI retrospectively reported were considered); fourfold antibody rise between postvaccination and spring sera. Surveillance was passive
NotesInfluenza B strain contained in the commercial and monovalent vaccines was not described. Strains used yearly to develop cold adapted and inactivated vaccines were antigenically comparable. Since cold adapted influenza B vaccines were not sufficiently characterised to include in the study, authors used monovalent inactivated influenza B vaccine in all subjects in cold adapted arm and as placebo in the control group of inactivated arm. Only cold adapted comparison was included in analysis. Circulating strain was Shanghai/11/87 (H3N2). Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

El'shina 1996

MethodsRandomised controlled trial
Participants432 healthy subjects aged between 18 and 22 years who did not receive any influenza immunisation during the previous 2 to 3 years
InterventionsPolymer-subunit influenza vaccine "Grippol" prepared with the strains A/Victoria/36/88, Wib - 26 , B/Panama 45/90. Two types containing 5 or 2.5 mcg hemagglutinin of each strain respectively were compared with whole-virion inactivated trivalent vaccine (reference preparation, containing 35 mcg of hemagglutinin) and placebo (consisting of sterile physiological solution). One 0.5-ml dose subcutaneously administered
OutcomesAfter immunisation subjects were placed under medical observation. Fever (48 hours follow up) : weak (37.1 to 37.5°C) , moderate (37.6 to 38.5 °C) , severe (? 38.6 °C).Systemic reactions (3 to 4 days follow up): feeling unwell, sore throat, hyperaemia of nasopharynx, head cold, cough, headache, blocked nose, dizziness, shivering, drowsiness, nausea, hoarseness. Local reaction : All (moderate weak); pain at site of injection
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Evans 1976

MethodsRandomised controlled trial
Participants162 healthy subjects aged 18 to 61 years
InterventionsBivalent live attenuated vaccine WRL 105 (recombinant of A/Okuda/57 and A/Finland/4/74) containing 107.0 EID50 virus/ 0.5 ml dose vs. placebo. Both preparations were administered intranasally 3 to 4 weeks apart
OutcomesReactions to immunisation were observed for 7 days after each dose. Local symptoms (referable to the upper respiratory tract, mainly nasal obstruction, nasal discharge or sore throat) reported as mild moderate or severe. General symptoms (mainly headache fever or myalgia).These two are further reported in different intensity class (mild, moderate, severe, lasting for at least 4 days) reported as mild moderate or severe. Use of analgesics
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Forsyth 1967

MethodsFrom this report, only the first phase of the first trial is of interest for the purposes of this review, in which administration of whole virus, oil adjuvanted influenza vaccine Invirin (GSK) or placebo in semi-randomised allocation. The trial was performed in November to December 1962
ParticipantsMedical students (n = 380) at the Queen's University of Belfast, UK
InterventionsTrivalent aqueous vaccine (Invirin, Glaxo) one 0.25 ml dose I.M. containing strains A/Singapore/1/57, A/England/1/61, B/England/939/59. Placebo (phosphate-buffered saline) was administered as control. Subjects born on odd days were given placebo (n = 186), those born on even days received vaccine (n = 194)
OutcomesLocal reactions: pain, erythema, tenderness, bruises. Stratified by means of scores ranging from 0 to 3 depending on their severity. Systemic reactions: coryza, migraine, paroxysmal tachycardia. All assessed at day 0, 1, 3, 7, 21 after inoculation. Data are referred to a 3-day follow up
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Goodeve 1983

MethodsRandomised controlled trial, double blind
Participants119 healthy young adults from the Medical and Science Faculties of Sheffield University, UK, aged 18 to 19 years without egg allergy
InterventionsPurified subunit monovalent B/Hong Kong/73 flu vaccine prepared in 4 antigen concentration 40, 20, 10, 5 mcg of HA per each 0.5 ml dose VS saline placebo (0.5 ml dose) subcutaneously administered. Participants were divided in 5 groups of equal dimensions (no further description), each group received one of the tested coded preparations. Artificial challenge one month later with live attenuated RB77 virus
OutcomesLocal and systemic reactions were assessed by means of questionnaires completed by participants 24 hours after immunisation. Local reactions (including redness, swelling, itching), local pain (including pain on pressure, pain on contact, continuous pain)
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Hammond 1978

MethodsControlled clinical trial, double blinded conducted in Australia during 1976 influenza season. Follow up lasted the whole epidemic period. Epidemic influenza was defined by virus isolation and serology tests and lasted from middle April to middle August 1976 (17 weeks). Coded identical-looking vials were sequentially administered to enrolled participants. Throat swab was collected from ill people. Serological confirmation was performed on all subjects
Participants225 medical students or staff members: 116 treated and 109 placebo. Age of participants was not indicated
InterventionsTrivalent parenteral subunit vaccine. Schedule and dose were: single dose. Vaccine composition was: 250 IU of A/Victoria/3/75, 250 IU of A/Scotland/840/74 and 300 IU of B/Hong Kong/8/73. Placebo was diphtheria and tetanus toxoids. Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness, influenza. Clinical illnesses were not defined. Influenza was defined as respiratory illness which was associated with the isolation of influenza virus, a four-fold or greater rise in antibody titre occurring between post-vaccination and post-epidemic sera, or both. Surveillance was active
NotesClinical illness was not defined and data were included in analysis as "clinical cases without clear definition". Circulating strain was A/Vic/3/75-like. Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Hrabar 1977

MethodsRandomised controlled trial, double blind, carried out during the season 1976 to 1977
Participants167 students at the technical school in Zagreb, former Republic of Yugoslavia, without sensitivity to egg proteins, pregnancy, acute or chronic diseases
InterventionsCold-adapted recombinant A/Victoria/3/75 vaccine administered in 3 different antigen concentration (107.5, 106.5, 105.5 EID50 /0.5 ml) versus placebo. One 0.5 ml dose intranasal
OutcomesSubjects were medically examined on each of the successive 5 days after immunisation (lasting for at least 1 day). Throat infection, granular palate, oedematous uvula, fever (no cases) as cases and subject-days. For the following outcomes, authors give the total number of observed cases, without indication of the corresponding arm: malaise, swollen tonsils, fever (1), rhinorrhea (1), conjunctivitis (7), laryngitis or hoarseness (3), cough (1), swollen tonsils (1), malaise (1). Surveillance was active
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Kaplan 1982

MethodsSurveillance population-based study conducted in USA, during the 1979 to 1980 and 1980 to 1981 influenza season. The study tested the association between influenza vaccination and Guillan-Barrè Syndrome. Reports form for each case was obtained from neurologists. All case reports were included. Follow up period was 01/09/79 to 31/03/80 and 01/09/80 to 31/03/81
ParticipantsUSA (minus Maryland) adult population, 18 years or older
InterventionsSeasonal parenteral vaccine
OutcomesCases of Guillain-Barré syndrome. Vaccine associated cases were defined as those with onset within the eight-week period after influenza vaccination
NotesVaccination rates in population were obtained from national immunisation survey
Rare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Keitel 1988a

MethodsRandomised controlled trial, double-blind conducted in USA during 1983 to 1984 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined as the interval during which community surveillance recovered influenza viruses from 10% or more of persons with febrile respiratory illness per calendar week (from January 8 to March 17, 1984) and lasted 9 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected
Participants598 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 300 treated and 298 placebo. Age of participants was 30 to 60
InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: single dose; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Philippines/2/82 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore/222/79. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesOutcomes were: ILI, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between post-vaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera
NotesInfluenza-like illness and influenza were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strain was A/Victoria/7/83 (H1N1) and B/USSR/100/83. Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1988b

MethodsRandomised controlled trial, double-blind conducted in USA during 1984 to 1985 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined as the interval during which community surveillance recovered influenza viruses from 10% or more of persons with febrile respiratory illness per calendar week (from January 6 to March 9, 1985) and lasted 9 weeks. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected
Participants697 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 456 treated and 241 placebo. Age of participants was 30 to 60
Interventions456 trivalent, killed whole, intramuscularly administered vaccine: 241 treated and 30 - 60 placebo. Age of participants was: healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies
OutcomesOutcomes were: ILI, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between postvaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was passive
NotesEfficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1993a

MethodsThis paper reports results of two randomised controlled trials carried out in the USA
ParticipantsHealthy volunteers recruited at Texas A&M University and Texas Medical Center, aged between 18 and 40 years
InterventionsTwo 0.5 ml doses of cold adapted recombinant influenza vaccines, 1 month apart , containing 107.1 TCID50 of each strain/dose. Two studies were carried out in which four groups were formed: 1) placebo 1st and 2nd dose. 2) 1st : A/Kawasaki/9/86 (H1N1, CR 125) + A/Bethesda/1/85 (H3N2, CR90) + B/Ann Arbor/1/86 (B, CRB117)
OutcomesMild upper respiratory symptoms. Fever >= 37.8°C within one week after each inoculation
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1993b

MethodsThis paper reports about results of two randomised controlled trials carried out in the USA
ParticipantsHealthy volunteers recruited at Texas A&M University and Texas Medical Center , aged between 18 and 40 years
InterventionsA/Kawasaki/9/86 (H1N1, CR 125, but different lot from 1st) + A/Los Angeles/2/87 (H3N2, CR149) + B/Ann Arbor/1/86 (B, CRB117 but different lot from 1st)3) 1st : A/Kawasaki/9/86 (H1N1, CR125) + A/Bethesda/1/85 (H3N2, CR90)2nd : B/Ann Arbor/1/86 (B, CRB117)4) 1st : B/Ann Arbor/1/86 (B, CRB1172nd : A/Kawasaki/9/86 (H1N1, CR125) + A/Los Angeles/2/87 (H3N2, CR149)
OutcomesMild upper respiratory symptoms. Fever >= 37.8°C Within one week after each inoculation
NotesSee Keitel 1993 a. Safety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1997a

MethodsRandomised controlled trial, double-blind conducted in USA during 1985 to 1986 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined by viral surveillance. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected
Participants830 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 577 treated and 253 placebo. Age of participants was 30 to 60
InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: single dose; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Philippines/2/82 (H3N2), A/Chile/1/83 (H1N1) and B/USSR/100/83. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between post-vaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was active
NotesInfluenza-like illness and influenza cases were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strains were B/Ann Arbor/1/86, A/Mississippi/1/85
Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1997b

MethodsRandomised controlled trial, double-blind conducted in USA during 1986 to 1987 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined by viral surveillance. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected
Participants940 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 723 treated and 217 placebo. Age of participants was 30 to 60
InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: two doses; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Mississippi/1/85/H3N2), A/Chile/1/83 (H1N1) and B/Ann Arbor/1/86 plus A/Taiwan/1/86 (H1N1). Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between postvaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was passive
NotesInfluenza-like illness and influenza cases were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strain was A/Taiwan/1/86. Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Keitel 1997c

MethodsRandomised controlled trial, double-blind conducted in USA during 1987 to 1988 influenza season. Follow up lasted the whole epidemic period. Influenza period was defined by viral surveillance. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers according to prior vaccination experience. Specimens for culture and acute-convalescent blood specimens were obtained from ill people. At spring time volunteers were asked to record any illness occurred during epidemic period and blood specimens were collected
Participants934 healthy employees working in the Texas Medical Center in Houston, Texas, or in surrounding industrial companies: 789 treated and 145 placebo. Age of participants was 30 to 60
InterventionsTrivalent, killed whole, intramuscularly administered vaccine. Schedule and dose were: single dose; 15 micrograms of hemagglutinin of each influenza strains. Vaccine composition was: A/Leningrad/360/86 (H3N2), A/Taiwan/1/86 (H1N1), B/Ann Arbor/1/86. Placebo was sterile saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness, influenza. Illnesses were classified in "any", "flu-like" (lower respiratory and/or systemic illness) and "febrile" (oral temperature of 37.8 or higher). Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between postvaccination (pre-epidemic), acute, convalescent and/or spring (post-epidemic) sera. Surveillance was passive
NotesInfluenza-like illness and influenza cases were detected in three groups: first vaccinated, multi vaccinated and placebo. Febrile illnesses were included in analysis; first two groups cases were added up. Circulating strains were A/Sichuan/1/87, B/Victoria/2/87. Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Langley 2005

MethodsRandomised controlled trial
ParticipantsHealthy adults aged 18 to 50 years
InterventionsInactivated A/New Caledonia/20/99 (H1N1) + A/Panama/2007/99 (H3N2) + B/Guangdong/120/2000 non covalent associated with outer membrane protein of N. meningitidis. Single nasal dose containing 15, 30, 45 mcg versus placebo (phosphate buffered saline) intranasal administered
OutcomesLocal : Within 7 days, graphic - rhinorrhea, congestion, itch/burn, nosebleed, red/puffy eyes, sneezing, sore throat. Systemic : within 7 days - cough, shortness of breath, headache, muscle/joint aches, poor appetite, fatigue within 48 hours, nasal mucosa inflammation, nasal discharge, pharyngeal inflammation, sinusitis, enlarged cervical/post-auricular nodes
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskC - Inadequate

Lasky 1998

MethodsSurveillance population-based study conducted in USA (four 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 01/09/92 to 28/02/93 and 01/09/93 to 28/02/94
ParticipantsApproximately 21 million people, 18 years or older
InterventionsSeasonal parenteral vaccine
OutcomesCases of Guillain-Barré syndrome. Vaccine associated cases were defined a priori as those with onset within the six-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 dialling telephone survey. Rare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Lauteria 1974

MethodsControlled trial. Randomisation procedure was neither described nor mentioned. Subjects were paired according to age and sex , in each pair one individual received vaccine, the other placebo. Double blind
Participants37 volunteers aged 18 to 24 years, with titre of serum neutralising antibodies to A/Hong Kong/8/68 ? 1:16
InterventionsLive attenuated A/England/ 8/68 grown in presence of heated equine serum. Two 0.5 ml doses containing 104 TCID50 of this strain or placebo (0.85% NaCl) were administered intranasally 2 to 3 weeks apart
OutcomesIndividual observed for 4 days, beginning 24 hours after immunisation. Fever, myalgia, rhinitis, cough, pharyngitis
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Leibovitz 1971

MethodsControlled clinical trial conducted in USA during 1969 to 1970 influenza season. The study period was January 30 to May 18. Follow up lasted first seven weeks of training . Influenza was detected from February 11 to May 13 and lasted weeks. Subjects were allocated to vaccine or control group according to the last non-zero digit of the social security number. Blinding was not mentioned. Specimens for culture and acute-convalescent blood specimens were obtained from people hospitalised with acute respiratory disease
Participants9616 military trainees: 1682 treated and 7934 placebo. Age of participants was 18 to 20
InterventionsMonovalent inactivated, experimental, intramuscularly administered vaccine. Schedule and dose were: single dose, 556 CCA. Recombinant virus derived from HK/Aichi/68 and A0/PR8/34 was compared against no vaccination. Vaccine was not recommended but matched circulating strain
OutcomesOutcomes were: hospitalization for upper respiratory infection (without definition), hospitalization for influenza. Laboratory confirmation was based on culture and/or four-fold or greater rise in antibody titre occurred between acute and convalescent sera. Surveillance was passive
NotesRecruitment and immunisation period overlapped outbreak period. Most of the illness were due to adenovirus. Illness during the first one or two weeks after vaccination were not excluded, but authors stated that this fact did not affect the results. Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskC - Inadequate

Mastrangelo 2000

MethodsCase-control study assessing the association between influenza vaccines and cutaneous melanoma
Participants99 cases and 104 controls
InterventionsInfluenza vaccine exposure is not described
Outcomes 
NotesThe authors report a protective effect of repeated influenza vaccination on the risk cutaneous melanoma (OR 0.43, 95% CI 0.19 to 1.00). The study is at high risk of bias because of the selective nature of cases (all patients in the authors' hospital), attrition bias (4 cases and 4 controls eliminated because of "failure to collaborate", recall bias (up to 5 years exposure data were based on patients' recollection) and ascertainment bias (non-blinded exposure survey)
Rare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Mesa Duque 2001

MethodsRandomised controlled trial, double-blind conducted in Columbia during 1997 influenza season. Follow up lasted from March, 15 to August, 31. Influenza period was not defined. Volunteers were randomly allocated to receive vaccine or placebo using a table of random numbers. Double-blind was ensured by pre-labelled, coded identical looking vials. Virologic surveillance was not performed
Participants493 bank employees: 247 treated and 246 placebo. Age of participants was 18 to 60
InterventionsSub-unit inactivated, intramuscularly administered vaccine. Schedule and dose were: single dose. Vaccine composition was: A/Wahan/359/95, A/Texas/36/91 and B/Beijing/184/93. Placebo was vitamin C. Vaccine was recommended and matched circulating strain
OutcomesEpisodes of clinical illness, working days lost (wdl), and adverse effects. Clinical disease was defined as upper respiratory illness (fever, sore throat and cough lasting more than 24 hours) according to ICD IX codes 381, 382, 460, 466, 480 and from 487 to 490. Local adverse effects were oedema, erythema, pain, swelling. Systemic adverse effects were fever, headache and indisposition within 5 days by vaccination. Surveillance was passive
NotesCirculating strains were not isolated from local cases but by WHO and Columbia surveillance system, and matched vaccine components. Wdl were detected all the year round, so they were not included in analysis. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Miller 1977

MethodsRandomised controlled trial
Participants43 seronegative healthy adults aged between 22 and 50 years
InterventionsLive attenuated serum inhibitor resistant flu B vaccine R75 (a recombinant of B/Hong Kong/5/72 with B/Russia/69) containing 107.2 EID50 of R75 / 0.5 ml dose versus placebo (sucrose 5%). Intranasal, 2 doses, 2 weeks apart
OutcomesParticipants were interviewed during the 5 days following each immunisation. Local reaction (defined as immediate complains and comprising bad taste or burning, lasting for few moments). Systemic reaction (consisting essentially in headache and rhinorrhea)
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Mixéu 2002

MethodsRandomised controlled trial, double-blind conducted in Brazil during 1997 influenza season. Follow up lasted 6 to 7 months. Influenza period was not defined. Authors did not describe the methods used to ensure randomisation and blinding. Virologic surveillance was not performed
Participants813 flight crews of an airline company: 405 vaccinated and 408 given placebo. Age of participants was 18 to 64
InterventionsSplit trivalent, intramuscularly administered vaccine. Schedule and dose were: single dose. Vaccine composition was: A/Nanchang/933/95, A/Texas/36/91 and B/Harbin/7/94. Placebo was vaccine diluent . Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness, working days lost. Clinical illness was defined as follow: fever > 37.6°C and cough, headache, myalgia, rhinorrhea, sore throat lasting at least 24 hours. Surveillance was passive
NotesLocal and systemic effects were reported together and therefore not included in the review. Only 294 treated subjects and 299 controls completed follow up. Efficacy data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Mogabgab 1970a

MethodsRandomised study conducted in USA during 1968 to 1969 influenza season. Influenza outbreak lasted 9 weeks, from December 9 to February 3. Randomisation methods were not described. Laboratory confirmation was obtained (by culture or 4-fold antibody titre increase in acute convalescent sera) on 20 men randomly selected each week among the ill
Participants1402 airmen previously unvaccinated: 881 vaccinated and 521 given placebo. Age of participants was 18 to 21
InterventionsMonovalent inactivated parenteral influenza A vaccine. Schedule and dose were: single dose. Vaccine composition was: A2/Aichi 2/68 300 CCA. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesInfluenza-like illness and influenza, complications and admissions. All respiratory illnesses were classified as febrile (38.3°C or greater), afebrile, pharyngitis, bronchitis or pneumonia (complications). Surveillance was passive
NotesCases occurring during the first 15 days after vaccination were not included in analysis. Circulating strain was A2/Hong Kong. Efficacy data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Mogabgab 1970b

MethodsRandomised study conducted in USA during 1968 to 1969 influenza season. Influenza outbreak lasted 9 weeks, from December 9 to February 3 and lasted. Randomisation methods were not described. Laboratory confirmation was obtained (by culture or 4-fold antibody titre increase in acute convalescent sera) on 20 men randomly selected each week among the ill
Participants1551 airmen previously unvaccinated: 1030 vaccinated and 521 given placebo. Age of participants was 18 to 21
InterventionsPolyvalent inactivated influenza A and B vaccine (the 1967 military formula). Schedule and dose were: single dose. Vaccine composition was: A/Swine/33 100 CCA, A/PR8/34 100 CCA, A1/AA/1/57 100 CCA, A2/Taiwan 1/64 400 CCA, B/Lee/40 100 CCA, B/Mass 3/66 200 CCA . Placebo was saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesInfluenza-like illness and influenza cases, complications and admissions. All respiratory illnesses were classified as febrile (38.3°C or greater), afebrile, pharyngitis, bronchitis or pneumonia (complications). Surveillance was passive
NotesCases occurring during the first 15 days after vaccination were not included in analysis. Circulating strain was A2/Hong Kong. Efficacy data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Monto 1982

MethodsRandomised, single blind study conducted in USA during the 1979 to 1980 influenza season. Follow up lasted the whole epidemic period. The epidemic period was defined by first and last isolation (February 11 to march 18) and lasted 5 weeks. Each subject was given a serial number that had previously been assigned randomly by a code to either the vaccine or the placebo group. Specimens for culture were obtained from ill people. At spring time blood specimens were collected
Participants306 students: 154 vaccinated and 152 given placebo. Age of participants was not reported
InterventionsMonovalent, live attenuated, intranasal influenza B . Schedule and dose were: single dose. Vaccine composition was: the vaccine virus, cold recombinant, was produced by recombining the attenuated B/Ann Arbor/1/66 with a wild strain B/Hong Kong/8/73. Placebo was vaccine diluent. Vaccine was not recommended and did not match circulating strain
OutcomesClinical and laboratory confirmed cases and adverse effects. Patients suffered a respiratory illness if they had at least 2 respiratory symptoms. Cases were laboratory confirmed if they had an increase in antibody titre against 3 influenza B virus antigens, i.e. if there was a four-fold increase from an initial sample. Side effects were sore throat, coryza, hoarseness, cough, muscle aches, temperature >100 F occurring during the first three days after vaccination. Surveillance was active
NotesVaccine content was not recommended nor matching. Circulating strain was B/Singapore/79-like and B/Buenos Aires/79-like
Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Mutsch 2004

MethodsOne case-control study and case-series based in the German-speaking regions of Switzerland which assessed the association between an intranasal inactivated virosomal influenza vaccine and Bell's palsy
Participants250 cases that could be evaluated (from an original 773 cases identified) were matched to 722 controls for age, date of clinic visit. All were aged around 50
InterventionsImmunisation with influenza vaccine took place within 91 days before disease onset
Outcomes 
NotesThe study reports a massive increase in risk (adjusted OR 84, 95% CI 20.1 to 351.9) within 1 to 91 days since vaccination. Despite its many limitations (case attrition - 187 cases could not be identified - and ascertainment bias - physicians picked controls for their own cases - confounding by indication - different vaccine exposure rate between controls and the reference population) it is unlikely that such a large OR could have been affected significantly by systematic error. The authors called for larger pre-licence safety trials, given the rarity of Bell's palsy. On the basis of this study the vaccine was withdrawn from commerce
Rare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Nichol 1995

MethodsRandomised controlled trial conducted in the USA during 1994 to 1995 influenza season. Follow up lasted from December 1, 1994 through to March 31, 1995. Influenza period was not defined. Randomisation was performed according to a computer-generated randomisation schedule. Double blinding was ensured by preloaded, coded identical looking syringes. Virologic surveillance was not performed
Participants841 full-time employed: 419 treated and 422 placebo. Age of participants was 18 to 64
InterventionsSubvirion, trivalent, parenteral influenza A and B vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Texas/36/91, A/Shangdong/9/93, B/Panama/45/90. Placebo was vaccine diluent. Vaccine was recommended and matched circulating strain
OutcomesCases (symptom-defined), working days lost because of respiratory illness, side effects. Patients were defined as cases if they had at least one upper respiratory illness (a sore throat associated with either fever or cough that lasted at least 24 hours). Local adverse effects were defined as arm soreness. Systemic adverse effects were defined as fever, tiredness, "feeling under the weather", muscle ache, headache (within a week after vaccination). Surveillance was active
NotesCirculating strain was not indicated. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Nichol 1999a

MethodsRandomised controlled trial conducted in USA during 1997 to 1998 influenza season. Follow up lasted from November to March. Site specific peak outbreak period was defined as weeks including 80% of the isolates of a specific area. Total outbreak period lasted from December 14, 1997 through to March 21, 1998. Total outbreak period was included in analysis and lasted 14 weeks. Subjects were recruited from seven organisations and assigned to one of the study groups using a permuted block randomisation scheme that was stratified by treatment center and age group. Sealed randomisation envelopes contained vaccine codes. Influenza virus surveillance was carried out in the area
Participants4561 healthy working adults: 3041 treated and 1520 placebo. Age of participants was 18 to 64
InterventionsTrivalent, live attenuated influenza A and B vaccine in a single dose. Vaccine composition was: A/Shenzhen/227/95, A/Wuhan/395/95, B/Harbin/7/94-like. Placebo was egg allantoic fluid. Vaccine was recommended but did not match circulating strain
OutcomesClinical cases (symptom-defined), working days lost and adverse effects. Case definition had three specifications: febrile illness (fever for at least 1 day and two or more symptoms for at least 2 days: fever, chills, headache, cough, runny nose, sore throat, muscle aches, tiredness); severe febrile illness (3 days of symptoms and 1 day of fever); febrile upper respiratory tract illness (3 days of upper respiratory tract symptoms and 1 day of fever). We chose the febrile illness outcome for analysis. Systemic adverse effects were defined as headache, muscle aches, chills, tiredness and fever. Surveillance was passive
NotesComplete follow up data were obtained for 2874 subjects in the treatment arm and for 1433 subject in the placebo arm. The outcome working days lost is presented as rate ratio, even if data are presented in a way that allows to compute difference in mean days lost but not to compute the standard error. Circulating strain was A/Sidney/5/97-like. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Payne 2006

MethodsCase control study assessing the association between influenza and other vaccines (data not extracted for this review) and optic neuritis
ParticipantsUS military personnel aged at least 18 years
InterventionsCases (n = 1131) were subjects with a diagnosis of optic neuritis between 1.1.1998 and 31.12.2003. The following ICD-9 codes were considered : 377.30-32, 377.39.
Controls (n = 4524): subjects were matched to the cases on the basis of sex, deployment during the 18 weeks before diagnosis, military component. The study was carried out by using data from the Defense Medical Surveillance System, a longitudinal surveillance database
OutcomesDate of case diagnosis was ascertained and immunisation status (Anthrax, smallpox, Hepatitis b, influenza) verified by means of electronic record in respect of three time intervals: 6, 12, 18 weeks before onset. For controls vaccination status was determined for the three interval before index date. Results were focused on the 18-week time interval
NotesRare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Phyroenen 1981

MethodsRandomised controlled trial carried out in the 1976 to 1977 season in Finland
Participants307 healthy adults
InterventionsOne of the following 4 preparations were administered to one of the 4 groups of participants: Live attenuated A/Victoria/3/75 ; two 2 ml doses (2 104.5 Bivalent subunit vaccine containing 1200 IU of A/Victoria/3/75 (H3N2) and 800 IU of B/Hong Kong/8/73 per dose (0.5 ml) B versus placebo (phosphate buffered saline). Participant received one dose subcutaneously administered. Vaccination were performed between Dec 15-23, 1976, epidemics occurred Feb to Jun 1977
OutcomesHarms assessed by questionnaires filled out by each subject within 3 days after immunisation. Fever: vacc 11/151; Pl 9/154 - muscle ache; vacc 26/ 151; Pl 12/154 - redness: vacc 53/151; Pl 3/154 - tenderness at vaccination site: vacc 89/151; Pl 12/154 - tenderness of axillary glands: vacc 6/151 ; Pl 2/154
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Powers 1995a

MethodsRandomised controlled trial conducted in USA during 1993 to 1994 influenza season. Follow up was not indicated. Influenza period was not defined. Subjects were randomly assigned to receive one of the following five vaccine preparations in a double-blinded manner: 15 mg of rHA0, 15 mg of rHA0 plus alum, 90 mg of rHA0, licensed and placebo. Spring sera were collected
Participants34 healthy university students: 26 treated and 8 placebo. Age of participants was: 18 to 45
InterventionsSubvirion licensed trivalent parenteral AB vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Texas/36/91 (H1N1), A/Beijing/32/92 (H3N2) and B/Panama/45/90. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesClinical and laboratory confirmed cases and adverse effects. An "influenza-like illness" was defined as the presence of any respiratory symptom(s) for >= 2 days, accompanied by fever or systemic symptoms of myalgias or chills. Laboratory evidence of influenza A (H3N2) virus infection was defined as either or both of the isolation of virus from nasopharyngeal secretion and a >= four-fold increase in serum HAI antibody titre between the 3-week post-vaccination (preseason) specimen and the corresponding post-season specimen collected in the following spring. Local adverse effects were erythema, pain, tenderness, induration, arm stiffness; systemic adverse effects: were headache, generalized myalgia, diarrhea, nausea, feverishness, temperature > 37.8°C
NotesEfficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Powers 1995b

MethodsSingle blind randomised controlled trial conducted in USA during 1974 to 1975 influenza season. Follow up lasted from winter to spring. A "two month" epidemic period was described by the authors with no reference to a definition and lasted 6 weeks. Study subjects were randomly assigned into three subgroups to receive either two doses of the vaccine (n = 47), one dose of vaccine and one dose of placebo (n = 48) or two doses of placebo (n = 48) at 14 days apart. Six months sera were collected on all study subjects
Participants34 healthy university students: 26 treated and 8 placebo. Age of participants was 18 to 45
InterventionsSubvirion monovalent parenteral vaccine. Schedule and dose were: single dose; 90 micrograms rHAO. Vaccine composition was: The recombinant HA vaccine contained full-length uncleaved haemagglutinin (HA0) glycoprotein from the influenza A/Beijing/32/92 (H3N2) virus. Placebo was saline for injection. Vaccine was not recommended but matched circulating strain
OutcomesClinical and laboratory confirmed cases. An "influenza-like illness" was defined as the presence of any respiratory symptom(s) for >= 2 days, accompanied by fever or systemic symptoms of myalgias or chills. Laboratory evidence of influenza A (H3N2) virus infection was defined as either or both of the isolation of virus from nasopharyngeal secretion and a >= four-fold increase in serum HAI antibody titre between the 3-week post-vaccination (preseason) specimen and the corresponding post-season specimen collected in the following spring
NotesSafety data were not included; effectiveness data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Powers 1995c

MethodsRandomised controlled trial conducted in USA during 1993 to 1994 influenza season. Follow up was not indicated. Influenza period was not defined. Subjects were randomly assigned to receive one of the following five vaccine preparations in a double-blinded manner: 15 mg of rHA0, 15 mg of rHA0 plus alum, 90 mg of rHA0, licensed and placebo. Spring sera were collected
Participants59 healthy university students: 51 treated and 8 placebo. Age of participants was 18 to 45
InterventionsSubvirion monovalent parenteral vaccine. Schedule and dose were: single dose; 15 micrograms rHAO. Vaccine composition was: The recombinant HA vaccine contained full-length uncleaved haemagglutinin (HA0) glycoprotein from the influenza A/Beijing/32/92 (H3N2) virus. Placebo was saline for injection. Vaccine was not recommended but matched circulating strain
OutcomesClinical and laboratory confirmed cases. An "influenza-like illness" was defined as the presence of any respiratory symptom(s) for >= 2 days, accompanied by fever or systemic symptoms of myalgias or chills. Laboratory evidence of influenza A (H3N2) virus infection was defined as either or both of the isolation of virus from nasopharyngeal secretion and a >= four-fold increase in serum HAI antibody titre between the 3-week post-vaccination (preseason) specimen and the corresponding post-season specimen collected in the following spring
NotesEfficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Reeve 1982

MethodsRandomised controlled trial carried out in Wien
Participants20 University students aged 20 to 24 years
InterventionsFirst phase: Cold-recombinant, live flu vaccine II RB-77 (B/Ann Arbor/1/66 and B/Tecumse/10/77) containing 107.2 EID50 per 0.5 ml dose versus placebo. One dose intranasal. During this phase, subjects live under sequestered condition and close contact between vaccine and placebo recipients was possible. 2nd phase: Three weeks after the 1st dose all subjects were immunised with one dose of the same vaccine
OutcomesDuring the 5 days following immunisation, subjects were medically observed and temperature recorded morning and evening. Occurring symptoms were attributed scores (0 to 3) depending on their severity (no, light, moderate, severe). Fever (oral temp > 38°C): 0 / 10 ; 0 / 10 sneezing: 1 / 10 ; 0 / 10 stuffy nose: 7 / 10 ; 1 / 10 running nose: 3 / 10 ; 0 / 10 afebrile subjective symptoms: 8 / 10 ; 2 / 10
NotesSafety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Rocchi 1979a

MethodsCluster-randomised controlled trial carried out during the 1976 to 1977 season
Participants496 healthy military recruits (aged 18 to 20 years) belonging to 4 different companies from "Scuola Allievi Sottoufficiali" in Viterbo, Italy
InterventionsOne of the following 4 preparations were administered to one of the 4 groups of participants: Live attenuated A/Victoria/3/75 ; two 2 ml doses (2 104.5 EID50/dose) oral. Live attenuated recombinant A/Puerto Rico/8/34 , A/Victoria/3/75 ; two 0.5 ml doses intranasal (107 EID50 /dose) Inactivated A/Victoria/3/75 (600 i.u.), B/Hong Kong/5/72 (300 i.u.) and AlPO4, intramuscular placebo (vaccine diluent) administered intranasally. The 2 doses were administered 2 to 3 weeks apart
OutcomesWithin 15 days after administration of the 1st dose. Malaise, myalgia, headache, sore throat, cough, fever equal to or more than 38.5 °C, fever equal to or more than 37.5 °C, three or more symptoms, any symptoms. Surveillance was passive
NotesUnits of randomisation appear to be companies. No description of allocation manner is mentioned. Blind (only for the cases of intranasal a administration). Influenza outbreak occurred when the immunisation began (intraepidermic study). Safety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Rocchi 1979b

MethodsAs above
Participants 
Interventions 
Outcomes 
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Rytel 1977

MethodsSingle blind randomised controlled trial conducted in the USA during 1974 to 1975 influenza season. Follow up lasted from winter to spring. A "two month" epidemic period was described by the authors with no reference to a definition and lasted 6 weeks. Study subjects were randomly assigned into three subgroups to receive either two doses of the vaccine (n = 47), one dose of vaccine and one dose of placebo (n = 48) or two doses of placebo (n = 48) at 14 days apart. Six months sera were collected on all study subjects
Participants143 young adult female student nurse volunteers: 95 treated and 48 placebo. Age of participants was 18 to 35
InterventionsLive attenuated, bivalent, intranasal influenza A (containing 107,2 EID50) and B (containing 107,8 EID50 ) vaccines. Schedule and dose were single or double doses. Vaccine composition was: A/England/42/72 (H3N2) and B/Hong Kong/5/72. Placebo was 5% sucrose. Vaccine was not recommended and did not match circulating strain
OutcomesInfluenza and adverse effects. An influenza case was defined as the presence of an influenza-like illness (three or more symptoms of acute respiratory disease and temperature greater then 37.2) and virus isolation and/or four fold rise in antibody titre in sera obtained ad 30 days and 6 months following immunisation. Local adverse effects were upper respiratory symptoms and cough. These were subdivided into moderate and severe. A definition of general adverse effects (again distinguished among moderate and severe) was not given
NotesOne dose and two doses were analyzed together. Circulating strain was A/PortChalmers/1/73 (H3N2). Efficacy and safety data extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Saxen 1999

MethodsRandomised controlled trial, double blind conducted in Finland during 1996 to 1997 influenza season. Randomisation methods were not described
Participants216 health care workers: 211 treated and 427 placebo
InterventionsTrivalent inactivated intramuscular vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Wahan/359/95, A/Singapore/6/86 and B/Beijing/184/93. Placebo was saline for injection. Vaccine was recommended
OutcomesWorking days lost because of respiratory infections, episodes of respiratory infections, days ill and antimicrobial prescriptions. Respiratory infection was a common cold; febrile influenza-like illnesses were not detected. Local adverse effects were defined as local pain. Systemic adverse effects were defined as fever and fatigue
NotesEfficacy data were not extracted because episodes of respiratory infections were unclearly defined. Safety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Scheifele 2003

MethodsRandomised double-blind placebo controlled cross over trial assessing the association between exposure to the vaccine and onset of oculo-respiratory syndrome (ORS) in healthy adults with no previous history of ORS. The trial took place in five centres in Canada in September 2001 and was one of the conditions of registration of the vaccine, given the high incidence of ORS in the previous season. Centralised randomisation and allocation of centrally prepared coded opaque syringes took place. Cross over to either vaccine or placebo took place 5 to 7 days after the initial injection
ParticipantsSix hundred and fifty one adults with a mean age of 45 took part. Seventeen participants are unaccounted for
InterventionsFluviral (Shire) split trivalent containing A/New Caledonia/20/99 (H1N1); A/Panama/2007/99 (H3N2) ; B/Victoria/504/2000 with additional splitting with Triton X-100 splitting agent or saline placebo 0.5 mls. Additional splitting was necessary to test the hypothesis that large clumps of virions were responsible for the ORS seen the previous season
OutcomesORS (bilateral conjunctivitis, facial swelling - lip, lid or mouth, difficulty in breathing and chest discomfort, including cough, wheeze, dysphagia or sore throat). Local signs/symptoms (redness, swelling, pain). Follow up was by phone interview at 24 hours and 6 days after vaccination
NotesThe authors conclude that (mild) ORS is significantly associated with split TIV immunisation (attributable risk 2.9%, 0.6 to 5.2). Other adverse effects associated with TIV are hoarseness (1.3%, 0.3 to 1.3) and coughing 1.2%, 0.2 to 1.6). The study is good quality and the authors conclusions are robust. It is extraordinary that no one has looked for these symptoms before but it may be that the relatively young age of participants and the hypothesis contributed to this. Safety-only study
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Shoenberger 1979

MethodsSurveillance population-based study conducted in USA, during the 1976 to 1977 influenza season. The study tested the association between influenza vaccination and Guillan-Barrè Syndrome. 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 01/10/76-31/01/77
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
Rare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Siscovick 2000

MethodsStudy assessing the association between influenza vaccination the previous year and the risk of primary (i.e. occurring in people with no previous history of cardiac disease) cardiac arrest. Case-control study on 360 cases and 418 controls
ParticipantsCases: subjects who experienced primary cardiac arrest, aged between 25 to 74 years
Controls: healthy subjects selected randomly from the community, who were matched to the cases for age and sex
InterventionsImmunisation with influenza vaccine, assessed by means of questionnaires
OutcomesCardiac arrest
NotesThe authors concluded that vaccination is protective against primary cardiac arrest (OR 0.51, 95% CI 0.33 to 0.79). The difficulty of case ascertainment (77% of potential cases had no ME report and/or autopsy), recall bias (spouses provided exposure data for 304 cases, while 56 survivor cases provided data jointly with their spouses) make the conclusions of this study unreliable. It is impossible to judge the reliability of this study because of a lack of details on the circulation of influenza in the study areas in the 12 months preceding cardiac arrest (the causal hypothesis is based on the effects of influenza infection on the oxygen supply to the myocardium through lung infection and inflammation). Rare events (safety)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskD - Not used

Spencer 1977

MethodsControlled trial, single blind
Participants21 pairs of students and employers at the University of California, aged between 24 and 50 years who lived together or worked in close proximity
InterventionsRecombinant, live attenuated R 75 vaccine (B/Hong Kong/5/72 and B/Russia/69) containing 107.5 EID / dose versus placebo (allantoic fluid). Lyophilized vaccine was supplied by Smith, Kline and French Laboratories and diluted with 2.5 ml of a 5% sucrose solution just before administration. Both preparations were administered intranasally (5 drops/nostril). In each pair one individual received vaccine and the other one placebo. A second dose was administered 14 days apart
OutcomesAny clinical symptoms within 7 days after each immunisation (rhinitis, cough, pharyngitis, headache, malaise and myalgia were the prominent observed symptoms, but given as aggregates)
NotesReported safety data don't allow quantitative analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Sumarokow 1971

MethodsField trial conducted in Russia during the 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. The epidemic period was defined as the period of highest influenza morbidity and lasted 11 weeks, from the last ten days of January to the first ten days of April. Vaccinations were carried out using coded preparation. Sampling virological and serological survey of ill people was performed
Participants19,887 population: 9945 treated and 9942 placebo. Age of participants was 13 to 25
InterventionsLive allantoic intranasal vaccine. Schedule and dose were: 3 doses. Vaccine composition was not indicated. Placebo was not described. Vaccine was not recommended and did not match circulating strain
OutcomesClinical cases, deaths, severity of illness. Clinical outcomes were all the acute respiratory infections. Laboratory confirmation was obtained on a sample of ill participants by virus isolation or demonstration of seroconversion. Bronchitis, otitis and pneumonia were considered as complications. Passive surveillance was carried out
NotesA first study group with children 3 to 12 years old was excluded. A second study group with subjects aged 13 to 25 was included in analysis. The trial compared two live vaccines (allantoic intranasal vaccine and tissue vaccine for oral administration) against placebo. Only intranasal vaccine was included in analysis. Deaths from flu were not recorded. Circulating strain was A2/Hong Kong/68
Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Tannock 1984

MethodsControlled clinical trial, double blind, conducted in Australia during the 1981 influenza season. Follow up lasted from winter to spring. Influenza period was not defined. Voluntary were alternatively allocated to groups in a double blind manner. Six months sera were collected
Participants88 volunteer staff from Newcastle Hospital and the Commonwealth Steel Corporation: 56 treated and 32 placebo. Age of participants was 16 to 64
InterventionsTrivalent subunit parenteral vaccine. Schedule and dose were: 7 micrograms each, one or two doses. Vaccine composition was: A/Brazil/11/78, A/Bangkok/1/79, B/Singapore/222/79. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesInfluenza and adverse effects. A case of influenza was defined as a respiratory illness, retrospectively reported, associated with a 4-fold antibody titre increase between post-vaccination and post-epidemic sera. Local side effects were redness, swelling, warmth or irritation, pain on contact, pain with pressure, continuous pain, or restriction of arm movement; systemic reactions were fever, chills, sweating, drowsiness or insomnia
NotesOne dose and two doses were analyzed together; very high drop out . Circulating strain was A/Bangkok/1/79. Safety data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)High riskC - Inadequate

Waldman 1969a

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples
Participants524 school teachers: 465 treated and 118 placebo. Age of participants was not indicated
InterventionsMonovalent inactivated intramuscular vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A/Hong Kong/68. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose. Passive surveillance was carried out
NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Effectiveness data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1969b

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples
Participants590 school teachers: 471 treated and 119 placebo. Age of participants was not indicated
InterventionsPolyvalent inactivated intramuscular vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA, B/Massachusetts/3/66 300 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a "temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose. Passive surveillance was carried out.
NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1969c

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples
Participants597 school teachers: 479 treated and 118 placebo. Age of participants was not indicated
InterventionsMonovalent inactivated aerosol vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A/Hong Kong/68. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a "temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose. Passive surveillance was carried out
NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1969d

MethodsRandomised controlled trial, double blind, conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Randomisation methods were not described. One half of the volunteers gave serial blood and nasal wash samples
Participants590 school teachers: 471 treated and 119 placebo. Age of participants was not indicated
InterventionsPolyvalent inactivated aerosol vaccine. Schedule and dose were: 1 or 2 doses. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA, B/Massachusetts/3/66 300 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesClinical cases and side effects. Clinical case definition was based on the presence of a "temperature > 100°F or a feverish feeling plus any 2 of the following symptoms: sore throat, muscle or joint pain, cough, stuffy or runny nose". Passive surveillance was carried out.
NotesData concerning adverse effects were only partially reported by graph. Circulating strain was A2/Hong Kong/68. Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Waldman 1972a

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed
Participants244 volunteer students and staff members: 195 treated and 49 placebo. Age of participants was not indicated
InterventionsMonovalent A aerosol vaccine. Schedule and dose were: 200 CCA . Vaccine composition was: A2/Aichi/1/68. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out
NotesIllness during the first one or two weeks after vaccination was not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Waldman 1972b

MethodsRandomised controlled trial, double blind conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed
Participants239 volunteer students and staff members: 190 treated and 49 placebo. Age of participants was not indicated
InterventionsMonovalent A subcutaneous vaccine. Schedule and dose were: 200 CCA. Vaccine composition was: A2/Aichi/1/69. Placebo was saline for injection. Vaccine was recommended and matched circulating strain
OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out
NotesIllness during the first one or two weeks after vaccination was not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Waldman 1972c

MethodsRandomised controlled trial, double blind, conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed
Participants243 volunteer students and staff members: 194 treated and 49 placebo. Age of participants was not indicated
InterventionsBivalent AB aerosol vaccine. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA and B/Massachusset/3/66 200 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out
NotesIllness during the first one or two weeks after vaccination were not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Waldman 1972d

MethodsRandomised controlled trial, double blind, conducted in USA during 1968 to 1969 influenza season. Follow up lasted the whole epidemic period. Epidemic curve was traced by absenteeism in the local industries and schools and virus isolation and lasted 7 weeks. Identical looking coded vials were used to dispense material. Sampling virological and serological survey of ill people was performed. Two doses were administered but as outbreak occurred mostly between them only effectiveness of the first dose was assessed
Participants236 volunteer students and staff members: 187 treated and 49 placebo. Age of participants was not indicated
InterventionsBivalent AB subcutaneous vaccine. Vaccine composition was: A2/Japan/170/62 150 CCA, A2/Taiwan/1/64 150 CCA and B/Massachusset/3/66 200 CCA. Placebo was saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesClinical cases and adverse effects. Clinical cases were defined as febrile respiratory illness with oral temperature higher then 99.5 F. Local adverse effects were defined as pain and/or tenderness and redness and/or swelling. Systemic adverse effects were defined as general (fever, muscle pain, nausea or vomiting, diarrhea and malaise) or respiratory (runny and/or stuffy nose, sore throat, cough, shortness of breath). Passive surveillance was carried out
NotesIllness during the first one or two weeks after vaccination was not excluded, but authors stated that this fact did not affect the results. Circulating strain was A2/Aichi/2/68. Efficacy and safety data were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Weingarten 1988

MethodsRandomised controlled trial, double blind conducted in USA during 1985 to 1986 influenza season. Follow up was not indicated. Epidemic influenza was defined according to population surveillance data (without better explanation), begun in December 1985 and concluded in February 1986. Participants were assigned using a random-number generator to receive either the influenza vaccine or placebo. Virologic surveillance was not performed
Participants179 healthy volunteer hospital employees: 91 treated and 88 placebo. Age of participants was 21 to 65
InterventionsSplit trivalent intramuscular vaccine. Schedule and dose were: single dose; 15 micrograms each strain. Vaccine composition was: A/Chile/1/83 (H1N1), A/Philippines/2/82 (H3N2), and B/USSR/100/83 . Placebo was saline for injection. Vaccine was recommended but did not match circulating strain
OutcomesClinical cases symptoms defined, wdl regardless of causes, and adverse effects. Influenza illness was defined by the CDC case definition: a documented temperature greater than 100 °F and at least the symptoms of cough or sore throat
NotesData regarding wdl and adverse effects were not complete and they were not considered. Most of the influenza infections were caused by type B.
Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskA - Adequate

Zhilova 1986a

MethodsSemi-randomised double blind placebo controlled clinical trial that took place in Leningrad, USSR during 1981 to 1982 influenza season. The study tested the reactogenicity, safety and effectiveness of an inactivated and a live attenuated vaccines, both administered singly or in combination. Allocation was made on the basis of school classes and it is unclear whether this is a cluster randomised, or clinical controlled trial. We have opted for the latter as the text mentions random selection to maintain "equivalence". "Double blind" is mentioned in the text. In January to May 1982 there was a rise in the level of ILI due to influenza and other agents
Participants3961 participants were enrolled. Participants were healthy "students" aged 18 to 23. Numbers in each of the four arms are uneven throughout the trial but no reason is given for this
InterventionsInactivated vaccine trivalent (Ministry of Health USSR) by subcutaneous injection 0.2 mls once (arm 1), or intranasal live "recombinant" "mono"vaccine 0.5 mls spray 2 to 3 times (Ministry of Health USSR) (arm 2), or combined (arm 3) or subcutaneous and intranasal spray NaCl saline placebo (arm 4). The strains contained were H1N1, H3N2 and B. Vaccine matching was not good
OutcomesSerological
Antibody titres - sub study on 1221 participants
Effectiveness
Influenza-like illness (not defined and from the text it is impossible to understand how many Influenza-like illness cases were matched to positive laboratory findings)
Safety data are not reported in sufficient detail to allow extraction
NotesThe authors conclude that simultaneous inoculation of the vaccines appeared to produce better humoral antibody responses, especially in the last season. However, the correlation between clinical protection and antibody rises is reported as dubious. The authors make the reasonable point that perhaps live attenuated vaccines work better because they stimulate production of secretory antibodies. This is a poorly reported study. No mention is made of how placebo could have been correctly used in the schedule (i.e. they should have had six arms instead of four with subcutaneous placebo, spray placebo separately as well combined - maybe this is a problem of translation). Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Zhilova 1986b

  1. a

    FEV1 = Forced respiratory volume in 1 second
    FVC = Forced expiratory vital capacity
    ITT = intention-to-treat
    I.M. = intramuscular
    ADR =
    wdl = working days lost
    vacc = vaccine
    i.u. = international units
    TIV = trivalent inactivated vaccine

MethodsSemi-randomised double blind placebo controlled clinical trial that took place in Leningrad, USSR during 1982 to 1983 influenza season. The study tested the reactogenicity, safety and effectiveness of an inactivated and a live attenuated vaccines, both administered singly or in combination. Allocation was made on the basis of school classes and it is unclear whether this is a cluster randomised, or clinical controlled trial. We have opted for the latter as the text mentions random selection to maintain "equivalence". "Double blind" is mentioned in the text. In the season there was an outbreak of A (H3N2) lasting 4 to 5 weeks. However, influenza accounted for only up to 30% of isolates from ill people
Participants3944 participants were enrolled. Participants were healthy "students" aged 18 to 23. Numbers in each of the four arms are uneven throughout the trial but no reason is given for this
InterventionsInactivated vaccine trivalent (Ministry of Health USSR) by subcutaneous injection 0.2 mls once (arm 1), or intranasal live "recombinant" "mono" vaccine 0.5 mls spray 2 to 3 times (Ministry of Health USSR) (arm 2), or combined (arm 3) or subcutaneous and intranasal spray NaCl saline placebo (arm 4). The strains contained were H1N1, H3N2 and B
Vaccine matching was good
OutcomesSerological
Antibody titres - sub study on 1221 participants
Effectiveness
Influenza-like illness (not defined and from the text it is impossible to understand how many Influenza-like illness cases were matched to positive laboratory findings)
Safety data are not reported in sufficient detail to allow extraction
Passive surveillance was carried out
NotesThe authors conclude that simultaneous inoculation of the vaccines appeared to produce better humoral antibody responses, especially in the last season. However, the correlation between clinical protection and antibody rises is reported as dubious. The authors make the reasonable point that perhaps live attenuated vaccines work better because they stimulate production of secretory antibodies. This is a poorly reported study. No mention is made of how placebo could have been correctly used in the schedule (i.e. they should have had six arms instead of four with subcutaneous placebo, spray placebo separately as well combined - maybe this is a problem of translation). Efficacy data only were extracted
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskB - Unclear

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ambrosch 1976Data tables and figure missing
Aoki 1986Randomised controlled trial, single blind. Outcomes were clinical cases and adverse effects. Follow up data were not reported by arms
Atmar 1995No outcomes of interest
Ausseil 1999No design (average days of sick leave in vaccinated and not vaccinated subjects during 1996 and 1997 in staff personal of an international banking institution)
Banzhoff 2001No design (cohort), no safety outcomes
Belongia 2009Case control study, no harm assessment
Belshe 2001No original data
Benke 2004Questionnaire survey; non comparative analysis
Betts 1977bTrial with swine vaccine (Hsw1N1, A/New Jersey/76)
Beyer 1996Review
Carlson 1979No adequate control, no outcome of interest
Cate 1977Trial with swine vaccine (Hsw1N1, A/New Jersey/76)
Chlibek 2002The study is not a randomised controlled trial
Chou 2007Case report
Clover 1991Randomised controlled trial. More than 75% of the study population is out of the range of age stated in the protocol
Confavreux 2001Participants are MS cases
Das Gupta 2002The study does not contain effectiveness data
Davies 1972Cohort with efficacy outcomes. Experimental and control group were separately selected
Davies 1973The study was not randomised. Subjects volunteered for immunisation and comparison was made with a randomly selected non immunised control group
De Serres 2003aNo comparison, absence of adequate control group
De Serres 2003bNo control
De Serres 2004Population at risk of further Oculo-respiratory syndrome episodes
Dolin 1977Trial with swine vaccine (Hsw1N1, A/New Jersey/76)
Edmonson 1970Influenza B vaccine was used as control
El'shina 1998Major inconsistencies in the study text
Finklea 1969Randomised controlled trial, double blind. Two bivalent inactivated influenza vaccines, with the same viral composition, differing in purification procedures, were compared.
Outcomes were clinical cases and adverse effects.
Raw data about clinical cases were not reported by arm.
Circulating virus showed significant antigenic differences from the A2 vaccine strain
Foy 1981Absence of adequate control
Frank 1981No usable safety data (scores)
Freestone 1976Conference proceedings
Gerstoft 2001The study is not a randomised controlled trial
Greenbaum 2002No outcome of interest
Gross 1999Outcome measures outside inclusion criteria
Grotto 1998The study is not a randomised controlled trial
Gruber 1994Randomised controlled trial conducted in USA on 41 cystic fibrosis (CF) patients and 89 family members, recruited through a clinic. Subjects were randomly assigned in a double-blinded fashion by family to receive either intranasal live cold-adapted influenza A vaccine or the recommended intramuscular trivalent inactivated influenza vaccine.
The study lasted 3 years (from 1989 to 1991). Subjects were immunised each fall staying in the same assigned vaccine group. The live vaccine arm counted 20 CF and 33 family members; the trivalent vaccine arm 21 and 56 respectively.
69 of them (17 CF patients and 52 family members) dropped out. The reasons were stated in the article.
The live vaccine was the same all over the period: A/Kawasaki/9/86 (H1N1) 107,3 pfu, A/Los Angeles/2/87 107,3 pfu.
The viral strains used in the inactivated vaccines were:
- 1989-1990: A/Taiwan/1/86 (H1N1), A/Shaghai/11/87 (H3N2), B/Yagamata/16/88,15 mg/dose of each
- 1990-1991: A/Taiwan/1/86 (H1N1), A/Shaghai/16/89 (H3N2), B/Yagamata/16/88,15 mg/dose of each
- 1991-1992: A/Taiwan/1/86 (H1N1), A/Beijing/353/89 (H3N2), B/Panama/45/90, 15 mg/dose of each
Live vaccine recipient also received monovalent inactivated influenza B vaccine (identical to that contained in the trivalent vaccine) as intramuscular placebo. Allantoic fluid was the placebo for aerosol administration.
Data were extracted and loaded for family members only.
Outcomes were clinical and laboratory confirmed cases, working days lost (WDL), admissions, deaths and adverse effects.
Clinical cases were classified as "respiratory illness" or "febrile respiratory illness". Laboratory-confirmed cases were defined by an influenza virus isolation from a throat swab.
Adverse effects were defined as temperature > 38°C, rhinorrhea, sore throat, cough, increasing sputum, redness, swelling, chills. Results are expressed as % of subject-days with symptoms.
Subjects were followed throughout the period. Owing to the drop outs, vaccinated were counted as subject-years: 54 in the live vaccine arm; 56 in the trivalent vaccine arm.
The influenza illness surveillance period for study subjects was defined as the interval from the date of the first influenza isolate from population under routine surveillance to 2 weeks after the last isolate for each year.
Viral strains circulating during the outbreaks were:
- 1989-1990: A/Shaghai/11/87 (H3N2)
- 1990-1991: A/Beijing/353/89 (H3N2), B/Panama/45/90-like
- 1991-1992: A/Beijing/353/89 (H3N2).
This trial was excluded since it was not placebo controlled and authors didn't specify if the strains used to develop cold adapted and inactivated vaccines were antigenically comparable or not
Haber 2004Analysis of temporal trends of Guillan Barrè Syndrome (GBS) 1990-2003, comparison with temporal trends of non-GBS Adverse Event reports from the Vaccine Adverse Event Reporting System (VAERS)
Haigh 1973The study is not randomised: all the volunteers were immunised on a single day and the intention to allocate patients randomly was not strictly adhered to
Halperin 2002Outcome measures outside inclusion criteria
Hobson 1970Polivalent influenza vaccine was used as control
Hobson 1973Randomised controlled trial. Clinical outcomes were side effects only
Hoskins 1973Influenza B vaccine was used as control
Hoskins 1976aThe trial was excluded since it was not placebo/do-nothing controlled
Hoskins 1976bThe trial was excluded since it was not placebo/do-nothing controlled
Hoskins 1979No control group
Howell 1967The study is not prospective. It appears as an historical cohort
Hurwitz 1983Report of GBS surveillance 1978-79, non-comparative study
Jianping 1999The study is not a randomised controlled trial
Keitel 2001Efficacy outcome measures outside inclusion criteria. The safety data are presented in a non-analysable way
Khazeni 2009the study is review and a cost effectiveness analysis
Kiderman 2001Tables and text show inconsistencies that do not allow data extraction
Kunz 1977No adequate control
Langley 2004Review
Liem 1973Liem reported the results of 9 placebo controlled clinical trials and two field studies, involving a total of about 10000 subjects, carried out in several countries to assess the efficacy of killed influenza spray vaccines. Studies were conducted during the years 1969-71.
Allocation of the subjects to the arms of the trials was done according to a pre-determined randomisation scheme. 8 of them were double-blind. The field studies were not randomised. The attack rate for influenza among the population study was very low, and in two of the trials vaccination procedure started too late, when the outbreak was ongoing. The attack rates, exclusively based on the serologically confirmed cases, are only reported by a graph and it is impossible to derive the crude data
Mackenzie 1975No design (allocation is arbitrary and groups with different characteristics were formed)
Mair 1974Influenza B vaccine was used as control
Maynard 1968Influenza B vaccine was used as control
McCarthy 2004Review
Mendelman 2001The study does not repot original results
Merelli 2000Review
Meyers 2003aReview
Meyers 2003bReview
Monto 2000The study is not a randomised controlled trial
Morris 1975Design is unclear (no standard random allocation. Only 25 out of 30 seem to have been immunized, but in the method description 30 were considered for exposure to natural influenza A/Scotland/840/74. One of these was prior excluded because had tonsillitis
Mostow 1977Outcomes were safety only. Absence of adequate control
Muennig 2001The study is not a randomised controlled trial
Nichol 1996Same data as Nichol 1995
Nichol 1999bThe study is a review
Nichol 2001The study is not a randomised controlled trial
Nichol 2003The study contain data from previous studies
Nichol 2004Re-analysis of Nichol 1999 (already included)
Pyhala 2001The study is not a randomised controlled trial
Rimmelzwaan 2000Outcome measures outside inclusion criteria
Rocchi 1979cVery poor reporting, unclear definition, no description of methods
Ruben 1972Absence of adequate control
Ruben 1973The study was excluded since both arms contained the same vaccine strains
Safranek 1991Re-assessment of Schoenberger 1979
Sarateanu 1980Absence of adequate control
Schonberger 1981Review of the evidence of the aetiology of GBS, no original data presented
Schwartz 1996Report about Nichol 1995
Skowronski 2002Non-comparative (survey)
Skowronski 2003Population at risk of further ORS episodes
Smith 1977aThe article reports a little part of the Hoskins trial. It compared illness occurring among a group of vaccinated boys against non vaccinated controls that had no part in the trial
Smith 1977bTrial with swine vaccine (Hsw1N1, A/New Jersey/76)
Spencer 1975Authors didn't report crude data on the clinical outcomes
Spencer 1979Reporting doesn't allow one to understand the methods used to allocate subjects and to conceal allocation. Clinical outcome data are not reported
Taylor 1969No outcomes of interest, rhinovirus vaccine as control
Treanor 2001Outcome measures outside inclusion criteria
Treanor 2002Outcome measures outside inclusion criteria
Tyrrell 1970None of the 3 studies reported in this paper are includible for the following reasons
1. No design, no comparison, no outcomes
2. Probable controlled clinical trial, but subjects age probably out of range (schools)
3. No design, even if an unvaccinated control group for school 3 and ICI is present
Warshauer 1976The study was not randomised. Data reporting was not complete
Wilde 1999Pneumococcal vaccine was used as control
Williams 1973No placebo/do-nothing control
Wood 1999The study is not a randomised controlled trial
Wood 2000The study is not a randomised controlled trial

Ancillary