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Vaccines for preventing influenza in the elderly

  1. Tom Jefferson1,*,
  2. Carlo Di Pietrantonj2,
  3. Lubna A Al-Ansary3,
  4. Eliana Ferroni4,
  5. Sarah Thorning5,
  6. Roger E Thomas6

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 17 FEB 2010

Assessed as up-to-date: 6 OCT 2009

DOI: 10.1002/14651858.CD004876.pub3

How to Cite

Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE. Vaccines for preventing influenza in the elderly. Cochrane Database of Systematic Reviews 2010, Issue 2. Art. No.: CD004876. DOI: 10.1002/14651858.CD004876.pub3.

Author Information

  1. 1

    The Cochrane Collaboration, Vaccines Field, Roma, Italy

  2. 2

    Azienda Sanitaria Locale ASL AL, Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Alessandria, Piemonte, Italy

  3. 3

    College of Medicine, King Saud University, Department of Family & Community Medicine, Holder of "Shaikh Abdullah S. Bahamdan" Research Chair for Evidence-Based Health Care and Knowledge Translation, Riyadh, Saudi Arabia

  4. 4

    Public Health Agency of Lazio Region, Infectious Diseases Unit, Rome, Italy

  5. 5

    Bond University, Faculty of Health Sciences and Medicine, Gold Coast, Queensland, Australia

  6. 6

    University of Calgary, Department of Medicine, Calgary, Alberta, Canada

*Tom Jefferson, Vaccines Field, The Cochrane Collaboration, Via Adige 28a, Anguillara Sabazia, Roma, 00061, Italy. jefferson.tom@gmail.com. jefferson@assr.it.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 17 FEB 2010

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Description of the condition

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

 

Description of the intervention

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

 

How the intervention might work

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

 

Why it is important to do this review

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

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

  1. To identify and appraise all the comparative studies evaluating the effects of influenza vaccines in the elderly (aged 65 years and older), irrespective of setting.
  2. To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly.
  3. To document the types and frequency of adverse effects associated with influenza vaccines in the elderly.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

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

 

Types of participants

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

 

Types of interventions

  1. Vaccination with any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo, or with no intervention.
  2. We also considered new, as yet unlicensed, types of vaccines (for example, live attenuated and DNA vaccines).
  3. Vaccination of staff in order to protect patients and residents admitted into hospitals, nursing homes and long-term care facilities has been assessed by a separate review (Thomas 2010).
  4. We excluded studies in which a vaccine was administered after the beginning of the epidemic period.
  5. We excluded old oil adjuvant vaccine or vaccines with a content greater than 15 µg of haemagglutinin/strain/dose from the safety assessment.

 

Types of outcome measures

 

Primary outcomes

 
For treatment efficacy and effectiveness

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

  1. Cases of influenza, clinically defined from a list of likely respiratory and systemic signs and symptoms. We accepted the trial authors' definition of clinical illness because some states have their own official definition.
  2. Cases of influenza, laboratory confirmed (by means of viral isolation, serological supporting evidence, or both).
  3. Cases of influenza (as defined above) admitted to hospital.
  4. Deaths (total).
  5. Deaths due to influenza (as defined above) or to its complications.
  6. Other direct or indirect indicator of disease impact: pneumonia; hospitalisation due to any respiratory disease, hospitalisation due to heart disease.

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

 

Secondary outcomes

 
For adverse events

  1. Local events for aerosol vaccines (upper respiratory tract infection symptoms such as cough, coryza, sore throat, hoarseness) within seven days of vaccination.
  2. Local events for parenteral vaccines (tenderness/soreness, erythema, induration, arm stiffness) within seven days from vaccination.
  3. Systemic events (myalgia, fever, headache, fatigue, indisposition, rash, angioedema, asthma) within seven days from vaccination.
  4. Rare events (thrombocytopenia, neurological disorders, Guillan Barré Syndrome (GBS).

 

Search methods for identification of studies

 

Electronic searches

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

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

 

MEDLINE (OVID)

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

 

Searching other resources

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

In order to identify additional published and unpublished studies:

  • we used the Science Citation Index to identify articles that cite the relevant studies;
  • we keyed the relevant studies into PubMed and used the Related Articles feature;
  • we searched the bibliographies of all relevant articles obtained, any published reviews and proceedings from relevant conferences for additional studies;
  • we explored Internet sources: NHS National Research Register (http://www.update-software.com/national/), the metaRegister of Clinical Trials (http://www.controlled-trials.com/) and the digital dissertations web site (http://wwwlib.umi.com/dissertations);
  • we searched the Vaccine Adverse Event Reporting System web site (http://www.vaers.org); and
  • we contacted vaccine manufacturers listed at the WHO web site.

 

Data collection and analysis

 

Selection of studies

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

 

Data extraction and management

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

We extracted data on the following:

  • methodological quality of studies;
  • study design (Appendix 1);
  • description of setting;
  • characteristics of participants;
  • description of vaccines (content and antigenic match);
  • description of viral circulation degree;
  • description of outcomes;
  • length of the follow up;
  • publication status;
  • date of study; and
  • location of study.

 

Assessment of risk of bias in included studies

 

Experimental studies

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

We classified studies according to the following criteria:

 
Randomisation

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

 
Generation of the allocation sequence

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

 
Allocation concealment

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

 
Blinding

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

 
Follow up

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

 

Non-experimental studies

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

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

 

Measures of treatment effect

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

 

Unit of analysis issues

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

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

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

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

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

 

Dealing with missing data

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

 

Assessment of heterogeneity

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

 

Assessment of reporting biases

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

 

Data synthesis

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

 

Subgroup analysis and investigation of heterogeneity

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

 

Sensitivity analysis

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

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

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

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

 

Included studies

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

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

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

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

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

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

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

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

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

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

 

Excluded studies

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

 

Risk of bias in included studies

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

 

Cohort/case-control studies

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

 

Surveillance studies

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

 

Allocation

 

Experimental studies

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

 

Blinding

See Discussion 'Potential biases in the review process'.

 

Incomplete outcome data

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

 

Selective reporting

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

 

Other potential sources of bias

See Discussion 'Potential biases in the review process'.

 

Effects of interventions

 

RCTs

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

 

Cohort studies in long-term care facilities

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

 

Studies recorded during outbreaks or periods of high viral circulation

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

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

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

 FigureFigure 1.

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

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

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

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

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

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

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

 

Studies carried out during low viral circulation

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

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

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

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

 

Cohort studies in community-dwelling elderly

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

 

Inactivated influenza vaccines in all community-dwelling elderly

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

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

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

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

 

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

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

 

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

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

 

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

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

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

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

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

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

 

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

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

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

 

Adjuvant influenza vaccines in all community-dwelling elderly

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

 

Case-control studies

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

 

Inactivated influenza vaccines on community-dwelling elderly

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

 

Inactivated influenza vaccines on community-dwelling elderly - adjusted analysis

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

 

Inactivated influenza and (PPV) vaccines

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

 

Possible causes of observed heterogeneity - post hoc analysis

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

 

Safety

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

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

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Summary of main results

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

 

Overall completeness and applicability of evidence

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

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

 

Quality of the evidence

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

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

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

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

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

 

Potential biases in the review process

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

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

 

Agreements and disagreements with other studies or reviews

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

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

 

Implications for practice

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

 
Implications for research

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

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

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

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

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
Download statistical data

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI2612388Risk Ratio (M-H, Random, 95% CI)0.76 [0.66, 0.88]

    1.1 Outbreak - vaccine matching (circulating strains)
165963Risk Ratio (M-H, Random, 95% CI)0.77 [0.64, 0.94]

    1.2 Outbreak - vaccine matching absent or unknown
64096Risk Ratio (M-H, Random, 95% CI)0.80 [0.60, 1.05]

    1.3 No outbreak - vaccine matching
42329Risk Ratio (M-H, Random, 95% CI)0.67 [0.46, 0.98]

   1.4 No outbreak - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 2 Influenza81941Risk Ratio (M-H, Random, 95% CI)0.65 [0.32, 1.29]

    2.1 Outbreak - vaccine matching
4658Risk Ratio (M-H, Random, 95% CI)1.04 [0.43, 2.51]

    2.2 Outbreak - vaccine matching absent or unknown
2592Risk Ratio (M-H, Random, 95% CI)0.47 [0.22, 1.04]

    2.3 No outbreak - vaccine matching
2691Risk Ratio (M-H, Random, 95% CI)0.23 [0.05, 1.03]

   2.4 No outbreak - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 3 Pneumonia1710274Risk Ratio (M-H, Random, 95% CI)0.53 [0.43, 0.66]

    3.1 Outbreak - vaccine matching
84482Risk Ratio (M-H, Random, 95% CI)0.54 [0.42, 0.70]

    3.2 Outbreak - vaccine matching absent or unknown
53991Risk Ratio (M-H, Random, 95% CI)0.68 [0.39, 1.21]

   3.3 No outbreak - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    3.4 No outbreak - matching absent or unknown
41801Risk Ratio (M-H, Random, 95% CI)0.35 [0.18, 0.68]

 4 Hospitalisation for ILI or pneumonia1228032Risk Ratio (M-H, Random, 95% CI)0.51 [0.32, 0.81]

    4.1 Outbreak - vaccine matching
82027Risk Ratio (M-H, Random, 95% CI)0.55 [0.36, 0.84]

    4.2 Outbreak - vaccine matching absent or unknown
23301Risk Ratio (M-H, Random, 95% CI)0.82 [0.43, 1.58]

    4.3 No outbreak - vaccine matching
222704Risk Ratio (M-H, Random, 95% CI)0.32 [0.14, 0.76]

   4.4 No outbreak - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 5 Deaths from flu or pneumonia2732179Risk Ratio (M-H, Random, 95% CI)0.46 [0.33, 0.63]

    5.1 Outbreak - vaccine matching
166127Risk Ratio (M-H, Random, 95% CI)0.58 [0.41, 0.83]

    5.2 Outbreak - vaccine matching absent or unknown
41089Risk Ratio (M-H, Random, 95% CI)0.34 [0.11, 1.02]

    5.3 No outbreak - vaccine matching
323162Risk Ratio (M-H, Random, 95% CI)0.27 [0.09, 0.87]

    5.4 No outbreak - vaccine matching absent or unknown
41801Risk Ratio (M-H, Random, 95% CI)0.30 [0.14, 0.67]

 6 All deaths1305Risk Ratio (M-H, Random, 95% CI)0.40 [0.21, 0.77]

    6.1 Outbreak - vaccine matching
1305Risk Ratio (M-H, Random, 95% CI)0.40 [0.21, 0.77]

   6.2 Outbreak - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   6.3 No outbreak - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   6.4 No outbreak - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 7 Influenza cases (clinically defined without clear definition)724238Risk Ratio (M-H, Random, 95% CI)0.52 [0.27, 1.02]

    7.1 Outbreak - vaccine matching
2271Risk Ratio (M-H, Random, 95% CI)0.70 [0.11, 4.56]

    7.2 Outbreak - vaccine matching absent or unknown
1155Risk Ratio (M-H, Random, 95% CI)0.23 [0.09, 0.59]

    7.3 No outbreak - vaccine matching
122462Risk Ratio (M-H, Random, 95% CI)0.40 [0.35, 0.46]

    7.4 No outbreak - vaccine matching absent or unknown
31350Risk Ratio (M-H, Random, 95% CI)0.72 [0.41, 1.28]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI49613Risk Ratio (M-H, Random, 95% CI)0.75 [0.42, 1.33]

   1.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   1.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.3 Non epidemic year - vaccine matching
24636Risk Ratio (M-H, Random, 95% CI)1.08 [0.58, 2.03]

    1.4 Non epidemic year - vaccine matching absent or unknown
1268Risk Ratio (M-H, Random, 95% CI)0.85 [0.16, 4.55]

    1.5 Epidemic year - vaccine not matching
14709Risk Ratio (M-H, Random, 95% CI)0.44 [0.24, 0.81]

 2 Influenza218249Risk Ratio (M-H, Random, 95% CI)0.19 [0.02, 2.01]

    2.1 Epidemic year - vaccine matching
1427Risk Ratio (M-H, Random, 95% CI)0.05 [0.01, 0.37]

   2.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    2.3 Non epidemic year - vaccine matching
117822Risk Ratio (M-H, Random, 95% CI)0.5 [0.27, 0.91]

   2.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 3 Pneumonia218090Risk Ratio (M-H, Random, 95% CI)0.88 [0.64, 1.20]

   3.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    3.3 Non epidemic year - vaccine matching
117822Risk Ratio (M-H, Random, 95% CI)0.87 [0.63, 1.19]

    3.4 Non epidemic year - vaccine matching absent or unknown
1268Risk Ratio (M-H, Random, 95% CI)3.0 [0.16, 57.42]

 4 Hospitalisation for flu or pneumonia9784643Risk Ratio (M-H, Random, 95% CI)0.73 [0.62, 0.85]

    4.1 Epidemic year - vaccine matching
6727776Risk Ratio (M-H, Random, 95% CI)0.74 [0.62, 0.88]

   4.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    4.3 Non epidemic year - vaccine matching
125532Risk Ratio (M-H, Random, 95% CI)0.55 [0.37, 0.83]

    4.4 Non epidemic year - vaccine matching absent or unknown
126626Risk Ratio (M-H, Random, 95% CI)0.73 [0.54, 0.99]

    4.5 Epidemic year - vaccine not matching
14709Risk Ratio (M-H, Random, 95% CI)0.89 [0.33, 2.40]

 5 Hospitalisation for any respiratory disease5567299Risk Ratio (M-H, Random, 95% CI)0.88 [0.54, 1.43]

    5.1 Epidemic year - vaccine matching
3515141Risk Ratio (M-H, Random, 95% CI)0.78 [0.37, 1.64]

   5.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    5.3 Non epidemic year - vaccine matching
125532Risk Ratio (M-H, Random, 95% CI)0.94 [0.79, 1.12]

    5.4 Non epidemic year - vaccine matching absent or unknown
126626Risk Ratio (M-H, Random, 95% CI)1.16 [1.01, 1.34]

 6 Deaths from flu or pneumonia1163391Risk Ratio (M-H, Random, 95% CI)0.87 [0.70, 1.09]

    6.1 Epidemic year - vaccine matching
1163391Risk Ratio (M-H, Random, 95% CI)0.87 [0.70, 1.09]

   6.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   6.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   6.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 7 Deaths from respiratory disease1426668Risk Ratio (M-H, Random, 95% CI)1.32 [1.25, 1.39]

    7.1 Epidemic year - vaccine matching
1426668Risk Ratio (M-H, Random, 95% CI)1.32 [1.25, 1.39]

 8 All deaths8409468Risk Ratio (M-H, Random, 95% CI)0.61 [0.47, 0.80]

    8.1 Epidemic year - vaccine matching
4300332Risk Ratio (M-H, Random, 95% CI)0.59 [0.50, 0.70]

   8.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    8.3 Non epidemic year - vaccine matching
3104427Risk Ratio (M-H, Random, 95% CI)0.65 [0.30, 1.39]

   8.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    8.5 Epidemic year - vaccine not matching
14709Risk Ratio (M-H, Random, 95% CI)3.89 [0.90, 16.89]

 9 Hospitalisation for heart disease6433934Risk Ratio (M-H, Random, 95% CI)0.87 [0.67, 1.12]

    9.1 Epidemic year - vaccine matching
4381776Risk Ratio (M-H, Random, 95% CI)0.74 [0.56, 0.97]

   9.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    9.3 Non epidemic year - vaccine matching
125532Risk Ratio (M-H, Random, 95% CI)1.06 [0.81, 1.38]

    9.4 Non epidemic year - vaccine matching absent or unknown
126626Risk Ratio (M-H, Random, 95% CI)1.59 [1.07, 2.36]

 10 Combined outcome: all deaths or severe respiratory illness3290819Risk Ratio (M-H, Random, 95% CI)0.71 [0.58, 0.85]

    10.1 Epidemic year - vaccine matching
2132365Risk Ratio (M-H, Random, 95% CI)0.80 [0.42, 1.55]

    10.2 Epidemic year - vaccine matching absent or unknown
1158454Risk Ratio (M-H, Random, 95% CI)0.74 [0.69, 0.80]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza16423Risk Ratio (M-H, Random, 95% CI)0.40 [0.14, 1.17]

   1.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   1.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.3 Non epidemic year - vaccine matching
16423Risk Ratio (M-H, Random, 95% CI)0.40 [0.14, 1.17]

   1.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 2 Pneumonia16423Risk Ratio (M-H, Random, 95% CI)1.22 [0.76, 1.94]

   2.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   2.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    2.3 Non epidemic year - vaccine matching
16423Risk Ratio (M-H, Random, 95% CI)1.22 [0.76, 1.94]

   2.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 3 Hospitalisation for influenza or pneumonia145932Risk Ratio (M-H, Random, 95% CI)0.74 [0.63, 0.86]

    3.1 Epidemic year - vaccine matching
145932Risk Ratio (M-H, Random, 95% CI)0.74 [0.63, 0.86]

   3.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 4 Hospitalisation for any respiratory disease2189004Risk Ratio (M-H, Random, 95% CI)0.85 [0.80, 0.92]

    4.1 Epidemic year - vaccine matching
2189004Risk Ratio (M-H, Random, 95% CI)0.85 [0.80, 0.92]

   4.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   4.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   4.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 5 Deaths from respiratory disease1142464Risk Ratio (M-H, Random, 95% CI)0.92 [0.86, 0.98]

    5.1 Epidemic year - vaccine matching
1142464Risk Ratio (M-H, Random, 95% CI)0.92 [0.86, 0.98]

 6 All deaths368032Risk Ratio (M-H, Random, 95% CI)0.39 [0.16, 0.97]

    6.1 Epidemic year - vaccine matching
12344Risk Ratio (M-H, Random, 95% CI)0.13 [0.02, 0.92]

   6.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    6.3 Non epidemic year - vaccine matching
265688Risk Ratio (M-H, Random, 95% CI)0.47 [0.17, 1.28]

   6.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 7 Hospitalisation for heart disease145932Risk Ratio (M-H, Random, 95% CI)0.92 [0.83, 1.03]

    7.1 Epidemic year - vaccine matching
145932Risk Ratio (M-H, Random, 95% CI)0.92 [0.83, 1.03]

   7.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   7.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   7.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 8 Combined outcome: all deaths or severe respiratory illness2146248Risk Ratio (M-H, Random, 95% CI)0.60 [0.49, 0.74]

    8.1 Epidemic year - vaccine matching
154438Risk Ratio (M-H, Random, 95% CI)0.54 [0.49, 0.60]

    8.2 Epidemic year - vaccine matching absent or unknown
191810Risk Ratio (M-H, Random, 95% CI)0.67 [0.61, 0.72]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza111399Risk Ratio (M-H, Random, 95% CI)0.57 [0.27, 1.17]

   1.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   1.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.3 Non epidemic year - vaccine matching
111399Risk Ratio (M-H, Random, 95% CI)0.57 [0.27, 1.17]

   1.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 2 Pneumonia111399Risk Ratio (M-H, Random, 95% CI)0.59 [0.37, 0.92]

   2.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   2.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    2.3 Non epidemic year - vaccine matching
111399Risk Ratio (M-H, Random, 95% CI)0.59 [0.37, 0.92]

   2.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 3 Hospitalisation for influenza or pneumonia1101619Risk Ratio (M-H, Random, 95% CI)0.50 [0.40, 0.63]

    3.1 Epidemic year - vaccine matching
1101619Risk Ratio (M-H, Random, 95% CI)0.50 [0.40, 0.63]

   3.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 4 Hospitalisation for any respiratory disease2376324Risk Ratio (M-H, Random, 95% CI)0.84 [0.55, 1.27]

    4.1 Epidemic year - vaccine matching
2376324Risk Ratio (M-H, Random, 95% CI)0.84 [0.55, 1.27]

   4.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   4.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   4.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 5 Deaths from respiratory disease1281424Risk Ratio (M-H, Random, 95% CI)1.41 [1.31, 1.53]

    5.1 Epidemic year - vaccine matching
1281424Risk Ratio (M-H, Random, 95% CI)1.41 [1.31, 1.53]

 6 All deaths343821Risk Ratio (M-H, Random, 95% CI)0.65 [0.33, 1.29]

    6.1 Epidemic year - vaccine matching
17047Risk Ratio (M-H, Random, 95% CI)1.09 [0.26, 4.49]

   6.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    6.3 Non epidemic year - vaccine matching
236774Risk Ratio (M-H, Random, 95% CI)0.59 [0.27, 1.30]

   6.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 7 Hospitalisation for heart disease1101619Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.01]

    7.1 Epidemic year - vaccine matching
1101619Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.01]

   7.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   7.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   7.4 Non epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 8 Combined outcome: all deaths or severe respiratory illness2135180Risk Ratio (M-H, Random, 95% CI)0.62 [0.54, 0.70]

    8.1 Epidemic year - vaccine matching
168536Risk Ratio (M-H, Random, 95% CI)0.65 [0.54, 0.78]

    8.2 Epidemic year - vaccine matching absent or unknown
166644Risk Ratio (M-H, Random, 95% CI)0.58 [0.48, 0.71]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI1374Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]

   1.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   1.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.3 Non epidemic year - vaccine matching
1374Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]

 2 Hospitalisation for influenza or pneumonia or respiratory disease3518748Risk Ratio (M-H, Random, 95% CI)0.67 [0.64, 0.70]

    2.1 Epidemic year - vaccine matching
2518374Risk Ratio (M-H, Random, 95% CI)0.67 [0.63, 0.71]

   2.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    2.3 Non epidemic year - vaccine matching
1374Risk Ratio (M-H, Random, 95% CI)0.90 [0.10, 7.97]

 3 Deaths from influenza or pneumonia1259627Risk Ratio (M-H, Random, 95% CI)0.43 [0.33, 0.57]

    3.1 Epidemic year - vaccine matching
1259627Risk Ratio (M-H, Random, 95% CI)0.43 [0.33, 0.57]

   3.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.3 Non epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

 4 All deaths2260001Risk Ratio (M-H, Random, 95% CI)0.44 [0.41, 0.46]

    4.1 Epidemic year - vaccine matching
1259627Risk Ratio (M-H, Random, 95% CI)0.44 [0.41, 0.46]

   4.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    4.3 Non epidemic year - vaccine matching
1374Risk Ratio (M-H, Random, 95% CI)1.60 [0.08, 30.65]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI2498Risk Ratio (M-H, Random, 95% CI)0.30 [0.16, 0.56]

    1.1 Epidemic year - vaccine matching
1263Risk Ratio (M-H, Random, 95% CI)0.20 [0.07, 0.54]

   1.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.3 Non epidemic year - vaccine matching
1235Risk Ratio (M-H, Random, 95% CI)0.38 [0.18, 0.82]

 2 Hospitalisation for influenza or pneumonia or respiratory disease2498Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.28]

   2.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   2.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    2.3 Non epidemic year - vaccine matching
2498Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.28]

 3 All deaths1235Risk Ratio (M-H, Random, 95% CI)2.10 [0.10, 43.10]

   3.1 Epidemic year - vaccine matching
00Risk Ratio (M-H, Random, 95% CI)Not estimable

   3.2 Epidemic year - vaccine matching absent or unknown
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    3.3 Non epidemic year - vaccine matching
1235Risk Ratio (M-H, Random, 95% CI)2.10 [0.10, 43.10]

 
Comparison 7. Influenza vaccines versus no vaccination - Cohort studies in community - adjusted rates

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisation for influenza or pneumonia8Odds Ratio (Random, 95% CI)0.73 [0.67, 0.79]

    1.1 Epidemic - vaccine matching
6Odds Ratio (Random, 95% CI)0.71 [0.65, 0.77]

    1.2 Non epidemic - vaccine not matching
1Odds Ratio (Random, 95% CI)0.90 [0.58, 1.38]

    1.3 Epidemic year - vaccine matching absent or unknown
1Odds Ratio (Random, 95% CI)0.82 [0.68, 0.98]

 2 Hospitalisation for any respiratory disease13Odds Ratio (Random, 95% CI)0.78 [0.72, 0.85]

    2.1 Epidemic matching vaccine
9Odds Ratio (Random, 95% CI)0.71 [0.67, 0.74]

    2.2 Non epidemic non matching
2Odds Ratio (Random, 95% CI)0.91 [0.76, 1.08]

    2.3 Non epidemic year and matching vaccine
2Odds Ratio (Random, 95% CI)0.94 [0.84, 1.06]

 3 Hospitalisation for heart disease6Odds Ratio (Random, 95% CI)0.76 [0.70, 0.82]

    3.1 Epidemic year - vaccine matching
5Odds Ratio (Random, 95% CI)0.75 [0.70, 0.82]

    3.2 Non epidemic - vaccine not matching
1Odds Ratio (Random, 95% CI)0.80 [0.55, 1.16]

 4 All deaths7Odds Ratio (Random, 95% CI)0.53 [0.46, 0.61]

    4.1 Epidemic year - vaccine matching
5Odds Ratio (Random, 95% CI)0.47 [0.42, 0.53]

    4.2 Epidemic year - vaccine matching absent or unknown
1Odds Ratio (Random, 95% CI)0.65 [0.57, 0.75]

    4.3 Non epidemic year - vaccine matching
1Odds Ratio (Random, 95% CI)0.76 [0.60, 0.97]

 5 Combined outcome: all deaths or severe respiratory illness1Odds Ratio (Random, 95% CI)0.70 [0.37, 1.34]

    5.1 Epidemic year - vaccine matching
1Odds Ratio (Random, 95% CI)0.70 [0.37, 1.34]

 
Comparison 8. Influenza vaccines versus no vaccination - Case-control studies in community

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisations for influenza or pneumonia21074Odds Ratio (M-H, Random, 95% CI)0.89 [0.69, 1.15]

   1.1 Outbreak - vaccine matching (circulating strains)
00Odds Ratio (M-H, Random, 95% CI)Not estimable

    1.2 Outbreak - vaccine matching absent or unknown
1825Odds Ratio (M-H, Random, 95% CI)0.92 [0.69, 1.22]

    1.3 No outbreak - vaccine matching
1249Odds Ratio (M-H, Random, 95% CI)0.82 [0.48, 1.40]

 2 Hospitalisations for any respiratory disease421378Odds Ratio (M-H, Random, 95% CI)1.08 [0.95, 1.23]

    2.1 Outbreak - vaccine matching
320582Odds Ratio (M-H, Random, 95% CI)1.08 [0.92, 1.26]

    2.2 No outbreak - not matching
1796Odds Ratio (M-H, Random, 95% CI)1.02 [0.68, 1.52]

 3 Deaths from influenza or pneumonia11092Odds Ratio (M-H, Random, 95% CI)0.74 [0.53, 1.04]

    3.1 Outbreak - vaccine matching
11092Odds Ratio (M-H, Random, 95% CI)0.74 [0.53, 1.04]

 4 Pneumonia (no better defined)1519Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.33]

    4.1 Outbreak - partially matching
1519Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.33]

 
Comparison 9. Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in community

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisations for influenza or pneumonia46629Odds Ratio (M-H, Random, 95% CI)0.97 [0.85, 1.09]

    1.1 Outbreak - vaccine matching
23617Odds Ratio (M-H, Random, 95% CI)0.95 [0.69, 1.31]

    1.2 No outbreak - vaccine matching
23012Odds Ratio (M-H, Random, 95% CI)0.93 [0.80, 1.08]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI11198Odds Ratio (M-H, Random, 95% CI)0.52 [0.40, 0.68]

    1.1 Outbreak - vaccine matching
11198Odds Ratio (M-H, Random, 95% CI)0.52 [0.40, 0.68]

 
Comparison 11. Influenza vaccines versus no vaccination - Case-control studies in community - adjusted rates

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisations for influenza or pneumonia5Odds Ratio (Random, 95% CI)0.59 [0.47, 0.74]

    1.1 Epidemic - vaccine matching
1Odds Ratio (Random, 95% CI)0.55 [0.36, 0.85]

   1.2 Non epidemic - vaccine not matching
0Odds Ratio (Random, 95% CI)Not estimable

    1.3 Epidemic year - vaccine matching absent or unknown
2Odds Ratio (Random, 95% CI)0.68 [0.58, 0.79]

    1.4 Non epidemic - vaccine matching
2Odds Ratio (Random, 95% CI)0.37 [0.16, 0.87]

 2 Hospitalisations for any respiratory disease3Odds Ratio (Random, 95% CI)0.71 [0.56, 0.90]

    2.1 Epidemic - vaccine matching
3Odds Ratio (Random, 95% CI)0.71 [0.56, 0.90]

   2.2 Non epidemic - vaccine matching
0Odds Ratio (Random, 95% CI)Not estimable

   2.3 Non epidemic year - vaccine matching
0Odds Ratio (Random, 95% CI)Not estimable

 3 Deaths from pneumonia or influenza2Odds Ratio (Random, 95% CI)0.74 [0.60, 0.92]

    3.1 Epidemic year - vaccine matching
1Odds Ratio (Random, 95% CI)0.76 [0.60, 0.97]

    3.2 Epidemic year - vaccine matching absent or unknown
1Odds Ratio (Random, 95% CI)0.67 [0.42, 1.07]

 
Comparison 12. Influenza and pneumococcal vaccines versus no vaccination - Case-control studies in community - adjusted rates

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisations for influenza or pneumonia2Odds Ratio (Random, 95% CI)0.68 [0.54, 0.86]

    1.1 Epidemic - vaccine matching
1Odds Ratio (Random, 95% CI)0.68 [0.50, 0.93]

   1.2 Non epidemic - vaccine not matching
0Odds Ratio (Random, 95% CI)Not estimable

   1.3 Epidemic year - vaccine matching absent or unknown
0Odds Ratio (Random, 95% CI)Not estimable

    1.4 Non epidemic - vaccine matching
1Odds Ratio (Random, 95% CI)0.69 [0.49, 0.97]

 
Comparison 13. Influenza vaccines versus placebo - RCT - parenteral vaccine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI46894Risk Ratio (M-H, Random, 95% CI)0.59 [0.47, 0.73]

    1.1 Outbreak - vaccine matching (circulating strains) - community - healthy
22047Risk Ratio (M-H, Random, 95% CI)0.57 [0.42, 0.79]

    1.2 Outbreak - vaccine matching - community - risk groups
1490Risk Ratio (M-H, Random, 95% CI)0.87 [0.49, 1.53]

    1.3 Outbreak - vaccine matching - nursing home - healthy
14180Risk Ratio (M-H, Random, 95% CI)0.54 [0.37, 0.80]

    1.4 Outbreak - vaccine matching - psychiatric hospital
1177Risk Ratio (M-H, Random, 95% CI)0.35 [0.13, 0.92]

 2 Influenza32217Risk Ratio (M-H, Random, 95% CI)0.42 [0.27, 0.66]

    2.1 Outbreak - vaccine matching - community - healthy and ill
11838Risk Ratio (M-H, Random, 95% CI)0.41 [0.23, 0.74]

    2.2 outbreak - vaccine matching - psychiatric hospital
1177Risk Ratio (M-H, Random, 95% CI)0.35 [0.12, 1.06]

    2.3 No outbreak - vaccine matching - nursing home - healthy and ill
1202Risk Ratio (M-H, Random, 95% CI)0.50 [0.20, 1.25]

 3 Pneumonia1699Risk Ratio (M-H, Random, 95% CI)Not estimable

    3.1 Outbreak - vaccine matching - community - healthy
1699Risk Ratio (M-H, Random, 95% CI)Not estimable

 4 All deaths1699Risk Ratio (M-H, Random, 95% CI)1.02 [0.11, 9.72]

    4.1 Outbreak - vaccine matching - community - healthy
1699Risk Ratio (M-H, Random, 95% CI)1.02 [0.11, 9.72]

 
Comparison 14. Vaccine versus placebo - inactivated aerosol vaccine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI1176Risk Ratio (M-H, Random, 95% CI)0.84 [0.41, 1.71]

    1.1 Outbreak - vaccine matching - psychiatric hospital
1176Risk Ratio (M-H, Random, 95% CI)0.84 [0.41, 1.71]

 2 Influenza1176Risk Ratio (M-H, Random, 95% CI)0.89 [0.40, 1.99]

    2.1 outbreak - vaccine matching - psychiatric hospital
1176Risk Ratio (M-H, Random, 95% CI)0.89 [0.40, 1.99]

 
Comparison 15. Vaccine versus placebo - live aerosol vaccine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Influenza1220Risk Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.17]

    1.1 No outbreak - vaccine matching - nursing home - healthy and ill
1220Risk Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.17]

 
Comparison 16. Sensitivity analysis Comparison 01: subgroup analysis by study quality

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ILI259211Risk Ratio (M-H, Random, 95% CI)0.75 [0.65, 0.87]

    1.1 Quality A
84502Risk Ratio (M-H, Random, 95% CI)0.78 [0.65, 0.94]

    1.2 Quality B
133854Risk Ratio (M-H, Random, 95% CI)0.82 [0.65, 1.03]

    1.3 Quality C
3389Risk Ratio (M-H, Random, 95% CI)0.66 [0.43, 1.00]

    1.4 Quality D
1466Risk Ratio (M-H, Random, 95% CI)0.44 [0.35, 0.57]

 
Comparison 17. Influenza vaccines versus placebo - RCT - parenteral vaccine - adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 General malaise42560Risk Ratio (M-H, Random, 95% CI)1.18 [0.87, 1.61]

 2 Fever32519Risk Ratio (M-H, Random, 95% CI)1.57 [0.92, 2.71]

 3 Upper respiratory tract symptoms2713Risk Ratio (M-H, Random, 95% CI)1.35 [0.90, 2.01]

 4 Headache32519Risk Ratio (M-H, Random, 95% CI)1.10 [0.76, 1.58]

 5 Nausea1672Risk Ratio (M-H, Random, 95% CI)1.75 [0.74, 4.12]

 6 Local tenderness/sore arm42560Risk Ratio (M-H, Random, 95% CI)3.56 [2.61, 4.87]

 7 Swelling - erythema - induration21847Risk Ratio (M-H, Random, 95% CI)8.23 [3.98, 17.05]

 
Comparison 18. Influenza vaccines versus placebo - RCT - live aerosol vaccine - adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 General malaise145Risk Ratio (M-H, Random, 95% CI)3.09 [0.18, 53.20]

 2 Fever145Risk Ratio (M-H, Random, 95% CI)1.71 [0.09, 33.24]

 3 Upper respiratory tract symptoms145Risk Ratio (M-H, Random, 95% CI)1.62 [0.42, 6.29]

 4 Lower respiratory tract symptoms145Risk Ratio (M-H, Random, 95% CI)2.91 [0.41, 20.48]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Appendix 1. Included studies design

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

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

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

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

 

Appendix 2. Methodological quality of non-randomised studies

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
CASE-CONTROL STUDIES

Selection

  1. Is the case definition adequate?
    1. yes, with independent validation
    2. yes, e.g. record linkage or based on self reports
    3. no description
  2. Representation of the cases
    1. consecutive or obviously representative series of cases
    2. potential for selection biases or not stated
  3. Selection of controls
    1. community controls
    2. hospital controls
    3. no description
  4. Definition of controls
    1. no history of disease (endpoint)
    2. no description of source

Comparability

  1. Comparability of cases and controls on the basis of the design or analysis
    1. study controls for _______________ (select the most important factor)
    2. study controls for any additional factor (this criteria could be modified to indicate specific control for a second important factor)

Exposure

  1. Ascertainment of exposure
    1. secure record (e.g. surgical records)
    2. structured interview where blind to case/control status
    3. interview not blinded to case/control status
    4. written self-report or medical record only
    5. no description
  2. Same method of ascertainment for cases and controls
    1. yes
    2. no

  1. Non-response rate
    1. same rate for both groups
    2. non-respondents described
    3. rate different and no designation

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
COHORT STUDIES

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

Selection

  1. Representation of the exposed cohort
    1. truly representative of the average _______________ (describe) in the community
    2. somewhat representative of the average ______________ in the community
    3. selected group of users e.g. nurses, volunteers
    4. no description of the derivation of the cohort
  2. Selection of the non-exposed cohort
    1. drawn from the same community as the exposed cohort
    2. drawn from a different source
    3. no description of the derivation of the non-exposed cohort
  3. Ascertainment of exposure
    1. secure record (e.g. surgical records)
    2. structured interview
    3. written self-report
    4. no description
  4. Demonstration that outcome of interest was not present at start of study
    1. yes
    2. no

Comparability

  1. Comparability of cohorts on the basis of the design or analysis
    1. study controls for _____________ (select the most important factor)
    2. study controls for any additional factor * (this criteria could be modified to indicate specific control for a second important factor)

Outcome

  1. Assessment of outcome
    1. independent blind assessment
    2. record linkage
    3. self-report
    4. no description
  2. Was follow up long enough for outcomes to occur
    1. yes (select an adequate follow-up period for outcome of interest)
    2. no
  3. Adequacy of follow up of cohorts
    1. complete follow up - all subjects accounted for
    2. subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an adequate %) follow up, or description provided of those lost) *
    3. follow up rate < ____% (select an adequate %) and no description of those lost
    4. no statement

 

Appendix 3. Data extraction form

 

PART 1

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

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

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

Description of study
Methods
Participants
Interventions/exposure
Outcomes
Notes

 

PART 2a

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

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

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

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

Follow up:

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

 

PART 2b

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

Status: primary, secondary or tertiary immunisation.

Vaccine Batch Numbers

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

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

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

Investigators to be contacted for more information? Yes/No

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

 

PART 2c

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

Notes (for statistical use only)

 

PART 3a

Methodological Quality Assessment. Non-randomised studies only

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

 

PART 3b

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

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

Vaccine Batch Numbers

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

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

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

Investigators to be contacted for more information? Yes/No

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

 

PART 3c

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

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

Notes (for statistical use only)

 

PART 3d

Description of studies. Case-control studies only

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

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

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

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

Notes (for statistical use only)

 

Part 3e

Data extraction and manipulation. Case-control studies only

Status | Numerator | Denominator
Cases
Control

Notes (for statistical use only)

 

Appendix 4. Previous search

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

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

 

MEDLINE (OVID)

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

 

Appendix 5. EMBASE search strategy

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

 

Appendix 6. Web of Science search strategy

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

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

Timespan = 2006 to 2009.

 

Appendix 7. SIGN filter for observational studies

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

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

MEDLINE


1Epidemiologic studies/

2Exp case control studies/

3Exp cohort studies/

4Case control.tw.

5(cohort adj (study or studies)).tw.

6Cohort analy$.tw.

7(Follow up adj (study or studies)).tw.

8(observational adj (study or studies)).tw.

9Longitudinal.tw.

10Retrospective.tw.

11Cross sectional.tw.

12Cross-sectional studies/

13Or/1-12



EMBASE


1Clinical study/

2Case control study

3Family study/

4Longitudinal study/

5Retrospective study/

6Prospective study/

7Randomised controlled trials/

86 not 7

9Cohort analysis/

10(Cohort adj (study or studies)).mp.

11(Case control adj (study or studies)).tw.

12(follow up adj (study or studies)).tw.

13(observational adj (study or studies)).tw.

14(epidemiologic$ adj (study or studies)).tw.

15(cross sectional adj (study or studies)).tw.

16Or/1-5,8-15



 

Feedback

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Vaccines for preventing influenza in the elderly

 

Summary

Dear Dr Rivetti,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

Reply

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

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

 

Contributors

Keiji Hayashi
Feedback comment and reply added 25 July 2007

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

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


DateEventDescription

7 October 2009New citation required and conclusions have changedThree new authors (EF, LAA, ST) joined the review team while previous authors no longer contributed to this update. Our conclusion partly changed. In part this was due to the re-evaluation of the whole topic and partly because of the ambiguity in the previous text which readers found confusing.

7 October 2009New search has been performedSearches conducted. We identified 18 potential trials. We included four new trials, two case-control studies (Jordan 2007; Puig-Barbera 2007) and two cohort studies (Hara 2006; Leung 2007). We excluded 13 new trials (Castilla 2006; Garcia Garcia 2009; Hara 2008; Isahak 2007; Landi 2006; Manzoli 2007; Moreno 2009; Nichol 2007; Ortqvist 2007; Skull 2009; Tsai 2007; van Vuuren 2009; Voordouw 2006). One excluded trial (Vila-Corcoles 2005) was formerly awaiting classification.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

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


DateEventDescription

8 May 2008AmendedConverted to new review format.

25 July 2007Feedback has been incorporatedFeedback comment and reply added to review.

29 March 2006New search has been performedSearches conducted.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

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

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

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

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

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

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Internal sources

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

 

External sources

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

References

References to studies included in this review

  1. Top of page
  2. Abstract摘要Résumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Ahmed 1995 {published data only}
Ahmed 1997 {published data only}
  • Ahmed AH, Nicholson KG, Nguyen-van Tam JS, Pearson JC. Effectiveness of influenza vaccine in reducing hospital admissions during the 1989-90 epidemic. Epidemiology and Infection 1997;118(1):27-33.
Allsup 2004 {published data only}
  • Allsup S, Haycox A, Regan M, Gosney M. Is influenza vaccination cost effective for healthy people between ages 65 and 74 years? A randomised controlled trial. Vaccine 2004;23(5):639-45.
Arden 1988 {published data only}
  • Arden NH, Patriarca PA, Fasano MB, Lui KJ, Harmon MW, Kendal AP, et al. The roles of vaccination and amantadine prophylaxis in controlling an outbreak of influenza A (H3N2) in a nursing home. Archive of Internal Medicine 1988;148(4):865-8.
Arroyo 1984 {published data only}
  • Arroyo JC, Postic B, Brown A, Harrison K, Birgenheier R, Dowda H. Influenza A/Philippines/2/82 outbreak in a nursing home: limitations of influenza vaccination in the aged. American Journal of Infection Control 1984;12(6):329-34.
Aymard 1979a {published data only}
  • Aymard M, Bentejac MC, Larbaigt G, Michaut D, Triau R. Efficacy of the antiinfluenza A vaccination during epidemics due to A/VIC/3/75 and A/Texas/1/77 viruses. Developments in Biological Standardization 1979;43:231-9.
Aymard 1979b {published data only}
  • Aymard M, Bentejac MC, Larbaigt G, Michaut D, Triau R. Efficacy of the antiinfluenza A vaccination during epidemics due to A/VIC/3/75 and A/Texas/1/77 viruses. Developments in biological standardization 1979;43:231-9.
Caminiti 1994 {published data only}
  • Caminiti C, Ricco D, Tanzi ML, Borrini B, Corsello A, Biasio LR, et al. Field evaluation of influenza vaccine efficacy in a population of institutionalized elderly. L’igiene Moderna 1994;101(2):163-75.
Cartter 1990a {published data only}
  • Cartter ML, Renzullo PO, Helgerson SD, Martin SM, Jekel JF. Influenza outbreaks in nursing homes: how effective is influenza vaccine in the institutionalized elderly?. Infection Control and Hospital Epidemiology 1990;11(9):473-8.
Cartter 1990b {published data only}
  • Cartter ML, Renzullo PO, Helgerson SD, Martin SM, Jekel JF. Influenza outbreaks in nursing homes: how effective is influenza vaccine in the institutionalized elderly?. Infection Control and Hospital Epidemiology 1990;11(9):473-8.
Cartter 1990c {published data only}
  • Cartter ML, Renzullo PO, Helgerson SD, Martin SM, Jekel JF. Influenza outbreaks in nursing homes: how effective is influenza vaccine in the institutionalized elderly?. Infection Control and Hospital Epidemiology 1990;11(9):473-8.
Christenson 2001a {published data only}
  • Christenson B, Lundbergh P, Hedlund J, Ortqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in adults aged 65 years or older: a prospective study. Lancet 2001;357(9261):1008-11.
Christenson 2001b {published data only}
  • Christenson B, Lundbergh P, Hedlund J, Ortqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in adults aged 65 years or older: a prospective study. Lancet 2001;357(9261):1008-11.
Christenson 2004a {published data only}
Christenson 2004b {published data only}
Coles 1992 {published data only}
  • Coles FB, Balzano GJ, Morse DL. An outbreak of influenza A (H3N2) in a well immunized nursing home population. Journal of the American Geriatrics Society 1992;40(6):589-92.
Comeri 1995 {published data only}
  • Comeri L, Tinella M, Croce E, Arzese M. Protective efficacy of antiinfluenza vaccination in the elderly. L’igiene Moderna 1995;103(6):651-6.
Consonni 2004a {published data only}
  • Consonni S, Sandrini C, Segato E, Perruchini E, Bergamaschini L, Vergani C. Tolerability and efficacy of anti-influenza vaccination alone and associated with antipneumococcal vaccination in an elderly ambulatory population and adherence to the vaccination campaign. Journal of Preventive Medicine and Hygiene 2004;45:45-50.
Consonni 2004b {published data only}
  • Consonni S, Sandrini C, Segato E, Perruchini E, Bergamaschini L, Vergani C. Tolerability and efficacy of anti-influenza vaccination alone and associated with antipneumococcal vaccination in an elderly ambulatory population and adherence to the vaccination campaign. Journal of Preventive Medicine and Hygiene 2004;45:45-50.
Crocetti 2001 {published data only}
  • Crocetti E, Arniani S, Bordoni F, Maciocco G, Zappa M, Buiatti E. Effectiveness of influenza vaccination in the elderly in a community in Italy. European Journal of Epidemiology 2001;17(2):163-8.
Cuneo Crovari 1980 {published data only}
  • Cuneo Crovari P, Gasparini R, Crovari P. Efficacy of influenza vaccination: results in a community controlled for 2 years. Bollettino dell’Istituto Sieroterapico Milanese 1980;59(4):306-13.
Currier 1988 {published data only}
  • Currier M, Coffman T, Boyd P, Fremd B, Israel E. Influenza vaccine efficacy in a Maryland nursing home. Maryland Medical Journal 1988;37(10):781-3.
D'Alessio 1969 {published data only}
Davis 2001a {published data only}
Davis 2001b {published data only}
Davis 2001c {published data only}
Deguchi 2001 {published data only}
  • Deguchi Y, Nishimura K. Efficacy of influenza vaccine in elderly persons in welfare nursing homes: reduction in risks of mortality and morbidity during an influenza A (H3N2) epidemic. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2001;56(6):M391-4.
Edmondson 1971 {published data only}
  • Edmondson WP Jr, Rothenberg R, White PW, Gwaltney JM Jr. A comparison of subcutaneous, nasal, and combined influenza vaccination. II. Protection against natural challenge. American Journal of Epidemiology 1971;93(6):480-6.
Fedson 1993a {published data only}
Fedson 1993b {published data only}
Feery 1976 {published data only}
  • Feery BJ, Evered MG, Morrison EI. Different protection rates in various groups of volunteers given subunit influenza virus vaccine in 1976. Journal of Infectious Diseases 1979;139(2):237-41.
Fleming 1995 {published data only}
  • Fleming DM, Watson JM, Nicholas S, Smith GE, Swan AV. Study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989-90 using a general practice database. Epidemiology and Infection 1995;115(3):581-9.
Foster 1992 {published data only}
  • Foster DA, Talsma A, Furumoto-Dawson A, Ohmit SE, Margulies JR, Arden NH, et al. Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly. American Journal of Epidemiology 1992;136(3):296-307.
Fyson 1983a {published data only}
  • Fyson RE. Influenza outbreaks in two institutions for the elderly - Ontari. Canadian Diseases Weekly Report 1983;9:37.
Fyson 1983b {published data only}
  • Fyson RE. Influenza outbreaks in two institutions for the elderly - Ontario. Canadian Diseases Weekly Report 1983;9:37.
Gavira Iglesias 1987 {published data only}
  • Gavira Iglesias FJ, Rodriguez Lopez FC, Berni Maestre RM. Analysis of an influenza vaccination campaign in rural environment. Revista de Sanidad e Higiene Publica 1987;61(7-8):759-81.
Gené Badia 1991 {published data only}
  • Gene Badia J, Calero Munoz S, Castanera Ribe C, Gran Rovireta A. Effectiveness of an anti-influenza vaccination program in 4 primary care centers. Gaceta Sanitaria 1991;5(26):203-8.
Goodman 1982 {published data only}
Govaert 1993 {published data only}
  • Govaert TM, Dinant GJ, Aretz K, Masurel N, Sprenger MJ, Knottnerus JA. Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial. BMJ 1993;307(6910):988-90.
Govaert 1994 {published data only}
  • Govaert TM, Thijs CT, Masurel N, Sprenger MJ, Dinant GJ, Knottnerus JA. The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial. JAMA 1994;272(21):1661-5.
Gross 1988 {published data only}
  • Gross PA, Quinnan GV, Rodstein M, LaMontagne JR, Kaslow RA, Saah AJ, et al. Association of influenza immunization with reduction in mortality in an elderly population. A prospective study. Archives of Internal Medicine 1988;148(3):562-5.
Hak 2002a {published data only}
  • Hak E, Nordin J, Wei F, Mullooly J, Poblete S, Strikas R, et al. Influence of high-risk medical conditions on the effectiveness of influenza vaccination among elderly members of 3 large managed-care organizations. Clinical Infectious Diseases 2002;35(4):370-7.
Hak 2002b {published data only}
  • Hak E, Nordin J, Wei F, Mullooly J, Poblete S, Strikas R, et al. Influence of high-risk medical conditions on the effectiveness of influenza vaccination among elderly members of 3 large managed-care organizations. Clinical Infectious Diseases 2002;35(4):370-7.
Hara 2006 {published data only}
  • Hara M, Sakamoto T, Tanaka K. Effectiveness of influenza vaccination in preventing influenza-like illness among community-dwelling elderly: population-based cohort study in Japan. Vaccine 2006;24(27-8):5546-51.
Horman 1986 {published data only}
Howarth 1987a {published data only}
  • Howarth DM, Chaston TM, Lickiss K, Weekes JR, O'Doherty C, Foster RE, et al. Age-related responses to influenza vaccination in the Newcastle region during 1983 and 1984. Medical Journal of Australia 1987;146(10):514-7.
Howarth 1987b {published data only}
  • Howarth DM, Chaston TM, Lickiss K, Weekes JR, O'Doherty C, Foster RE, et al. Age-related responses to influenza vaccination in the Newcastle region during 1983 and 1984. Medical Journal of Australia 1987;146(10):514-7.
Howells 1975a {published data only}
Howells 1975b {published data only}
Howells 1975c {published data only}
Isaacs 1997 {published data only}
  • Isaacs S, Dickinson C, Brimmer G. Outbreak of influenza A in an Ontario nursing home - January 1997. Canada Communicable Disease Report 1997;23(14):105-8.
Jordan 2007 {published data only}
  • Jordan RE, Hawker JI, Ayres JG, Tunnicliffe W, Adab P, Olowokure B, et al. A case-control study of elderly patients with acute respiratory illness: effect of influenza vaccination on admission to hospital in winter 2003-2004. Vaccine 2007;25(46):7909-13.
Kaplan 1982 {published data only}
  • Kaplan JE, Katona P, Hurwitz ES, Schonberger LB. Guillain-Barre syndrome in the United States, 1979-1980 and 1980-1981. Lack of an association with influenza vaccination. JAMA 1982;248(6):698-700.
Kaway 2003 {published data only}
  • Kawai N, Ikematsu H, Iwaki N, Satoh I, Kawashima T, Tsuchimoto T, et al. A prospective, internet-based study of the effectiveness and safety of influenza vaccination in the 2001-2002 influenza season. Vaccine 2003;21(31):4507-13.
Keitel 1996 {published data only}
  • Keitel WA, Cate TR, Atmar RL, Turner CS, Nino D, Dukes CM, et al. Increasing doses of purified influenza virus hemagglutinin and subvirion vaccines enhance antibody responses in the elderly. Clinical and Diagnostic Laboratory Immunology 1996;3(5):507-10.
Lasky 1998 {published data only}
  • Lasky T, Terracciano GJ, Magder L, Koski CL, Ballesteros M, Nash D, et al. The Guillain-Barre syndrome and the 1992-1993 and 1993-1994 influenza vaccines. New England Journal of Medicine 1998;339(25):1797-802.
Leung 2007 {published data only}
  • Leung JCK. Effectiveness of influenza vaccination among elderly home residents in Hong Kong: a retrospective cohort study. Hong Kong Practitioner 2007;29(4):123-33.
Lopez Hernandez 1994 {published data only}
  • Lopez Hernandez B, Vazquez J, Fernandez E, Martinez B, Romero J, Arribas L. Effectiveness of anti-flu vaccine in the elderly. Atencion Primaria 1994;14(1):532-6.
Mangtani 2004a {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004b {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004c {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004d {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004e {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004f {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004g {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004h {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004i {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Mangtani 2004j {published data only}
  • Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database. Journal of Infectious Diseases 2004;190(1):1-10.
Margolis 1990a {published data only}
Meiklejohn 1987 {published data only}
Monto 2001 {published data only}
Morens 1995 {published data only}
Mukerjee 1994 {published data only}
Mullooly 1994 {published data only}
  • Mullooly JP, Bennett MD, Hornbrook MC, Barker WH, Williams WW, Patriarca PA, et al. Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization. Annals of Internal Medicine 1994;121(12):947-52.
Murayama 1999 {published data only}
  • Murayama N, Suzuki H, Arakawa M, Nerome K, Mizuta K, Kameyama K. Two outbreaks of influenza A (H3N2) in a Japanese nursing home in the winter of 1996-1997, with differing vaccine efficacy. Tohoku Journal of Experimental Medicine 1999;188(4):289-98.
Nichol 1994a {published data only}
  • Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. New England Journal of Medicine 1994;331(12):778-84.
Nichol 1994b {published data only}
  • Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. New England Journal of Medicine 1994;331(12):778-84.
Nichol 1994c {published data only}
  • Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. New England Journal of Medicine 1994;331(12):778-84.
Nichol 1998a {published data only}
Nichol 1998b {published data only}
Nichol 2003a {published data only}
  • Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. New England Journal of Medicine 2003;348(14):1322-32.
Nichol 2003b {published data only}
  • Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. New England Journal of Medicine 2003;348(14):1322-32.
Nicholson 1999 {published data only}
  • Nicholson KG, Kent J, Hammersley V. Influenza A among community-dwelling elderly persons in Leicestershire during winter 1993-4; cigarette smoking as a risk factor and the efficacy of influenza vaccination. Epidemiology and Infection 1999;123(1):103-8.
Nordin 2001a {published data only}
  • Nordin J, Mullooly J, Poblete S, Strikas R, Petrucci R, Wei F, et al. Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans. Journal of Infectious Diseases 2001;184(6):665-70.
Nordin 2001b {published data only}
  • Nordin J, Mullooly J, Poblete S, Strikas R, Petrucci R, Wei F, et al. Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans. Journal of Infectious Diseases 2001;184(6):665-70.
Ohmit 1995a {published data only}
  • Ohmit SE, Monto AS. Influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type A and type B seasons. International Journal of Epidemiology 1995;24(6):1240-8.
Ohmit 1995b {published data only}
  • Ohmit SE, Monto AS. Influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type A and type B seasons. International Journal of Epidemiology 1995;24(6):1240-8.
Ohmit 1999 {published data only}
  • Ohmit SE, Arden NH, Monto AS. Effectiveness of inactivated influenza vaccine among nursing home residents during an influenza type A (H3N2) epidemic. Journal of the American Geriatric Society 1999;47(2):165-71.
Patriarca 1985a {published data only}
  • Patriarca PA, Weber JA, Parker RA, Hall WN, Kendal AP, Bregman DJ, et al. Efficacy of influenza vaccine in nursing homes. Reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA 1985;253(8):1136-9.
Patriarca 1985b {published data only}
  • Patriarca PA, Weber JA, Parker RA, Hall WN, Kendal AP, Bregman DJ, et al. Efficacy of influenza vaccine in nursing homes. Reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA 1985;253(8):1136-9.
Pregliasco 2002 {published data only}
  • Pregliasco F, Giardini G, Sandrini MC, Perucchini E, Vergani C. Efficacia protettiva di Inflexal V nel pazinte anziano. Vaccine at a Glance 2002;1(1):2-5.
Puig-Barbera 2007 {published data only}
  • Puig-Barberà J, Díez-Domingo J, Varea AB, Chavarri GS, Rodrigo JA, Hoyos SP, et al. Effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. Vaccine 2007;25(42):7313-21.
Puig-Barberà 1997 {published data only}
  • Puig-Barbera J, Marquez-Calderon S, Masoliver-Fores A, Lloria-Paes F, Ortega-Dicha A, Gil-Martin M, et al. Reduction in hospital admissions for pneumonia in non-institutionalised elderly people as a result of influenza vaccination: a case-control study in Spain. Journal of Epidemiology and Community Health 1997;51(5):526-30.
Puig-Barberà 2004 {published data only}
  • Puig-Barbera J, Diez-Domingo J, Perez Hoyos S, Belenguer Varea A, Gonzalez Vidal D. Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Vaccine 2004;23(3):283-9.
Ruben 1974 {published data only}
  • Ruben FL, Johnston F, Streiff EJ. Influenza in a partially immunized aged population. Effectiveness of killed Hong Kong vaccine against infection with the England strain. JAMA 1974;230(6):863-6.
Rudenko 2001 {published data only}
  • Rudenko LG, Arden NH, Grigorieva E, Naychin A, Rekstin A, Klimov AI, et al. Immunogenicity and efficacy of Russian live attenuated and US inactivated influenza vaccines used alone and in combination in nursing home residents. Vaccine 2000;19(2-3):308-18.
Saah 1986a {published data only}
  • Saah AJ, Neufeld R, Rodstein M, La Montagne JR, Blackwelder WC, Gross P, et al. Influenza vaccine and pneumonia mortality in a nursing home population. Archive of Internal Medicine 1986;146(12):2353-7.
Saah 1986b {published data only}
  • Saah AJ, Neufeld R, Rodstein M, La Montagne JR, Blackwelder WC, Gross P, et al. Influenza vaccine and pneumonia mortality in a nursing home population. Archive of Internal Medicine 1986;146(12):2353-7.
Saah 1986c {published data only}
  • Saah AJ, Neufeld R, Rodstein M, La Montagne JR, Blackwelder WC, Gross P, et al. Influenza vaccine and pneumonia mortality in a nursing home population. Archive of Internal Medicine 1986;146(12):2353-7.
Saito 2002a {published data only}
  • Saito R, Suzuki H, Oshitani H, Sakai T, Seki N, Tanabe N. The effectiveness of influenza vaccine against influenza a (H3N2) virus infections in nursing homes in Niigata, Japan, during the 1998-1999 and 1999-2000 seasons. Infection Control and Hospital Epidemiology 2002;23(2):82-6.
Saito 2002b {published data only}
  • Saito R, Suzuki H, Oshitani H, Sakai T, Seki N, Tanabe N. The effectiveness of influenza vaccine against influenza a (H3N2) virus infections in nursing homes in Niigata, Japan, during the 1998-1999 and 1999-2000 seasons. Infection Control and Hospital Epidemiology 2002;23(2):82-6.
Schonberger 1979 {published data only}
  • Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA, Ziegler DW, Retailliau HF, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976-1977. American Journal of Epidemiology 1979;110(2):105-23.
Shapiro 2003 {published data only}
  • Shapiro Y, Shemer J, Heymann A, Shalev V, Maharshak N, Chodik G, et al. Influenza vaccination: reduction in hospitalizations and death rates among members of "Maccabi Healthcare Services" during the 2000-2001 influenza season. Israel Medical Association Journal 2003;5(10):706-8.
Strassburg 1986 {published data only}
Stuart 1969 {published data only}
Taylor 1992 {published data only}
  • Taylor JL, Dwyer DM, Coffman T, Groves C, Patel J, Israel E. Nursing home outbreak of influenza A (H3N2): evaluation of vaccine efficacy and influenza case definitions. Infection Control and Hospital Epidemiology 1992;13(2):93-7.
Treanor 1994 {published data only}
  • Treanor J, Dumyati G, O'Brien D, Riley MA, Riley G, Erb S, et al. Evaluation of cold-adapted, reassortant influenza B virus vaccines in elderly and chronically ill adults. Journal of Infectious Diseases 1994;169(2):402-7.
Voordouw 2003 {published data only}
  • Voordouw BC, van der Linden PD, Simonian S, van der Lei J, Sturkenboom MC, Stricker BH. Influenza vaccination in community-dwelling elderly: impact on mortality and influenza-associated morbidity. Archives of Internal Medicine 2003;163(9):1089-94.

References to studies excluded from this review

  1. Top of page
  2. Abstract摘要Résumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Allsup 2001 {published data only}
  • Allsup SJ, Gosney M, Regan M, Haycox A, Fear S, Johnstone FC. Side effects of influenza vaccination in healthy older people: a randomised single-blind placebo-controlled trial. Gerontology 2001;47(6):311-4.
Allsup 2003 {published data only}
  • Allsup S, Gosney M, Haycox A, Regan M. Cost-benefit evaluation of routine influenza immunisation in people 65-74 years of age. Health Technology Assessment 2003;7(24):iii-x, 1-65.
Anonymous 1995 {published data only}
  • Anonymous. Influenza vaccination in the elderly: a bona fide clinical trial. Hospital Practice 1995;30(2):100.
Anonymous 2004b {published data only}
  • Anonymous. Vaccination protects against influenza deaths in elderly. Pharmaceutical Journal 2004;273(7318):410.
Ansaldi 2002 {published data only}
  • Ansaldi F, Tominz R, D'Agaro P, Michieletto F, Quadranti M, Cornelio G, et al. Influenza vaccination among the elderly in Trieste: comparison of a cross-sectional study and routine public health surveillance [Vaccinazione anti-influenzale negli anziani a Trieste: confronto fra uno studio trasversale ed il sistema di sorveglianza passivo]. Annali di Igiene: Medicina Preventiva e di Comunita` 2002;14(4):305-11.
Arden 1986 {published data only}
  • Arden NH, Patriarca PA, Kendal P. Experiences in the use and efficacy of inactivated influenza vaccine in nursing homes. In: Kendal AP, Patriarca PA editor(s). Options for the Control of Influenza. New York: Alan R. Liss, 1986:155-68.
Armstrong 2004 {published data only}
  • Armstrong BG, Mangtani P, Fletcher A, Kovats S, McMichael A, Pattenden S, et al. Effect of influenza vaccination on excess deaths occurring during periods of high circulation of influenza: cohort study in elderly people. BMJ 2004;329(7467):660.
Arroyo 1988 {published data only}
Arya 2003 {published data only}
Ayala-Montiel 2004 {published data only}
  • Ayala-Montiel O, Mascarenas de los Santos C, Garcia-Hernandez D, Rendon-Muniz J, Garcia-Olvera L. Reactogenicity of the simultaneous administration of influenza and pneumococcal vaccines in adults over 55 years of age. Revista de Investigacion Clinica 2004;56(1):27-31.
Baldo 1999 {published data only}
  • Baldo V, Menegon T, Buoro S, Scalici C, Vesco A, Perale S, et al. Vaccination against influenza in the elderly. Experience with adjuvant vaccines. Annali di Igiene: Medicina Preventiva e di Comunita` 1999;11(5):369-74.
Barker 1980 {published data only}
Bektimirov 1993 {published data only}
Belshe 2004 {published data only}
  • Belshe RB, Nichol KL, Black SB, Shinefield H, Cordova J, Walker R, et al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5-49 years. Clinical Infectious Diseases 2004;39(7):920-7.
Ben-Yehuda 2003 {published data only}
  • Ben-Yehuda A, Joseph A, Barenholz Y, Zeira E, Even-Chen S, Louria-Hayon I, et al. Immunogenicity and safety of a novel IL-2-supplemented liposomal influenza vaccine (INFLUSOME-VAC) in nursing-home residents. Vaccine 2003;21(23):3169-78.
Berg 2004 {published data only}
  • Berg GD, Thomas E, Silverstein S, Neel CL, Mireles M. Reducing medical service utilization by encouraging vaccines: randomized controlled trial. American Journal of Preventive Medicine 2004;27(4):284-8.
Buxton 2001 {published data only}
  • Buxton JA, Skowronski DM, Ng H, Marion SA, Li Y, King A, et al. Influenza revaccination of elderly travelers: antibody response to single influenza vaccination and revaccination at 12 weeks. Journal of Infectious Diseases 2001;184(2):188-91.
Carman 2000 {published data only}
  • Carman WF, Elder AG, Wallace LA, McAulay K, Walker A, Murray GD, et al. Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000;355(9198):93-7.
Castilla 2006 {published data only}
  • Castilla J, Arregui L, Baleztena J, Barricarte A, Brugos A, Carpintero M, et al. Incidence of influenza and influenza vaccine effectiveness in the 2004-2005 season. Anales del Sistema Sanitario de Navarra 2006;29(1):97-106.
Chen 2004 {published data only}
Chlibek 2002 {published data only}
  • Chlibek R, Beran J, Splino M. Effectiveness of influenza vaccination in healthy adults--a fourfold decrease in influenza morbidity during one influenza season. Epidemiologie, Mikrobiologie, Imunologie 2002;51(2):47-51.
Christenson 2002 {published data only}
Chumakov 1992 {published data only}
  • Chumakov MP, Beregovskii NA, Linev MB, Reizin FN, Malyshkina LP, Matrosovich MN, et al. Use of highly purified subvirion trivalent flue vaccine ("Grippovak") in groups with a high risk of complications. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1992;3:55-7.
Cohen 2004 {published data only}
Conne 1997 {published data only}
  • Conne P, Gauthey L, Vernet P, Althaus B, Que JU, Finkel B, Gluck R, et al. Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients. Vaccine 1997;15(15):1675-9.
Cruijff 1999 {published data only}
  • Cruijff M, Thijs C, Govaert T, Aretz K, Dinant GJ, Knottnerus A. The effect of smoking on influenza, influenza vaccination efficacy and on the antibody response to influenza vaccination. Vaccine 1999;17(5):426-32.
D'Alessandro 2004 {published data only}
  • D'Alessandro D, Ciriminna S, Rossini A, Bossa MC, Fara GM. Requests of medical examinations after pneumococcal & influenza vaccination in the elderly. Indian Journal of Medical Research 2004;119(Suppl):108-14.
de Bernardi 2002 {published data only}
  • de Bernardi di Valserra M, Zanasi A, Ragusa S, Gluck R, Herzog C. An open-label comparison of the immunogenicity and tolerability of intranasal and intramuscular formulations of virosomal influenza vaccine in healthy adults. Clinical Therapeutics 2002;24(1):100-11.
de Bruijn 2004 {published data only}
  • de Bruijn IA, Nauta J, Gerez L, Palache AM. Virosomal influenza vaccine: a safe and effective influenza vaccine with high efficacy in elderly and subjects with low pre-vaccination antibody titers. Virus Research 2004;103(1-2):139-45.
De Serres 2004 {published data only}
  • De Serres G, Skowronski DM, Guay M, Rochette L, Jacobsen K, Fuller T, et al. Recurrence risk of oculorespiratory syndrome after influenza vaccination: randomized controlled trial of previously affected persons. Archive of Internal Medicine 2004;164(20):2266-72.
Deguchi 2000 {published data only}
  • Deguchi Y, Takasugi Y. Efficacy of influenza vaccine in the elderly: reduction in risks of mortality and morbidity during an influenza A (H3N2) epidemic for the elderly in nursing homes. International Journal of Clinical & Laboratory Research 2000;30(1):1-4.
Deguchi 2000a {published data only}
  • Deguchi Y, Takasugi Y, Tatara K. Efficacy of influenza vaccine in the elderly in welfare nursing homes: reduction in risks of mortality and morbidity during an influenza A (H3N2) epidemic. Journal of Medical Microbiology 2000;49(6):553-6.
Deguchi 2000b {published data only}
  • Deguchi Y, Takasugi Y, Nishimura K. Vaccine effectiveness for influenza in the elderly in welfare nursing homes during an influenza A (H3N2) epidemic. Epidemiology and Infection 2000;125(2):393-7.
Deibel 1970 {published data only}
Elder 1996 {published data only}
  • Elder AG, O'Donnell B, McCruden EA, Symington IS, Carman WF. Incidence and recall of influenza in a cohort of Glasgow healthcare workers during the 1993-4 epidemic: results of serum testing and questionnaire. BMJ 1996;313(7067):1241-2.
Ender 2001 {published data only}
  • Ender PT, DeRussy PK, Caldwell MM, Taylor SE, Trevino SC, Ybarra D. The effect of a multivitamin on the immunologic response to the influenza vaccine in the elderly. Infectious Diseases in Clinical Practice. Vol. 10, Lippincott Williams & Wilkins, Inc., 2001:81-5.
Erofeeva 2001 {published data only}
  • Erofeeva MK, Paramonova MS, Maksakova VL, Kolyvanova IL, Nikolaeva EV, Shadrin AS. Vaccine prophylaxis in elderly patients. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 2001;3:91-3.
Fedson 1992 {published data only}
  • Fedson DS, Wajda A, Nicol JP, Roos LL. Disparity between influenza vaccination rates and risks for influenza-associated hospital discharge and death in Manitoba in 1982-1983. Annals of Internal Medicine 1992;116(7):550-5.
Fedson 1993 {published data only}
Fitzner 2001 {published data only}
Fukumi 1969 {published data only}
  • Fukumi H. Interpretation of influenza antibody patterns in man. Existence and significance of Hong Kong antibody in old people prior to the Hong Kong influenza epidemic. Bulletin of the World Health Organization 1969;41(3):469-73.
Fukushima 1999 {published data only}
Galanti 1976 {published data only}
  • Galanti B, Picciotto L, Ruggiero G, Romano E, Vaccaro L. Homologous and heterologous antibody response induced in man by anti-influenza vaccine containing A/England/42/72 and b/Massachusetts/71. Bollettino dell’Istituto Sieroterapico Milanese 1976;55(71):13-7.
Galasso 1977 {published data only}
  • Galasso GJ, Tyeryar FJ Jr, La Montagne JR. Overview of clinical trials of influenza vaccines, 1976. Journal of Infectious Diseases 1977;136(Suppl):425-8.
Garcia Garcia 2009 {published data only}
  • Garcia-Garcia L, Valdespino-Gómez JL, Lazcano-Ponce E, Jiminez-Corona A, Higuera-Iglesias A, Cruz-Hervert P, et al. Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case-control study in Mexico City. BMJ 2009;339:3928. [: 10.1136/bmj.b3928 ]
Garcia-Doval 2001 {published data only}
  • Garcia-Doval I, Roson E, Feal C, De la Torre C, Rodriguez T, Cruces MJ. Generalized bullous fixed drug eruption after influenza vaccination, simulating bullous pemphigoid. Acta Dermato-Venereologica 2001;81(6):450-1.
Gasparini 2002 {published data only}
  • Gasparini R, Lucioni C, Lai P, Maggioni P, Sticchi L, Durando P. Cost-benefit evaluation of influenza vaccination in the elderly in the Italian region of Liguria. Vaccine 2002;20(Suppl 5):B50-4.
Gavira 1990 {published data only}
  • Gavira FJ, Lardinois R. Cost-effectiveness analysis of antigrippal vaccination in a rural population (La Victoria, Cordoba). Medicina Clinica 1990;94(20):777-81.
Gendon 1988 {published data only}
  • Gendon I. Prevention of influenza in the aged. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1988;9(9):93-6.
Giglio 1994 {published data only}
  • Giglio E, Roggi L, Bonanni P, Giacchi M, Gasparini R. Influenza vaccination in subjects of the local health unit of Arezzo (Tuscany - Italy) during the winter 1990/91. Journal of Preventive Medicine and Hygiene 1994;35(3-4):125-30.
Glass 1978 {published data only}
  • Glass RI, Brann EA, Slade JD, Jones WE, Scally MJ, Craven RB, et al. Community-wide surveillance of influenza after outbreaks due to H3N2 (A/Victoria/75 and A/Texas/77) and H1N1 (A/USSR/77) influenza viruses, Mercer County, New Jersey, 1978. Journal of Infectious Diseases 1978;138(5):703-6.
Glezen 1987 {published data only}
Gomez de Caso 1996 {published data only}
  • Gomez de Caso JA, Franco Yague JA, Castillo Izquierdo JM, Ruiz Cosin C. Study of a disease outbreak in a home for the aged. Atencion Primaria 1996;17(3):211-4.
Govaert 1994 2 {published data only}
  • Govaert TM, Sprenger MJ, Dinant GJ, Aretz K, Masurel N, Knottnerus JA. Immune response to influenza vaccination of elderly people. A randomized double-blind placebo-controlled trial. Vaccine 1994;12(13):1185-9.
Gowda 1979 {published data only}
Grigor'eva 1994 {published data only}
  • Grigor'eva EP, Rekstin AR, Rudenko LG, Ramirez A, Barro M, Lisovskaia KV, et al. The immunogenic properties and prophylactic efficacy of a live polyvalent influenza vaccine in children 5 to 14 years old. Voprosy Virusologii 1994;39(1):26-9.
Grigor'eva 2002 {published data only}
  • Grigor'eva EP, Desheva IuA, Donina SA, Naikhin AN, Rekstin AR, Barantseva IB, et al. The comparative characteristics of the safety, immunogenic activity and prophylactic potency of the adult and children types of live influenza vaccine in schoolchildren aged 7-14 years. Voprosy Virusologii 2002;47(4):24-7.
Gross 1977 {published data only}
  • Gross PA. Reactogenicity and immunogenicity of bivalent influenza vaccine in one- and two-dose trials in children: a summary. Journal of Infectious Diseases 1977;136(Suppl):616-25.
Gross 1995 {published data only}
  • Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Annals of Internal Medicine 1995;123(7):518-27.
Guarino 1977 {published data only}
  • Guarino F, Di Peppe C, D'Antonio D, Melena E, Lattanzio FM. Immunity to the HSW1N1 virus in the older population of Chieti. Bollettino della Societa Italiana di Biologia Sperimentale 1977;53(21):1942-4.
Guillevin 1983 {published data only}
Gutierrez 2001 {published data only}
  • Gutierrez EB, Li HY, Santos AC, Lopes MH. Effectiveness of influenza vaccination in elderly outpatients in Sao Paulo city, Brazil. Revista do Instituto de Medicina Tropical de Sao Paulo 2001;43(6):317-20.
Hak 1998 {published data only}
  • Hak E, van Essen GA, Buskens E, Stalman W, de Melker RA. Is immunising all patients with chronic lung disease in the community against influenza cost effective? Evidence from a general practice based clinical prospective cohort study in Utrecht, The Netherlands. Journal of Epidemiology and Community Health 1998;52(2):120-5.
Hall 1981 {published data only}
Hampson 1997 {published data only}
  • Hampson AW, Irving LB. Influenza vaccination: cost-effective health care for the older adult?. Journal of Quality in Clinical Practice 1997;17(1):3-11.
Hara 2008 {published data only}
Harling 2004 {published data only}
  • Harling R, Hayward A, Watson JM. Implications of the incidence of influenza-like illness in nursing homes for influenza chemoprophylaxis: descriptive study. BMJ 2004;329(7467):663-4.
Harper 1985 {published data only}
Hedlund 2003 {published data only}
  • Hedlund J, Christenson B, Lundbergh P, Ortqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up. Vaccine 2003;21(25-6):3906-11.
Helliwell 1988 {published data only}
  • Helliwell BE, Drummond MF. The costs and benefits of preventing influenza in Ontario's elderly. Canadian Journal of Public Health 1988;79(3):175-80.
Hennessen 1978 {published data only}
Herzog 2003 {published data only}
  • Herzog NS, Bratzler DW, Houck PM, Jiang H, Nsa W, Shook C, et al. Effects of previous influenza vaccination on subsequent readmission and mortality in elderly patients hospitalized with pneumonia. American Journal of Medicine 2003;115(6):454-61.
Heymann 2004 {published data only}
  • Heymann AD, Shapiro Y, Chodick G, Shalev V, Kokia E, Kramer E, et al. Reduced hospitalizations and death associated with influenza vaccination among patients with and without diabetes. Diabetes Care 2004;27(11):2581-4.
Hirota 1997 {published data only}
Hoberman 2003 {published data only}
  • Hoberman A, Greenberg DP, Paradise JL, Rockette HE, Lave JR, Kearney DH, et al. Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial. JAMA 2003;290(12):1608-16.
Hope-Simpson 1970 {published data only}
Howell 1967 {published data only}
Hurwitz 1983 {published data only}
Icardi 2002 {published data only}
  • Icardi G, Durando P, Marasso P, Lai P. Vaccinations for adults at risk and the elderly. Annali di Igiene: Medicina Preventiva e di Comunita 2002;14(Suppl 3):51-8.
Ikematsu 1998 {published data only}
  • Ikematsu H, Nabeshima A, Kakuda K, Yamaji K, Hayashi J, Goto S, et al. Impact of influenza epidemics and efficacy of vaccination among geriatric inpatients. Kansenshogaku Zasshi 1998;72(1):60-6.
Ikematsu 2000 {published data only}
  • Ikematsu H, Nabeshima A, Yong C, Hayashi J, Goto S, Oka T, et al. The efficacy of influenza vaccine among geriatric inpatients. Kansenshogaku Zasshi 2000;74(1):17-23.
Isahak 2007 {published data only}
  • Isahak I, Mahayiddin AA, Ismail R. Effectiveness of influenza vaccination in prevention of influenza-like illness among inhabitants of old folk homes. Southeast Asian Journal of Tropical Medicine & Public Health 2007;38(5):841-8.
Jackson 1999 {published data only}
  • Jackson LA, Holmes SJ, Mendelman PM, Huggins L, Cho I, Rhorer J. Safety of a trivalent live attenuated intranasal influenza vaccine, FluMist, administered in addition to parenteral trivalent inactivated influenza vaccine to seniors with chronic medical conditions. Vaccine 1999;17(15-6):1905-9.
Jackson 2002 {published data only}
  • Jackson LA, Yu O, Heckbert SR, Psaty BM, Malais D, Barlow WE, et al. Influenza vaccination is not associated with a reduction in the risk of recurrent coronary events. American Journal of Epidemiology 2002;156(7):634-40.
Jahnz-Rozyk 2003 {published data only}
  • Jahnz-Rozyk K. Pharmaco-economics of anti-influenza vaccinations. Polski Merkuriusz Lekarski 2003;14(84):679-81.
Jani 1994 {published data only}
Jarstrand 1974 {published data only}
Jovanovic 1977 {published data only}
  • Jovanovic D, Delvaux AM. Clinical acceptability of live influenza vaccine in high risk subjects and children. Experience with three consecutive recombinant strains. Developments in Biological Standardization 1977;39:105-12.
Kaplan 1983 {published data only}
  • Kaplan JE, Schonberger LB, Hurwitz ES, Katona P. Guillain-Barre syndrome in the United States, 1978-1981: additional observations from the national surveillance system. Neurology 1983;33(5):633-7.
Keavey 1999 {published data only}
  • Keavey S. Preparing for the next influenza outbreak--or (inevitably) pandemic. JAAPA 1999;12(11):28-30, 33-4, 37-40.
King 1997 {published data only}
Knight 1984 {published data only}
Knottnerus 1996 {published data only}
Kurland 1984 {published data only}
  • Kurland LT, Molgaard CA, Kurland EM, Erdtmann FJ, Stebbing GE. Lack of association of swine flu vaccine and rheumatoid arthritis. Mayo Clinic Proceedings 1984;59(12):816-21.
Landi 2003 {published data only}
  • Landi F, Onder G, Cesari M, Gravina EM, Lattanzio F, Russo A, et al. Effects of influenza vaccination on mortality among frail, community-living elderly patients: an observational study. Aging Clinical and Experimental Research 2003;15(3):254-8.
Landi 2006 {published data only}
  • Landi F, Onder G, Cesari M, Russo A, Barillaro C, Bernabei R, et al. In a prospective observational study, influenza vaccination prevented hospitalization among older home care patients. Journal of Clinical Epidemiology 2006;59(10):1072-7.
Lavergne 1980 {published data only}
  • Lavergne B, Frappier-Davignon L, Chagnon A, Burr-Paxton M, Quevillon M, Pavilanis V, et al. Reactogenicity and serologic response to trivalent inactivated A/Texas, A/USSR and B/Hong Kong whole-virus influenza vaccine in human volunteers. Canadian Journal of Public Health 1980;71(1):25-31.
Lawson 2000 {published data only}
  • Lawson F, Baker V, Au D, McElhaney JE. Standing orders for influenza vaccination increased vaccination rates in inpatient settings compared with community rates. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 2000;55(9):M522-6.
Lindahl 1999 {published data only}
  • Lindahl G, Perman E. Influenza vaccine caused problems in joints. Compensation from the drug insurance authority. Lakartidningen 1999;96(37):3912-4.
Lohse 1999 {published data only}
  • Lohse A, Michel F, Auge B, Toussirot E, Wendling D. Vascular purpura and cryoglobulinemia after influenza vaccination. Case-report and literature review. Revue du Rhumatisme (English ed.) 1999;66(6):359-60.
Luce 2001 {published data only}
  • Luce BR, Zangwill KM, Palmer CS, Mendelman PM, Yan L, Wolff MC, et al. Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children. Pediatrics 2001;108(2):E24.
Mair 1974 {published data only}
Mandal 1973 {published data only}
Manzano 2000 {published data only}
  • Manzano E, Grau A, Sequeira E, Valles JA. Possible toxicoderma secondary to influenza vaccination. Atencion Primaria 2000;26(6):429.
Manzoli 2007 {published data only}
  • Manzoli L, Villari P, Granchelli C, Savino A, Carunchio C, Pacifico D, et al. Cohort analysis on influenza vaccine effectiveness for the elderly as a study case to evaluate an alternative approach involving general practitioners for routine assessment of vaccination impact. European Journal of Public Health 2007;17:28-9.
Margolis 1990b {published data only}
Marine 1973 {published data only}
Marinich 1997 {published data only}
  • Marinich IG, Paramonova MS, Erofeeva MK, Maksakova VL, Nikolaeva VM, Naikhin AN, et al. The immunoprophylaxis of influenza among elderly persons. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1997;3:60-4.
Martin 1997 {published data only}
Marwick 1995 {published data only}
Masurel 1979 {published data only}
  • Masurel N. Immunization of elderly subjects with subunit and total virus vaccine containing H1N1 influenza virus. Nederlands Tijdschrift Voor Geneeskunde 1979;123(6):196-9.
Maxim 1998 {published data only}
  • Maxim R. Adult immunization. Medicine and Health, Rhode Island 1998;81(8):272-3.
Mayon-White 1994 {published data only}
McCall 1996 {published data only}
McCarthy 1978 {published data only}
McElhaney 2002 {published data only}
McGuffey 1993 {published data only}
  • McGuffey EC. Flu vaccinations. American Pharmacy 1993;NS33(11):24.
Meiklejohn 1989 {published data only}
  • Meiklejohn G, Hoffman R, Graves P. Effectiveness of influenza vaccine when given during an outbreak of influenza A/H3N2 in a nursing home. Journal of the American Geriatrics Society 1989;37(5):407-10.
Mendelman 2001 {published data only}
  • Mendelman PM, Cordova J, Cho I. Safety, efficacy and effectiveness of the influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) in healthy children and healthy adults. Vaccine 2001;19(17-9):2221-6.
Meynaar 1991 {published data only}
Mignogna 2000 {published data only}
Miller 1975 {published data only}
  • Miller LW, Hume EB, O'Brien FR, Togo Y, Hornick RB. Alice strain live attenuated influenza (H3N2) vaccine in an elderly population. American Journal of Epidemiology 1975;101(4):340-6.
Modlin 1977 {published data only}
  • Modlin JF, Smith DH, Harding L. Clinical trials of bivalent A/New Jersey/76-A/Victoria/75 influenza vaccines in high-risk children. Journal of Infectious Diseases 1977;136(Suppl):626-31.
Monto 1994 {published data only}
Moreno 2009 {published data only}
Mostow 1969 {published data only}
  • Mostow SR, Schoenbaum SC, Dowdle WR, Coleman MT, Kaye HS. Studies with inactivated influenza vaccines purified by zonal centrifugation. 1. Adverse reactions and serological responses. Bulletin of the World Health Organization 1969;41(3):525-30.
Mostow 1988 {published data only}
Nguyen-van-Tam 1992 {published data only}
Nichol 1996 {published data only}
Nichol 1999a {published data only}
Nichol 1999b {published data only}
Nichol 1999c {published data only}
  • Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease. Annals of Internal Medicine 1999;130(5):397-403.
Nichol 1999d {published data only}
  • Nichol KL, Mendelman PM, Mallon KP, Jackson LA, Gorse GJ, Belshe RB, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA 1999;282(2):137-44.
Nichol 2002 {published data only}
Nichol 2007 {published data only}
Nicholson 1979 {published data only}
  • Nicholson KG, Tyrrell DA, Harrison P, Potter CW, Jennings R, Clark A, et al. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. Journal of Biological Standardization 1979;7(2):123-36.
Nicholson 1983 {published data only}
Nicholson 1990a {published data only}
  • Nicholson KG, Baker DJ, Farquhar A, Hurd D, Kent J, Smith SH. Acute upper respiratory tract viral illness and influenza immunization in homes for the elderly. Epidemiology and Infection 1990;105(3):609-18.
Nicholson 1990b {published data only}
Nicholson 1992 {published data only}
  • Nicholson KG, Baker DJ, Chakraverty P, Farquhar A, Hurd D, Kent J, et al. Immunogenicity of inactivated influenza vaccine in residential homes for elderly people. Age and Ageing 1992;21(3):182-8.
Nielsen 1996 {published data only}
  • Nielsen PV. Vaccination against influenza of the elderly population of Copenhagen. Ugeskrift for Laeger 1996;158(48):6928.
Nygaard 1999 {published data only}
  • Nygaard HA. Prevention of influenza in nursing homes. Tidsskrift for den Norske Laegeforening 1999;119(14):2079.
Odelin 1993 {published data only}
  • Odelin MF, Pozzetto B, Aymard M, Defayolle M, Jolly-Million J. Role of influenza vaccination in the elderly during an epidemic of A/H1N1 virus in 1988-1989: clinical and serological data. Gerontology 1993;39(2):109-16.
Odelin 2003 {published data only}
  • Odelin MF, Momplot C, Bourlet T, Gonthier R, Aymard M, Pozzetto B. Temporal surveillance of the humoral immunity against influenza vaccine in the elderly over 9 consecutive years. Gerontology 2003;49(4):233-9.
Ohmit 1995 {published data only}
  • Ohmit SE, Furumoto-Dawson A, Monto AS, Fasano N. Influenza vaccine use among an elderly population in a community intervention. American Journal of Preventive Medicine 1995;11(4):271-6.
Ortqvist 2007 {published data only}
  • Ortqvist A, Granath F, Askling J, Hedlund J. Influenza vaccination and mortality: prospective cohort study of the elderly in a large geographical area [see comment]. European Respiratory Journal 2007;30(3):414-22.
Oshitani 2000 {published data only}
  • Oshitani H, Saito R, Seki N, Tanabe N, Yamazaki O, Hayashi S, et al. Influenza vaccination levels and influenza-like illness in long-term-care facilities for elderly people in Niigata, Japan, during an influenza A (H3N2) epidemic. Infection Control and Hospital Epidemiology 2000;21(11):728-30.
Parkin 1978 {published data only}
  • Parkin WE, Beecham HJ, Streiff E, Sharrar RG, Harris JC. Relationship studied in Pennsylvania. Guillain-Barre syndrome and influenza immunization. Pennsylvania Medicine 1978;81(4):47-8, 50-2.
Parsons 1997 {published data only}
Patel 1988 {published data only}
Patriarca 1985 {published data only}
  • Patriarca PA, Weber JA, Meissner MK, Stricof RL, Dateno B, Braun JE. Use of influenza vaccine in nursing homes. Journal of the American Geriatrics Society 1985;33(7):463-6.
Patriarca 1994 {published data only}
Pena-Rey 2003 {published data only}
  • Pena-Rey I, Perez-Farinos N, Sarria-Santamera A. Determinants of flu vaccination in Galician women over 65 years old. Atencion Primaria 2003;31(7):462-3.
Perez 2000 {published data only}
Perez-Tirse 1992 {published data only}
  • Perez-Tirse J, Gross PA. Review of cost-benefit analyses of influenza vaccine. Pharmacoeconomics 1992;2(3):198-206.
Perucchini 2004 {published data only}
Peters 1988 {published data only}
  • Peters NL, Meiklejohn G, Jahnigen DW. Antibody response of an elderly population to a supplemental dose of influenza B vaccine. Journal of the American Geriatrics Society 1988;36(7):593-9.
Philip 1969 {published data only}
  • Philip RN, Bell JA, Davis DJ, Beem MO, Beigelman PM, Engler JI, et al. Epidemiologic studies on influenza in familial and general population groups, 1951-1956. V. Effectiveness of adjuvant vaccines. American Journal of Epidemiology 1969;90(6):471-83.
Phillips 1970 {published data only}
  • Phillips CA, Forsyth BR, Christmas WA, Gump DW, Whorton EB, Rogers I, et al. Purified influenza vaccine: clinical and serologic responses to varying doses and different routes of immunization. Journal of Infectious Diseases 1970;122(1):26-32.
Phillips 1971 {published data only}
Piedra 2002 {published data only}
  • Piedra PA, Yan L, Kotloff K, Zangwill K, Bernstein DI, King J, et al. Safety of the trivalent, cold-adapted influenza vaccine in preschool-aged children. Pediatrics 2002;110(4):662-72.
Poe 1977 {published data only}
  • Poe GS, Massey JT. Estimating influenza cases and vaccinations by means of weekly rapid reporting system; methodological considerations and results obtained in the U.S. health interview survey. Public Health Reports 1977;92(4):299-306.
Poland 2002 {published data only}
Potter 1997 {published data only}
  • Potter J, Stott DJ, Roberts MA, Elder AG, O'Donnell B, Knight PV, et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. Journal of Infectious Diseases 1997;175(1):1-6.
Powers 1991 {published data only}
  • Powers DC, Fries LF, Murphy BR, Thumar B, Clements ML. In elderly persons live attenuated influenza A virus vaccines do not offer an advantage over inactivated virus vaccine in inducing serum or secretory antibodies or local immunologic memory. Journal of Clinical Microbiology 1991;29(3):498-505.
Pregliasco 1997 {published data only}
  • Pregliasco F, Sodano L, Mensi C, Borghetti MC, Camorali L, D'Argenio P. Anti-influenza vaccination: knowledge, attitude and practice of the elderly residing in the city of Milan. Annali di Igiene: Medicina Preventiva e di Comunita 1997;9(2):127-31.
Pregliasco 1999 {published data only}
  • Pregliasco F, Sodano L, Mensi C, Selvaggi MT, Adamo B, D'Argenio P, et al. Influenza vaccination among the elderly in Italy. Bulletin of the World Health Organization 1999;77(2):127-31.
Profeta 1987 {published data only}
Provinciali 1994 {published data only}
  • Provinciali M, Di Stefano G, Muzzioli M, Scarpazza P, Colombo D, Migliorino M, et al. Impaired antibody response to influenza vaccine in institutionalized elderly. Annals of the New York Academy of Sciences 1994;717:307-14.
Puig Barberà 1995 {published data only}
  • Puig Barbera J, Marquez Calderon S. Effectiveness of influenza vaccine in the elderly. A critical review of the bibliography. Medicina Clinica 1995;105(17):645-8.
Puretz 1979 {published data only}
Pyhala 1997 {published data only}
  • Pyhala R, Hovi T. Influenza vaccinations--use with care. Duodecim 1997;113(21):2129, 2131.
Quinlisk 1990 {published data only}
  • Quinlisk P, Smithee L. Shanghai in Oklahoma?. Journal of the Oklahoma State Medical Association 1990;83(11):562-4.
Quinnan 1983 {published data only}
  • Quinnan GV, Schooley R, Dolin R, Ennis FA, Gross P, Gwaltney JM. Serologic responses and systemic reactions in adults after vaccination with monovalent A/USSR/77 and trivalent A/USSR/77, A/Texas/77, B/Hong Kong/72 influenza vaccines. Reviews of Infectious Diseases 1983;5(4):748-57.
Rao 1982 {published data only}
  • Rao BL, Kadam SS, Pavri KM, Kothavale VS. Epidemiological, clinical, and virological features of influenza outbreaks in Pune, India, 1980. Bulletin of the World Health Organization 1982;60(4):639-42.
Read 2000 {published data only}
  • Read CA, Mohsen A, Nguyen-Van-Tam JS, McKendrick M, Kudesia G. Outbreaks of influenza A in nursing homes in Sheffield during the 1997-1998 season: implications for diagnosis and control. Journal of Public Health Medicine 2000;22(1):116-20.
Reedy 2000 {published data only}
  • Reedy JL, Paul SM, Zanna MT. Influenza: prevention and treatment. New Jersey Medicine 2000;97(11):41-50.
Ruben 1973 {published data only}
Rubin 1973 {published data only}
Rudenko 1981 {published data only}
  • Rudenko LG, Zykov MP. Protection of the elderly against influenza (a review of the literature). Vrachebnoe Delo 1981;12:8-11.
Rudenko 1993 {published data only}
  • Rudenko LG, Slepushkin AN, Monto AS, Kendal AP, Grigorieva EP, Burtseva EP, et al. Efficacy of live attenuated and inactivated influenza vaccines in schoolchildren and their unvaccinated contacts in Novgorod, Russia. Journal of Infectious Diseases 1993;168(4):881-7.
Ruel 2002 {published data only}
  • Ruel N, Odelin MF, Jolly J, Momplot C, Diana MC, Bourlet T, et al. Outbreaks due to respiratory syncytial virus and influenza virus A/H3N in institutionalized aged. Role of immunological status to influenza vaccine and possible implication of caregivers in the transmission. Presse Medicale 2002;31(8):349-55.
Ruf 2004 {published data only}
  • Ruf BR, Colberg K, Frick M, Preusche A. Open, randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an MF59-adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly. Infection 2004;32(4):191-8.
Runehagen 2002 {published data only}
  • Runehagen A, Petersson C. Free vaccine and increased information suggested to increase the vaccination coverage. A questionnaire study concerning influenza vaccination of elderly persons and other risk groups. Lakartidningen 2002;99(6):496-7.
Russell 2001 {published data only}
  • Russell ML, Ferguson CA. Improving population influenza vaccine coverage through provider feedback and best practice identification. Canadian Journal of Public Health 2001;92(5):345-6.
Ryan 1984 {published data only}
  • Ryan MP, MacLeod AF. A comparison of adverse effects of two influenza vaccines, and the influence on subsequent uptake. Journal of the Royal College of General Practitioners 1984;34(265):442-4.
Sadler 2000 {published data only}
  • Sadler C. Needle work. Nursing Standard 2000;15(7):18-9.
Sandrini 1997 {published data only}
  • Sandrini MC, Pregliasco F, Mensi C, Giardini G, Lucchi T, Santambrogio D, et al. Immunogenicity and efficacy field evaluation (1994-1995 season) of influenza vaccine in a noninstitutionalized elderly population. Annali di Igiene: Medicina Preventiva e di Comunita 1997;9(5):373-9.
Saslaw 1966 {published data only}
  • Saslaw S, Carlisle HN, Perkins RL. Effect of dosage and influenza vaccine content on antibody response in an aged population. American Journal of the Medical Sciences 1966;251(2):195-206.
Satsuta 1985 {published data only}
  • Satsuta K, Ogawa M, Makabe A, Ichinose T. On death due to influenza. Nippon Ika Daigaku Zasshi 1985;52(3):347-51.
Schoenbaum 1969 {published data only}
  • Schoenbaum SC, Mostow SR, Dowdle WR, Coleman MT, Kaye HS. Studies with inactivated influenza vaccines purified by zonal centrifugation. 2. Efficacy. Bulletin of the World Health Organization 1969;41(3):531-5.
Schwartz 1995 {published data only}
  • Schwartz K. Efficacy of influenza vaccine in the elderly. Journal of Family Practice 1995;40(3):298-9.
Selvaraj 1998 {published data only}
Serie 1977 {published data only}
  • Serie C, Barme M, Hannoun C, Thibon M, Beck H, Aquino JP. Effects of vaccination on an influenza epidemic in a geriatric hospital. Developments in Biological Standardization 1977;39:317-21.
Sethi 2002 {published data only}
Sharbaugh 1997 {published data only}
  • Sharbaugh RJ. Influenza--it's that time again. Home Care Provider 1997;2(5):227-8.
Shinkawa 2002 {published data only}
Shoji 2003 {published data only}
Siewert 1988 {published data only}
Simonsen 2005 {published data only}
  • Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ, Miller MA. Impact of influenza vaccination on seasonal mortality in the US elderly population. Archive of Internal Medicine 2005;165(3):265-72.
Skowronski 2003 {published data only}
  • Skowronski DM, De Serres G, Scheifele D, Russell ML, Warrington R, Davies HD, et al. Randomized, double-blind, placebo-controlled trial to assess the rate of recurrence of oculorespiratory syndrome following influenza vaccination among persons previously affected. Clinical Infectious Diseases 2003;37(8):1059-66.
Skull 2009 {published data only}
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Slepuskin 1967 {published data only}
  • Slepuskin AN, Bobyleva TK, Russina AE, Vitkina BS, Ellengorn NS, Zdanov VM. Evaluation of the effectiveness of large-scale vaccination against influenza in the USSR. Bulletin of the World Health Organization 1967;36(3):385-95.
Sloan 1993 {published data only}
Socan 2004 {published data only}
Solomon 1984 {published data only}
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Solomon 1996 {published data only}
Solomon 1999 {published data only}
Spencer 1979 {published data only}
  • Spencer MJ, Cherry JD, Powell KR, Sumaya CV. A clinical trial with Alice/R-75 strain, live attenuated serum inhibitor-resistant intranasal bivalent influenza A/B vaccine. Medical Microbiology and Immunology 1979;167(1):1-9.
Sprenger 1990 {published data only}
Squarcione 2003 {published data only}
  • Squarcione S, Sgricia S, Biasio LR, Perinetti E. Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects. Vaccine 2003;21(11-2):1268-74.
Stamboulian 1999 {published data only}
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Stott 2001 {published data only}
Tamblyn 1997 {published data only}
Thompson 1988 {published data only}
  • Thompson MP. Is routine influenza immunization indicated for people over 65 years of age? An affirmative view. Journal of Family Practice 1988;26(2):211-4.
Treanor 1992 {published data only}
  • Treanor JJ, Mattison HR, Dumyati G, Yinnon A, Erb S, O'Brien D, et al. Protective efficacy of combined live intranasal and inactivated influenza A virus vaccines in the elderly. Annals of Internal Medicine 1992;117(8):625-33.
Treanor 1998 {published data only}
Tsai 2007 {published data only}
Upshur 2000 {published data only}
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Urquhart 1974 {published data only}
Uyeki 2003 {published data only}
  • Uyeki TM, Zane SB, Bodnar UR, Fielding KL, Buxton JA, Miller JM, et al. Large summertime influenza A outbreak among tourists in Alaska and the Yukon Territory. Clinical Infectious Diseases 2003;36(9):1095-102.
Vallee 2000 {published data only}
Van Horren 1976 {published data only}
van Vuuren 2009 {published data only}
Verde 1973 {published data only}
  • Verde F, Frezza G, Russo V, Visconti M. Antibody response to anti-influenza vaccination with vaccine purified by differential ultracentrifugation and with vaccine purified by zonal ultracentrifugation. Bollettino della Societa Italiana di Biologia Sperimentale 1973;49(4):178-81.
Verweij 2002 {published data only}
Vila-Corcoles 2005 {published data only}
  • Vila-Corcoles A, Ochoa-Gondar O, Ansa-Echeverria X, Gomez-Sorribes A, Espelt-Aluja P, Pascual-Moron I. Influenza vaccination and mortality in the elderly [see comment]. Medicina Clinica 2005;125(18):689-91.
Visconti 1973 {published data only}
  • Visconti M, Verde F, Frezza G, Russo V. Persistence of antibodies inhibiting hemagglutination by influenza viruses in aged vaccinated women. Changes in antibody titer after re-vaccination. Bollettino della Societa Italiana di Biologia Sperimentale 1973;49(4):173-7.
Voordouw 2004 {published data only}
  • Voordouw AC, Sturkenboom MC, Dieleman JP, Stijnen T, Smith DJ, van der Lei J, et al. Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. JAMA 2004;292(17):2089-95.
Voordouw 2006 {published data only}
  • Voordouw BC, Sturkenboom MC, Dieleman JP, Stijnen T, van der Lei J, Stricker BH. Annual influenza vaccination in community-dwelling elderly individuals and the risk of lower respiratory tract infections or pneumonia. Archives of Internal Medicine 2006;166(18):1980-5.
Vu 2002 {published data only}
Wagner 1993 {published data only}
  • Wagner TA, Skiba R. Tolerance of preventive influenza vaccination with a subunit vaccine. Bevolkerung und Kultur. Reihe 7: Gesundheitswesen 1993;55(11):587-8.
Wagner 1994 {published data only}
Wakefield 1990 {published data only}
Wang 1986 {published data only}
  • Wang A, Hannoun C, Cadiot P. Theoretical and practical prospects of influenza vaccination in aged persons [Perspectives theoriques et pratiques de la vaccination antigrippale chez la personne agee]. Medecine et Hygiene 1986;44(1656):1373-6.
Wang 2002 {published data only}
  • Wang CS, Wang ST, Chou P. Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community. Vaccine 2002;20(19-20):2494-9.
Warburton 1972 {published data only}
  • Warburton MF, Jacobs DS, Langsford WA, White GE. Herd immunity following subunit influenza vaccine administration. Medical Journal of Australia 1972;2(2):67-70.
Wareing 2001 {published data only}
Watson 1997 {published data only}
Weaver 2001 {published data only}
Wiehl 2001 {published data only}
  • Wiehl M. Influenza vaccination. Even colleagues try and avoid it. MMW Fortschritte der Medizin 2001;143(43):14.
Williams 1980 {published data only}
Wilson 1994 {published data only}
Winer 1984 {published data only}
Wise 1977 {published data only}
  • Wise TG, Dolin R, Mazur MH, Top FH Jr, Edelman R, Ennis FA. Serologic responses and systemic reactions in adults after vaccination with bivalent A/Victoria/75-A/New Jersey/76 and monovalent B/Hong Kong/72 influenza vaccines. Journal of Infectious Diseases 1977;136(Suppl):507-17.
Wood 2000 {published data only}
  • Wood SC, Nguyen VH, Schmidt C. Economic evaluations of influenza vaccination in the elderly: impact on public health policy (for bibl. only). Disease Management and Health Outcomes 2000;8(5):273-85.
Woratz 1984 {published data only}
  • Woratz C, Sinnecker H, Woratz G, Giard W, Muller D, Hajduk F, et al. Use of excess mortality as a criterion of effectiveness in vaccination for the prevention of influenza. Zeitschrift fur die Gesamte Hygiene und ihre Grenzgebiete 1984;30(9):488-90.
Yassi 1993 {published data only}
  • Yassi A, Mcgill M, Holton C, Nicolle L. Morbidity, cost and role of health care worker transmission in an outbreak in a tertiary care hospital. Canadian Journal of Infectious Diseases 1993;4(1):52-6.
Zambon 2001 {published data only}
  • Zambon M, Hays J, Webster A, Newman R, Keene O. Diagnosis of influenza in the community: relationship of clinical diagnosis to confirmed virological, serologic, or molecular detection of influenza. Archives of Internal Medicine 2001;161(17):2116-22.
Zimmerman 2004 {published data only}
  • Zimmerman RK, Nowalk MP, Bardella IJ, Fine MJ, Janosky JE, Santibanez TA, et al. Physician and practice factors related to influenza vaccination among the elderly. American Journal of Preventive Medicine 2004;26(1):1-10.
Zoffmann 1977 {published data only}
  • Zoffmann H, Von Magnus H. Swine influenza. Ugeskrift for Laeger 1977;139(5):259-61.
Zourbas 1973 {published data only}
  • Zourbas J, Barme M, Paillard R, Reynaud R, Morvan A, Megret P. New advance in influenza vaccination. 2. Clinical and immunologic study, in Rennes, of a Pasteur 30-c strain. Nouvelle Presse Medicale 1973;2(29):1939-43.
Zuckerman 1990 {published data only}
Zuckerman 1992 {published data only}
Zuckerman 1993 {published data only}

Additional references

  1. Top of page
  2. Abstract摘要Résumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
ACIP 2005
  • Advisory Committee on Immunization Practices. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Morbidity and Mortality Weekly Report 2005;54(RR-8):1-40.
CDC 2004
  • Centers for Disease Control. Updated interim influenza vaccination recommendations : 2004-2005 influenza season. http://www.cdc.gov/flu (accessed 31 December 2004) 2004.
DerSimonian 1986
Dickersin 1994
Eurich 2008
  • Eurich DT, Marrie TJ, Johnstone J, Majumdar SR. Mortality reduction with influenza vaccine in patients with pneumonia outside "flu" season: pleiotropic benefits or residual confounding? [see comment]. American Journal of Respiratory & Critical Care Medicine 2008;178(5):527-33.
Fukushima 2008
  • Fukushima W, Hayashi Y, Mizuno Y, Suzuki K, Kase T, Ohfuji S, et al. Selection bias in evaluating of influenza vaccine effectiveness: a lesson from an observational study of elderly nursing home residents. Vaccine 2008;26(50):6466-9.
Glezen 2006
  • Glezen WP, Simonsen L. Commentary: benefits of influenza vaccine in US elderly--new studies raise questions. International Journal of Epidemiology 2006;35(2):352-3. [: doi:10.1093/ije/dyi293]
Greenland 1987
Groenwold 2008
  • Groenwold RHH, Hoes AW, Nichol KL, Hak E. Quantifying the potential role of unmeasured confounders: the example of influenza vaccination. International Journal of Epidemiology 2008;37(6):1422-9.
Groenwold 2009
Hak 2006
  • Hak E, Hoes AW, Nordin J, Nichol KL. Benefits of influenza vaccine in US elderly - appreciating issues of confounding bias and precision. International Journal of Epidemiology 2006;35(3):800-2.
Higgins 2002
Higgins 2003
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008] The Cochrane Collaboration (available from www.cochrane-handbook.org.). Chichester, UK: Wiley-Blackwell, 2008.
Hirota 2008
Jackson 2006a
  • Jackson LA, Jackson ML, Nelson JC, Neuzil KM, Weiss NS. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. International Journal of Epidemiology 2006;35(2):337-44. [: doi:10.1093/ije/dyi274]
Jackson 2006b
  • Jackson LA, Nelson JC, Benson P, Neuzil KM, Reid RJ, Psaty BM, et al. Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors. International Journal of Epidemiology 2005;35(2):345-52. [: doi:10.1093/ije/dyi275]
Jackson 2006c
  • Jackson LA, Jackson ML, Weiss NS. Bias in studies of influenza vaccine effectiveness: the authors reply to Hak et al. International Journal of Epidemiology 2006;35(3):799-800.
Jackson 2006d
  • Jackson LA, Nelson JC, Benson P, Neuzil KM, Reid RJ, Psaty BM, et al. Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors [see comment]. International Journal of Epidemiology 2006;35(2):345-52.
Jackson 2006e
  • Jackson LA, Jackson ML, Nelson JC, Neuzil KM, Weiss NS. Evidence of bias in estimates of influenza vaccine effectiveness in seniors [see comment]. International Journal of Epidemiology 2006;35(2):337-44.
Jefferson 2009
  • Jefferson T, Di Pietrantonj C, Debalini MG, Rivetti A, Demicheli V. Study  quality, concordance, take home message, funding and impact: their relationship in influenza vaccines studies. BMJ (available http://www.bmj.com/cgi/content/abstract/338/feb12_2/b354?ct=ct) 2009;338:354.
Lefebvre 2008
  • Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews. Chichester, UK: Wiley-Blackwell, 2008.
Nichol 2008
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  • Scottish Intercollegiate Guideline Network. Search Filters, Methodology. http://www.sign.ac.uk/methodology/filters.html (last modified 3 August 2009; accessed 2 October 2009) 2009.
Thomas 2010
van Essen 2003
  • van Essen GA, Palache AM, Forleo E, Fedson DS. Influenza vaccination in 2000: recommendations and vaccine use in 50 developed and rapidly developing countries. Vaccine 2003;21(16):1780-5.
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References to other published versions of this review

  1. Top of page
  2. Abstract摘要Résumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Jefferson 2005
  • Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 2005;366(9492):1165-74.
Rivetti 2006