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Cochrane Database of Systematic Reviews Review - Intervention

Vaccines for preventing influenza in healthy adults

Authors' declarations of interest

Version published: 13 March 2014 Version history

https://doi.org/10.1002/14651858.CD001269.pub5

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Abstract

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Background

Different types of influenza vaccines are currently produced worldwide. Vaccination of pregnant women is recommended internationally, while healthy adults are targeted in North America.

Objectives

To identify, retrieve and assess all studies evaluating the effects (efficacy, effectiveness and harm) of vaccines against influenza in healthy adults, including pregnant women.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), MEDLINE (January 1966 to May 2013) and EMBASE (1990 to May 2013).

Selection criteria

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

Data collection and analysis

Two review authors independently assessed trial quality and extracted data.

Main results

We included 90 reports containing 116 data sets; among these 69 were clinical trials of over 70,000 people, 27 were comparative cohort studies (about eight million people) and 20 were case‐control studies (nearly 25,000 people). We retrieved 23 reports of the effectiveness and safety of vaccine administration in pregnant women (about 1.6 million mother‐child couples).

The overall effectiveness of parenteral inactivated vaccine against influenza‐like illness (ILI) is limited, corresponding to a number needed to vaccinate (NNV) of 40 (95% confidence interval (CI) 26 to 128). The overall efficacy of inactivated vaccines in preventing confirmed influenza has a NNV of 71 (95% CI 64 to 80). The difference between these two values depends on the different incidence of ILI and confirmed influenza among the study populations: 15.6% of unvaccinated participants versus 9.9% of vaccinated participants developed ILI symptoms, whilst only 2.4% and 1.1%, respectively, developed laboratory‐confirmed influenza.

No RCTs assessing vaccination in pregnant women were found. The only evidence available comes from observational studies with modest methodological quality. On this basis, vaccination shows very limited effects: NNV 92 (95% CI 63 to 201) against ILI in pregnant women and NNV 27 (95% CI 18 to 185) against laboratory‐confirmed influenza in newborns from vaccinated women.

Live aerosol vaccines have an overall effectiveness corresponding to a NNV 46 (95% CI 29 to 115).

The performance of one‐dose or two‐dose whole virion pandemic vaccines was higher, showing a NNV of 16 (95% CI 14 to 20) against ILI and a NNV of 35 (95% CI 33 to 47) against influenza, while a limited impact on hospitalisation was found (NNV 94, 95% CI 70 to 1022).

Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms. No evidence of association with serious adverse events was found, but the harms evidence base was limited.

The overall risk of bias in the included trials is unclear because it was not possible to assess the real impact of bias.

Authors' conclusions

Influenza vaccines have a very modest effect in reducing influenza symptoms and working days lost in the general population, including pregnant women. No evidence of association between influenza vaccination and serious adverse events was found in the comparative studies considered in the review. This review includes 90 studies, 24 of which (26.7%) were funded totally or partially by industry. Out of the 48 RCTs, 17 were industry‐funded (35.4%).

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Vaccines to prevent influenza in healthy adults

Review question

We evaluated the effect of immunisation with influenza vaccines on preventing influenza A or B infections (efficacy), influenza‐like illness (ILI) and its consequences (effectiveness), and determined whether exposure to influenza vaccines is associated with serious or severe harms. The target populations were healthy adults, including pregnant women and newborns.

Background

Over 200 viruses cause influenza and ILI, producing the same symptoms (fever, headache, aches, pains, cough and runny noses). Without laboratory tests, doctors cannot distinguish between them as both last for days and rarely lead to death or serious illness. At best, vaccines may only be effective against influenza A and B, which represent about 10% of all circulating viruses. Annually, the World Health Organization estimates which viral strains should be included in the next season's vaccinations.

Inactivated vaccine is prepared by treating influenza viruses with a specific chemical agent that “kills” the virus. Final preparations can contain either the complete viruses (whole vaccine) or the active part of them (split or subunit vaccines). These kind of vaccines are normally intramuscularly administered (parenteral route)

Live attenuated vaccines is prepared by growing the influenza viruses through a series of cell cultures or animal embryos. With each passage, the viruses lose their ability to replicate in human cells but can still stimulate the immune system. Live attenuated vaccine are administered as aerosol in the nostrils (intranasal route).

The virus strains contained in the vaccine are usually those that are expected to circulate in the following epidemic seasons (two type A and one B strains), accordingly to the recommendations of the World Health Organization (seasonal vaccine).

Pandemic vaccine contains only the virus strain that is responsible of the pandemic (i.e. the type A H1N1 for the 2009/2010 pandemic).

Study characteristics

The evidence is current to May 2013. In this update, 90 reports of 116 studies compared the effect of influenza vaccine with placebo or no intervention. Sixty‐nine reports were clinical trials (over 70,000 people), 27 were comparative cohort studies (about eight million people) and 20 were case‐control studies (nearly 25,000 people). Of the 116 studies, 23 (three case‐control and 20 cohort studies) were performed during pregnancy (about 1.6 million mother‐child couples).

Key results

The preventive effect of parenteral inactivated influenza vaccine on healthy adults is small: at least 40 people would need vaccination to avoid one ILI case (95% confidence interval (CI) 26 to 128) and 71 people would need vaccination to prevent one case of influenza (95% CI 64 to 80). Vaccination shows no appreciable effect on working days lost or hospitalisation.

The protection against ILI that is given by the administration of inactivated influenza vaccine to pregnant women is uncertain or at least very limited; the effect on their newborns is not statistically significant.

The effectiveness of live aerosol vaccines on healthy adults is similar to inactivated vaccines: 46 people (95% CI 29 to 115) would need immunisation to avoid one ILI case.

The administration of seasonal inactivated influenza vaccine is not associated with the onset of multiple sclerosis, optic neuritis (inflammation of the optic nerve of the eye) or immune thrombocytopaenic purpura (a disease that affects blood platelets). The administration of pandemic monovalent H1N1 inactivated vaccine is not associated with Guillain‐Barré syndrome (a disease that affects the nerves of the limbs and body).

Evidence suggests that the administration of both seasonal and 2009 pandemic vaccines during pregnancy has no significant effect on abortion or neonatal death.

Quality of the evidence

The real impact of biases could not be determined for about 70% of the included studies (e.g. insufficient reporting details, very different scores among the items evaluated). About 20% of the included studies (mainly cohorts) had a high risk of bias. Just under 10% had good methodological quality.

Authors' conclusions

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Implications for practice

The results of this review provide no evidence for the utilisation of vaccination against influenza in healthy adults as a routine public health measure. As healthy adults have a low risk of complications due to respiratory disease, the use of the vaccine may only be advised as an individual protective measure.

Implications for research

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

Background

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Description of the condition

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

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

Description of the intervention

Currently there are three types of influenza vaccines:

  1. whole virion vaccines which consist of complete viruses that have been 'killed' or inactivated, so that they are not infectious but retain their strain‐specific antigenic properties;

  2. subunit virion vaccines, which are made of surface antigens (H and N) only;

  3. split virion vaccines in which the viral structure is broken up by a disrupting agent.

These vaccines contain both surface and internal antigens. In addition, a variety of non‐European manufacturers produce live attenuated vaccines. Traditionally, whole virion vaccines are thought to be the less well tolerated because of the presence of a lipid stratum on the surface of the viral particles (a remnant of the host cell membrane coating the virion, when budding from the host cell).

Influenza vaccines are produced worldwide. Periodic antigenic drifts and shifts pose problems for vaccine production and procurement, as a new vaccine closely matching the circulating antigenic configuration must be produced and procured for the beginning of each new influenza 'season'. To achieve this, the World Health Organization (WHO) has established a worldwide surveillance system, allowing the identification and isolation of viral strains circulating the different parts of the globe. Sentinel practices recover viral particles from the nasopharynx of patients with influenza‐like symptoms and the samples are swiftly sent to the laboratories of the national influenza centres (110 laboratories in 79 countries). When new strains are detected the samples are sent to one of the four WHO reference centres (London, Atlanta, Tokyo and Melbourne) for antigenic analysis. Information on the circulating strain is then sent to the WHO, which in February of each year recommends, through a committee, the strains to be included in the vaccine for the forthcoming 'season'. Individual governments may or may not follow the WHO recommendations. Australia, New Zealand and, more recently, South Africa follow their own recommendations for vaccine content. Surveillance and early identification thus play a central part in the composition of the vaccine.

How the intervention might work

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

The ACIP 2010 document update recommends routine vaccination for all participants aged six months and older. It underlines the importance of focusing vaccination efforts, when vaccination supplies are limited, on healthy adults who are at increased risk of developing severe complications from influenza, such as:

  • people aged 50 years or over;

  • women who are or will be pregnant during the influenza season;

  • healthcare personnel;

  • household contacts and caregivers of children aged below five years and adults aged 50 years or over, with particular emphasis on vaccinating contacts of children younger than six months of age; and

  • household contacts and caregivers of persons with medical conditions that put them at higher risk of severe complications from influenza (ACIP 2010).

Pregnant women are included among priority recipients for seasonal influenza immunisation in many countries (AIH 2013; Green Book 2013; NACI 2012; STIKO 2010), because of the risk of influenza‐associated morbidity during pregnancy, the possible adverse neonatal outcomes associated with maternal influenza infections, and based on the evidence that vaccination of pregnant women protects their newborns from influenza and influenza‐related hospitalisations (NACI 2012).

Inactivated influenza vaccine could be administered at any stage of pregnancy, whereas live vaccine is not licensed for use during pregnancy as the available data about safety and efficacy in mothers and babies are very limited (ACIP 2010; Green Book 2013).

Why it is important to do this review

Given the very high cost of yearly vaccination for large parts of the population, the extreme variability of influenza incidence during each 'season' and the heterogeneity of public health recommendations, we carried out a systematic review of the evidence. To enhance its relevance for decision‐makers, in the 2007 update of the review we included comparative non‐randomised studies reporting evidence of serious or rare harms (or both) (Jefferson 2007). In the present update (2013), we have also included evidence about influenza vaccination in pregnant women and newborns.

Objectives

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To identify, retrieve and assess all studies evaluating the effects (efficacy, effectiveness and harm) of vaccines against influenza in healthy adults, including pregnant women.

We defined 'effects' as follows:

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

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

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

Methods

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Criteria for considering studies for this review

Types of studies

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

Comparative non‐randomised studies were included if they reported evidence on the association between influenza vaccines and serious adverse effects, such as Guillain‐Barré syndrome or oculo‐respiratory syndromes, or if they reported effectiveness or efficacy data for vaccine administration during pregnancy.

We defined as RCTs studies in which it appeared that the individuals (or other experimental units) included in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of healthcare using random allocation. A study was quasi‐randomised when it appeared that the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of healthcare using some quasi‐random method of allocation (such as by alternation, date of birth or case record number).

Types of participants

Healthy individuals aged 16 to 65 years, irrespective of influenza immune status. Studies considering more than 25% of individuals outside this age range were excluded from the review. Pregnant women together with their newborns were also included.

Types of interventions

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

Types of outcome measures

Primary outcomes
Clinical

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

Harms

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

  2. Maternal outcomes and outcomes related to the course of pregnancy. These include abortion (spontaneous, internal, fetal death, stillbirth), preterm birth (less than 37 weeks), maternal death.

  3. Neonatal outcomes: congenital malformations (minor and major), neonatal death.

Secondary outcomes

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

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (PubMed) (January 1966 to May 2013) and EMBASE.com (1990 to May 2013). Search strategies used for the present version of the review are reported in the appendices (see Appendix 1 for trials and Appendix 2 for observational studies searches).

See Appendix 3 for strategies used in the 2010 update and Appendix 4 for the MEDLINE search strategy used in 2004. There were no language or publication restrictions.

Searching other resources

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

Data collection and analysis

Selection of studies

Two review authors (AR, CDP) independently excluded all initially identified and retrieved articles not fulfilling the inclusion criteria. In the case of disagreement, one review author (VD) acted as arbitrator.

Data extraction and management

Two review authors (AR, CDP) performed data extraction using a data extraction form (Appendix 5). We checked and entered the data into Review Manager (RevMan 2012) software. We extracted data on the following:

  • methodological quality of studies;

  • study design (Appendix 6);

  • description of setting;

  • characteristics of participants;

  • description of vaccines (content and antigenic match);

  • description of outcomes;

  • publication status;

  • date of study;

  • location of study.

One review author (CDP) carried out statistical analyses.

Assessment of risk of bias in included studies

Experimental studies (trials)

The review authors independently assessed the methodological quality of the included studies using criteria from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). One review author (VD) acted as arbitrator in the case of disagreement between the two review authors (CDP, AR) in assigning quality judgements.

We classified studies according to the following key domains for assessing risk of bias (Higgins 2011).

Random sequence generation

  • Low risk of bias: if, for example, a table of random numbers or computer‐generated random numbers were used.

  • High risk of bias: if, for example, alternation, date of birth, day of the week or case record number were used.

  • Unclear risk of bias: if insufficient information was provided.

Allocation concealment

  • Low risk of bias: if, for example, numbered or coded identical containers were administered sequentially, an on‐site computer system that could only be accessed after entering the characteristics of an enrolled participant, or serially numbered, opaque, sealed envelopes, were used, or sealed envelopes that were not sequentially numbered or opaque were used.

  • High risk of bias: if, for example, an open table of random numbers was used.

  • Unclear risk of bias: if insufficient information was provided.

Blinding

  • Low risk of bias: if adequate double‐blinding, for example, placebo vaccine, or single‐blinding (i.e. blinded outcome assessment) were used.

  • High risk of bias: if there was no blinding.

  • Unclear risk of bias: if insufficient information was provided.

Incomplete outcome data

Number of losses to follow‐up:

  • Low risk of bias: no missing data or the proportion of missing data compared with the observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate.

  • High risk of bias: when the proportion of missing data compared with observed event risk was large enough to induce clinically relevant bias in the intervention effect estimate.

  • Unclear risk of bias: if insufficient information was provided.

Non‐experimental studies

We carried out quality assessment of non‐randomised studies in relation to the presence of potential confounders, which could make interpretation of the results difficult. We evaluated the quality of case‐control (prospective and retrospective) and cohort studies using the appropriate Newcastle‐Ottawa Scales (NOS) (Appendix 7).

Using quality at the analysis stage as a means of interpreting the results, we assigned 'Risk of bias' categories (Higgins 2011):

  • Low risk of bias: plausible bias unlikely to seriously alter the results.

  • Unclear risk of bias: plausible bias that raises some doubt about the results.

  • High risk of bias: plausible bias that seriously weakens confidence in the results.

Measures of treatment effect

We used the risk ratio (RR) and its 95% confidence interval (CI) as the summary measure. We calculated vaccine efficacy (or effectiveness) as VE=1‐RR, expressed as a percentage, for cohort and RCT/controlled clinical trial (CCT) studies. For case‐control studies we adopted an odds ratio (OR) with 95% CIs.

To enhance relevance to everyday practice, we also expressed the summary measure of the most reliable and significant comparisons (those from RCTs with influenza cases as an outcome by age group) as a risk difference (RD). This is a measure of absolute efficacy of the vaccines, which incorporates significant information such as the incidence in the control arm and allows the calculation of its reciprocal, the number needed to treat (NNT) or in this case the number needed to vaccinate (NNV). The NNV expresses the number of adults needed to be vaccinated to prevent one case of influenza. The NNV can be computed as 1/RD. Since meta‐analysis estimates from RD are affected by spurious heterogeneity we preferred to compute the NNV as 1/((RR‐1)*CER), where CER is the proportion of total events in the control group.

Unit of analysis issues

We summarised evidence from non‐randomised studies (cohort and case‐control) according to Higgins 2011.

We found four different definitions of the 'epidemic period'.

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

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

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

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

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

An ILI case (specific definition) was assumed to be the same as a 'flu‐like illness' according to a pre‐defined list of symptoms (like that of the Centers for Disease Control and Prevention (CDC) case definition for surveillance), or 'upper respiratory illness' according to a predefined list of symptoms.

The laboratory confirmations of influenza cases we found were:

  1. virus isolation from culture;

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

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

Several trials included more than one active vaccine arm. Where several active arms from the same trial were included in the same analysis, we split the placebo group equally between the different arms, so that the total number of participants in a single analysis did not exceed the actual number in the trials.

Dealing with missing data

For the first publication of this review (Demicheli 1999), we wrote to the trial authors and manufacturers to identify possible unpublished studies and missing data. The response was disappointing and we desisted from any further attempts. Our analysis relies on existing data. Whenever possible we used the intention‐to‐treat (ITT) population.

Assessment of heterogeneity

We calculated the I2 statistic for each pooled estimate, to assess the impact on statistical heterogeneity. The I2 statistic may be interpreted as the proportion of total variation among effect estimates that is due to heterogeneity rather than sampling error and it is intrinsically independent from the number of studies. When the I2 value is less than 30% there is little concern about statistical heterogeneity (Higgins 2011). We used random‐effects models throughout to take account of the between‐study variance in our findings (Higgins 2011). Variance is to be expected in influenza vaccine trials as there are unpredictable systematic differences between trials regarding the circulating strains, degree of antigenic matching of the vaccine, type of vaccine and the levels of immunity presented by different populations in different settings. Not all studies reported sufficient details to enable a full analysis of the sources of heterogeneity, but we were able to take into account vaccine matching and circulating strain.

Assessment of reporting biases

Due to the limited number of studies in each comparison or subgroup, assessment of publication bias was not applicable, since the evidence presented in this review originated mainly from published data. For this reason, our results could be affected by publication bias.

The overall quality of the retrieved studies was poor and was affected by poor reporting or limited descriptions of the studies' designs. A detailed description is provided in the Risk of bias in included studies section of the review.

The main problems with influenza vaccine studies are their poor quality and discrepancies between the data presented, their conclusions and the authors' recommendations.

Data synthesis

We calculated all meta‐analyses using a random‐effects model.

We constructed the data and analyses tables according to the following criteria.

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

  2. Live aerosol vaccines (Analysis 02).

  3. Inactivated aerosol vaccines (Analysis 03).

  4. Inactivated parenteral influenza vaccines versus placebo ‐ cohort studies (Analysis 04).

  5. Inactivated parenteral influenza vaccines versus placebo ‐ case‐controls (Analysis 05).

  6. Serious adverse events ‐ Guillain‐Barré syndrome ‐ cohort studies (Analysis 06).

  7. Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control (Analysis 07).

  8. Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies (Analysis 08).

  9. Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control (Analysis 09).

  10. Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies (Analysis 10).

  11. Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control (Analysis 11).

  12. 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo (Analysis 12).

  13. 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo (Analysis 13).

  14. 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo (Analysis 14).

  15. 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo (Analysis 15).

  16. 1968 to 1969 pandemic: live aerosol vaccine versus placebo (Analysis 16).

Since RCT/CCTs on vaccine efficacy/effectiveness in the general population (Analyses 1 to 3) were available, only this type of study design has been included. On the other hand, for vaccine efficacy/effectiveness in pregnancy (Analyses 4 and 5) no eligible RCTs were found, therefore evidence from observational studies was included.

Quantitative synthesis of the evidence from observational studies has been conducted using adjusted estimates when these were available, in some cases also original data (unadjusted data) have been used in order to compare meta‐analysis results from adjusted and unadjusted estimates.

For Analyses 1 to 3 and 12 to 16, we carried out subgroup analyses according to the degree of matching with that year's WHO recommended content and with circulating viruses ("WHO recommended and matching" when known). WHO recommendations on the content of vaccines have been published since 1973. Different dosages and schedules of the vaccine and the presence of different adjuvants were not compared and we pooled data from the arms of trials comparing only vaccine composition or dosage in the analysis. We checked compliance of the study vaccine with the official antigenic content and potency recommendations by reviewing the WHO records when possible. In case of uncertainty due to ambiguity in the wording used (in the oldest trials), we took the opinion given by the authors into account. We classified the compliance of a live attenuated vaccine with the recommendations according to the antigenic comparability of the wild strains.

The following outcomes were included:

  1. Cases of influenza (defined on the basis of a specific list of symptoms and/or signs backed up by laboratory confirmation of infection with influenza A or B viruses): Analyses 1 to 5 and 12 to 16.

  2. Cases of ILI (clinically defined on the basis of a specific list of symptoms and/or signs): Analyses 1 to 5 and 12 to 16.

  3. Effectiveness (ILI) pregnant women: Analysis 4.

  4. Effectiveness (ILI) in newborns: Analyses 4 and 5.

  5. Hospital admissions: Analyses 1, 12, 13.

  6. Complications: Analyses 2, 12, 13, 16.

  7. Working days lost: Analyses 1 and 13.

  8. Pregnancy outcome (abortion, congenital malformation, prematurity, infant death): Analyses 4 and 5.

  9. Local harms: Analyses 1 to 3.

  10. Systemic harms: Analyses 1 to 3.

  11. Severe/rare harms (Guillain‐Barré syndrome, demyelinating diseases, immune thrombocytopaenic purpura): Analyses 6 to 11.

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

We presented local symptoms separately from systemic symptoms. We have considered individual harms in the analysis, as well as a combined endpoint (any or highest symptom). We used all data included in the analysis as presented by the authors in the primary study, regardless of the number of drop‐outs. We decided on this approach (complete case scenario) because the majority of the studies did not make any attempt to use an intention‐to‐treat analysis or mention the reasons for the loss to follow‐up, and they did not contain detailed information to allow estimations of the real number of participants.

Studies investigating the association between influenza vaccination and Guillain‐Barré syndrome were included in Analysis 6 (cohort on seasonal vaccine) and Analysis 7 (case‐control on H1N1 vaccine). In Analysis 7, we have stratified studies according to three different exposure definitions, according to the time between vaccination to onset of symptoms (any time, within seven weeks, over seven weeks). In Analysis 6, evidence for the association between seasonal vaccine and Guillain‐Barré syndrome from cohort studies is presented.

Studies investigating the association between influenza vaccination and multiple sclerosis and optic neuritis are included in Analyses 8 and 9 (cohort and case‐control studies ‐ demyelinating diseases).

Studies investigating the association between influenza vaccination and immune thrombocytopaenic purpura (ITP) are included in Analyses 10 and 11 (cohort and case‐control studies ‐ ITP).

Subgroup analysis and investigation of heterogeneity

Since the degree of matching between vaccine and circulating strains could affect the effectiveness/efficacy of the vaccine, we have analysed the data in separate subgroups according to this parameter. For serious adverse events, when possible, we have analysed data from pregnant women and the general population in separate subgroups. When case‐control studies reported safety outcomes, when possible we performed analyses in separate subgroups according to time since exposure. Finally, we carried out a separate analysis of trials carried out during the 1968 to 1969 (H3N2) pandemic and the 2009 to 2010 (H1N1) pandemic.

Sensitivity analysis

As it was not possible to identify all sources of heterogeneity, we decided to carry out a sensitivity analysis on the results by applying fixed‐effect and random‐effects models to assess the impact of heterogeneity on our results. In order to assess the robustness of our conclusions, we performed a sensitivity analysis by excluding low‐quality studies and, in the case of observational studies, by comparing the results from the crude data with those from the adjusted data.

Results

Description of studies

Results of the search

The first publication of this review contained 20 trials (Demicheli 1999). The second publication added five more trials (Demicheli 2004). The third publication included 48 trials in total (Jefferson 2007). The fourth published update (Jefferson 2010) included two new trials (aa Beran 2009a; aa Beran 2009b) and excluded three new trials (Belongia 2009; Chou 2007; Khazeni 2009). In this 2013 update, 41 new study reports have been included and 63 new trials have been excluded.

Some of the included studies had more than two arms, comparing different vaccines, routes of administration, schedules or dosages, or reported data from different settings and epidemic seasons. We split these studies into sub‐studies (data sets). For the remainder of this review, the term 'study report' refers to the original study report, while the word 'data set' refers to the sub‐study; these sub‐studies could refer either to different study arms, to different influenza seasons or to different study designs. Risk of bias can be independently assessed for each sub‐study (or data set) study design.

More information about the division of study reports into data sets is given in the Characteristics of included studies table. In this 2013 update, 90 studies (116 data sets) are now included in the review (Figure 1).

Figure 1
Study flow diagram

Study flow diagram

Included studies

We have coded each trial on the basis of study design and the type of data contributed to the review as follows. The letter preceding the study represents the study design: (a) denotes RCTs, (b) denotes case‐control studies and (c) denotes cohort studies. The second letter indicates the contribution to the evidence in the data set: (a) efficacy/effectiveness or (b) harms. So, for example, a case‐control study contributing safety or harms data is coded as (bb) and a trial contributing efficacy/effectiveness data is coded as (aa). A (p) code has been added to refer to the studies on vaccination during pregnancy.

Seasonal vaccines: efficacy or effectiveness

  1. RCTs on inactivated parenteral vaccine: (20 studies/29 data sets) (aa Barrett 2011; aa Beran 2009a; aa Beran 2009b; aa Bridges 2000a; aa Bridges 2000b; aa Eddy 1970; aa Frey 2010; aa Hammond 1978; aa Jackson 2010a; aa Jackson 2010b; aa Keitel 1988a; aa Keitel 1988b; aa Keitel 1997a; aa Keitel 1997b; aa Keitel 1997c; aa Leibovitz 1971; aa Mesa Duque 2001; aa Mixéu 2002; aa Monto 2009; aa Nichol 1995; aa Ohmit 2006; aa Ohmit 2008; aa Powers 1995a; aa Powers 1995b; aa Powers 1995c; aa Tannock 1984; aa Weingarten 1988; aa Zhilova 1986a; aa Zhilova 1986b).

  2. RCTs on live aerosol vaccine: (eight studies/12 data sets) (aa Edwards 1994a; aa Edwards 1994b; aa Edwards 1994c; aa Edwards 1994d; aa Monto 1982; aa Monto 2009; aa Nichol 1999a; aa Ohmit 2006; aa Ohmit 2008; aa Rytel 1977; aa Zhilova 1986a; aa Zhilova 1986b).

  3. RCTs on inactivated aerosol vaccine: (one study/one data set) (aa Langley 2011).

Seasonal vaccines: safety (local and systemic harms)

  1. RCTs on inactivated parenteral vaccine: (20 studies/21 data sets) (aa Barrett 2011; aa Bridges 2000a; aa Bridges 2000b; aa Frey 2010; aa Jackson 2010a; aa Mesa Duque 2001; aa Monto 2009; aa Nichol 1995; aa Ohmit 2006; aa Ohmit 2008; aa Powers 1995a; aa Tannock 1984; aa Weingarten 1988; ab Caplan 1977; ab El'shina 1996; ab Forsyth 1967; ab Goodeve 1983; ab Pyrhönen 1981; ab Rocchi 1979a; ab Saxen 1999; ab Scheifele 2003).

  2. RCTs on live aerosol vaccine: (13 studies/14 data sets) (ab Atmar 1990; ab Betts 1977a; ab Evans 1976; ab Hrabar 1977; ab Keitel 1993a; ab Keitel 1993b; ab Lauteria 1974; ab Miller 1977; aa Monto 1982; aa Nichol 1999a; aa Ohmit 2006; aa Ohmit 2008; ab Rocchi 1979b; aa Rytel 1977).

  3. RCTs on inactivated aerosol vaccine: (three studies/three data sets) (ab Boyce 2000; ab Langley 2005; aa Langley 2011).

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

Administration during pregnancy ‐ efficacy/effectiveness in mothers

  1. Seasonal inactivated vaccine ‐ cohort studies: (two studies/two data sets) (pca Black 2004; pca Hulka 1964).

  2. 2009 to 2010 pandemic: inactivated vaccines ‐ cohort studies: (one study/one data set) (pca Yamada 2012).

Administration during pregnancy ‐ efficacy/effectiveness in newborns

  1. Seasonal inactivated vaccine ‐ cohort studies on effectiveness (ILI): (three studies/three data sets) (pca Black 2004; pca Eick 2011; pca France 2006).

  2. Seasonal inactivated vaccine ‐ cohort studies on efficacy (laboratory‐confirmed): (one study/one data set) (pca Eick 2011).

  3. Seasonal inactivated vaccine ‐ case‐control on effectiveness (ILI): (two studies/two data sets) (pba Benowitz 2010; pba Poehling 2011).

Administration during pregnancy ‐ pregnancy‐related outcomes (abortion, congenital malformation, prematurity, neonatal death)

  1. Seasonal inactivated vaccine ‐ cohort studies: (four studies/four data sets) (pca Black 2004; pca Munoz 2005; pcb Omer 2011; pcb Sheffield 2012).

  2. 2009 to 2010 pandemic: inactivated vaccine ‐ cohort studies: (nine studies/nine data sets) (pcb Fell 2012; pcb Håberg 2013; pcb Heikkinen 2012; pcb Källén 2012; pcb Launay 2012; pcb Lin 2012; pcb Oppermann 2012; pcb Pasternak 2012; pcb Richards 2013).

  3. Seasonal inactivated vaccine ‐ case‐control: (one study/one data set) (pbb Irving 2013).

One study has not been introduced in the quantitative synthesis because it is the only study about the A/NJ/8/76 vaccine (pcb Deinard 1981). The retrospective cohort of pcb Toback 2012 was also not included in the analysis because it did not contain useful outcomes.

Administration during pregnancy ‐ severe harms

One cohort study was introduced (pcb Nordin 2013), assessing the association between seasonal vaccine exposure during pregnancy and the following harms within 42 days from administration: Guillain‐Barré syndrome, demyelinating diseases and immune thrombocytopenic purpura.

Severe harms ‐ general population
Guillain‐Barré syndrome

  1. 2009 to 2010 pandemic ‐ case‐control: (two studies/six data sets) (bb Grimaldi Bensouda 2011; bb Dieleman 2011a; bb Dieleman 2011b; bb Dieleman 2011c; bb Dieleman 2011d; bb Dieleman 2011e).

  2. Seasonal inactivated vaccine ‐ case‐control: (one study/one data set) (bb Galeotti 2013).

  3. Seasonal inactivated vaccine ‐ cohort studies: (two studies/four data sets) (cb Kaplan 1982; cb Lasky 1998).

One cohort study assessing the association between the A/NJ/8/76 vaccine and Guillain‐Barré syndrome was not introduced into the analysis (cb Shonberger 1979).

Demyelinating diseases (optic neuritis or multiple sclerosis)

  1. Seasonal inactivated vaccine ‐ case‐control: (four studies/four data sets) (bb DeStefano 2003; bb Hernan 2004; bb Payne 2006; bb Zorzon 2003).

  2. 2009 to 2010 pandemic ‐ cohort study: (one study/one data set) (cb Moro 2013).

Immune thrombocytopenic purpura

  1. Seasonal inactivated vaccine ‐ case‐control: (two studies/two data sets) (bb Garbe 2012; bb Grimaldi‐Bensouda 2012).

Other serious adverse events

  1. Oculo‐respiratory syndrome: RCT ‐ cross‐over (one study) (ab Scheifele 2003).

  2. Respiratory function: RCT (ab Atmar 1990).

  3. Cutaneous melanoma: case‐control (bb Mastrangelo 2000).

  4. Bell's palsy: case‐control (bb Mutsch 2004).

  5. Cardiac arrest: case‐control (bb Siscovick 2000).

  6. Rheumatoid arthritis: case‐control (bb Ray 2011).

  7. Neurological and autoimmune disorders: cohort study (cb Bardage 2011).

  8. Other serious adverse events: cohort study (cb Baxter 2012).

Pandemic vaccine: efficacy or effectiveness

  1. RCT on inactivated parenteral vaccine: (four studies/seven data sets) (aa Eddy 1970; aa Mogabgab 1970a; aa Mogabgab 1970b; aa Waldman 1969a; aa Waldman 1969b; aa Waldman 1972b; aa Waldman 1972d).

  2. RCT on inactivated aerosol vaccine: (two studies/four data sets) (aa Waldman 1969c; aa Waldman 1969d; aa Waldman 1972a; aa Waldman 1972c).

  3. RCT on live aerosol vaccine (one study/one data set) (aa Sumarokow 1971).

Excluded studies

We excluded 155 studies (see Characteristics of excluded studies table).

Risk of bias in included studies

Out of the 116 included studies (sub‐study or data set), we classified 9.5% (11/116) as low risk of bias (nine RCTs, two case‐control); 19.8% (23/116) as high risk of bias (six RCTs, 14 cohorts, three case‐control) and finally 70.6% (82/116) did not present either sufficient information in one or more key domains or, although presenting a low risk of bias in a specific domain, scored a high risk of bias in one or more items used in the quality evaluation. Table 1 shows the summary quality assessment of all included studies and a graphical display of the quality assessment is presented in Figure 2 and Figure 3. We have highlighted that each 'paper' could include more than one study (data set) and these different studies required separate quality assessment. On the other hand, the funding source can be referred only to a single paper.

Figure 2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Open in table viewer
Table 1. Risk of bias in included studies

Study design

High risk

Low risk

Unclear risk

Total

Case‐control

3

2

15

20

Cohort

14

0

13

27

RCT/CCT

6

9

54

69

Total

23

11

82

116

Table 1 dispalys the overall methodological quality assessment of the included studies described in the text and represented in extended form (with all items of the tools) in Figure 1.

Allocation

In the included trials allocation concealment was adequate (low risk of bias) in 18 studies (26.1%), inadequate (high risk of bias) in six (8.7%) and unclear (unclear risk of bias) in 45 (65.2%).

Blinding

We judged blinding as low risk of bias in 16 RCTs (23.2%), as high risk of bias in two studies (2.9%) and as unclear in 51 studies (73.9%).

Incomplete outcome data

The majority of the included RCTs/CCTs did not report sufficient information about loss to follow‐up (63 studies; 91.3%).

Selective reporting

The assessment of selective reporting bias presents several difficulties and would require review of the original study protocols for the included studies, which are mainly unavailable.

Other potential sources of bias

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

It is now known that industry funding of influenza vaccine studies determines publication in high‐prestige journals and higher citation rates than other types of funding. In addition, industry funding is associated with optimistic conclusions, but the quality of the majority of influenza vaccine studies is low, irrespective of funding (see Table 2). A previously cited review showed a complex web of interrelationships between these variables (Jefferson 2009a), but how this impacts on policy‐making is not known.

Open in table viewer
Table 2. Funding source of included studies

Study design

Government, institutional or public

Industry

Mixed

Total

Case‐control

13

1

1

15

Cohort

22

3

2

27

RCT/CCT

31

12

5

48

Total

66

16

8

90
Case‐control studies ‐ quality assessment

  • Case selection (definition/representativeness): case identification is mainly performed by means of registers maintained at several healthcare organisations (HMO, Kaiser Permanente) or by hospital or GP (general practice) registers. A further case ascertainment is conducted by specialists in order to verify the agreement with the chosen case definition. In studies assessing vaccine efficacy, cases were identified by using a laboratory test performed on all participants having symptoms. For 19 out of 20 (95%), we classified case selection and definition as low risk of bias.

  • Control selection (definition): controls were selected from within the same registers used for case identification or from among participants living in the same catchment area of the hospitals in which the cases were identified. For 10 out of 20 studies (50%), we classified control selection and definition as low risk of bias and for 8 out of 20 (40%) we classified this as unclear risk of bias.

  • Comparability: the most frequent method used to ensure comparability between cases and controls consisted of matching for age, gender and index date (onset of symptoms for cases and GP visit for controls). Less frequently matching was also done for other possible parameters, such as the number of GP visits within a certain time interval, or by resorting to the use of a propensity score or multivariate models in order to reduce the impact of other possible confounders. Nevertheless many studies (16 out of 20 (80%)) did not provide sufficient information to be able to tell how comparable cases and controls effectively are.

  • Exposure ascertainment (same method of ascertainment for cases and controls/non‐response rate): for studies based on healthcare organisations or insurance registers assessment of vaccine exposure was certified in the same registers. In other studies vaccine exposure was ascertained with a structured interview and less frequently also with the recovering of the vaccination records. In many studies (14 out of 20 (70%)), ascertainment of the vaccine exposure was not fully reliable. For 5 out of 20 (25%), we judged exposure ascertainment as low risk of bias.

Cohort studies ‐ quality assessment

  • Selection exposed cohort (definition/representativeness): the majority of the studies are retrospective and use a data linkage method to select the exposed cohort. In 17 out of 27 studies (63%) this procedure was insufficiently described.

  • Selection non‐exposed cohort (definition/ascertainment): most of the studies are based on record linkage and the identification of the non‐exposed cohort was done by considering the absence of vaccination records. However, insufficient detail was provided and therefore we classified these kinds of studies as unclear risk of bias (17 out of 27 (63%)).

  • Comparability: in most of the included cohort studies matching procedures for the most probable confounders were applied by using a multivariate model to ensure comparability between exposed and unexposed cohorts. Sometimes a propensity score procedure was also used. Therefore in many studies only a few confounders were used to ensure comparability between exposed and non‐exposed cohorts, thus we classified no studies as low risk of bias.

  • Assessment of outcome (demonstration that outcome of interest was not present at the start of the study/whether follow‐up was long enough for outcomes to occur/adequacy of follow‐up of cohorts): outcomes of interest were generally documented in the registries used to identify the study population and consequently were almost always retrospectively assessed, thus we classified 9 out of 27 as low risk of bias.

Effects of interventions

Inactivated parenteral vaccines (Analysis 01)

The overall effectiveness of parenteral inactivated parenteral vaccine against influenza‐like illness (ILI) is 16% (95% confidence interval (CI) 5% to 25%), with a corresponding number needed to vaccinate (NNV) of 40 (95% CI 26 to 128). Heterogeneity amongst the studies in this comparison is relatively low (I2 statistic = 26%) and a sensitivity analysis made by comparing estimates obtained using the random‐effects model versus the fixed‐effect model does not change the conclusion. The CI of the NNV becomes narrower by applying the fixed‐effect model (NNV 38, 95% CI 29 to 49).

Inactivated parenteral vaccines are 16% effective (95% CI 9% to 23%) in preventing ILI symptoms when strains contained in the vaccine antigenically match those circulating (Analysis 1.1.1). The estimated NNV for this comparison is 17 (95% CI 12 to 29). On the other hand, inactivated vaccines are not significantly protective against ILI when the degree of matching between the vaccine and circulating influenza strains is absent or unknown (risk ratio (RR) 0.90, 95% CI 0.69 to 1.18, Analysis 1.1.2). In the subgroup Analysis 1.1.2 heterogeneity is particularly high (I2 statistic = 82%) and estimates using the fixed‐effect model show statistical significance: Vaccine Effectiveness 18% (95% CI 10% to 25%) and NNV 59 (95% CI 43 to 106).

The overall efficacy of inactivated vaccines in preventing confirmed influenza (Analysis 1.2) is 60% (95% CI 53% to 66%) with a NNV of 71 (95% CI 64 to 80). When the vaccine content matches the circulating strain, the efficacy is 62% (95% CI 52% to 69%) and the NNV is 58 (95% CI 52 to 69). The results are very similar when matching is absent or unknown (Vaccine Efficacy 55%, 95% CI 41% to 66% and NNV 60, 95% CI 50 to 80). Since heterogeneity was very low (I2 statistic = 17% for Analysis 1.2.1; I2 statistic = 14% for Analysis 1.2.2 and I2 statistic = 11% overall), there were no differences when comparing the estimates obtained by using a fixed‐effect model with those from a random‐effects model.

Looking at the NNV in Analysis 1.1 and Analysis 1.2, it seems that effectiveness against ILI is higher than efficacy against laboratory‐confirmed influenza (NNV‐ILI 40; NNV‐influenza 71). These paradoxical results, showing an apparently higher aspecific effectiveness and a lower specific efficacy, are mainly due to the fact that ILI and confirmed influenza have a very different incidence among the study population. We note that 15.6% of unvaccinated participants versus 9.9% of vaccinated participants developed ILI symptoms, whilst the corresponding figures for participants who developed laboratory‐confirmed influenza are 2.4% and 1.1% for unvaccinated and vaccinated people, respectively.

Based on the results from a single study (aa Bridges 2000b), physician visits appear 42% less frequent (95% CI 9% to 63%) in participants immunised with vaccines prepared with strains matching circulating viruses (Analysis 1.3.1), whereas there are no significant results when the degree of matching is unknown or absent (RR 1.28, 95% CI 0.90 to 1.83; Analysis 1.3.2). The overall effect is also not significant (RR 0.87, 95% CI 0.40 to 1.89) (Analysis 1.3). Even though the two data sets of aa Bridges 2000b showed very high heterogeneity (I2 statistic = 87%), no difference arose when comparing the results from the fixed‐effect with the random‐effects model analysis.

A similar conflicting result is observed when analysing the effect of inactivated vaccine administration on days of illness (Analysis 1.4), when the estimate (mean difference (MD)) obtained in good match conditions was compared with that where there was an unknown or absent degree of matching. As a consequence of the high overall heterogeneity (I2 statistic = 87%), the result obtained from the fixed‐effect model analysis (MD ‐0.31, 95% CI ‐0.54 to ‐0.07) differs substantially from that resulting from the application of a random‐effects model (MD ‐0.21, 95% CI ‐0.98 to 0.56).

There seems to be no effect on the time an antibiotic or drug was prescribed (Analysis 1.5; Analysis 1.6).

Four trials evaluated time off work, estimating that vaccination saves around 0.04 working days on average. This result is affected by high levels of heterogeneity (I2 statistic = 82%) and changes depending on whether a fixed‐effect (MD ‐0.04, 95% CI ‐0.06 to ‐0.01) or random‐effects model (MD ‐0.04, 95% CI ‐0.14 to 0.06) is used.

The effect on hospitalisation (Analysis 1.8) was evaluated in two trials (aa Bridges 2000a; aa Leibovitz 1971), but it was not statistically significant. No evidence was found for cases of pneumonia.

Harms

Local tenderness and soreness are more than three times as common among parenteral vaccine recipients than among those in the placebo group (RR 3.13, 95% CI 2.44 to 4.02) (Analysis 1.10.1). There are also increases in erythema (RR 2.59, 95% CI 1.77 to 3.78, Analysis 1.10.2) and induration (RR 4.28, 95% CI 1.25 to 14.67) but not in arm stiffness. The combined local effects endpoint was significantly higher for those receiving the vaccine (RR 2.44, 95% CI 1.82 to 3.28; Analysis 1.10.5).

Myalgia (Analysis 1.11.1) is significantly associated with vaccination (RR 1.77, 95% CI 1.40 to 2.24), as well as systemic fever (RR 1.54, 95% CI 1.22 to 1.95), headache (RR 1.17, 95% CI 1.01 to 1.36), fatigue or indisposition (RR 1.23, 95% CI 1.07 to 1.42) and malaise (RR 1.51, 95% CI 1.18 to 1.92). The combined endpoint was not increased (RR 1.16, 95% CI 0.87 to 1.53; Analysis 1.11.7).

Live aerosol vaccines (Analysis 02)

Live aerosol vaccines have an overall effectiveness of 10% (95% CI 4% to 16%; NNV 46, 95% CI 29 to 115) and content and matching appear not to affect their performance significantly (Analysis 2.1). Overall efficacy (Analysis 2.2) is 53% (95% CI 38% to 65%) and the NNV is 39 (95% CI 32 to 54). Again, neither content nor matching appear to affect their performance significantly.

No evidence is available on complications (e.g. bronchitis, otitis, pneumonia).

The effectiveness of the aerosol vaccines against ILI (with no clear definition) is significant only for vaccines with absent or unknown matching (37%, 95% CI 20% to 51%) and the NNV is 69 (95% CI 23 to 46) (Analysis 2.3).

The conclusions of this comparison were unaffected by analysis using either the fixed‐effect or random‐effects models.

Harms

Significantly more recipients experienced local symptoms after vaccine administration than after placebo administration (Analysis 2.4).

  • Upper respiratory infection (RR 1.66, 95% CI 1.22 to 2.27).

  • Cough (RR 1.51, 95% CI 1.08 to 2.10).

  • Coryza (RR 1.56, 95% CI 1.26 to 1.94).

  • Sore throat (RR 1.66, 95% CI 1.49 to 1.86).

  • Combined endpoint (any or highest symptom) (RR 1.56, 95% CI 1.31 to 1.87).

There is no significant increase in systemic harms (combined endpoint: any or highest symptom RR 1.40, 95% CI 0.82 to 2.38), although rates of myalgia (RR 2.47, 95% CI 1.26 to 4.85) and headache (RR 1.54, 95% CI 1.09 to 2.18) are higher in the vaccine than in the placebo groups (Analysis 2.5).

Inactivated aerosol vaccines (Analysis 03)

No RCTs assessing the effectiveness of inactivated aerosol vaccines in preventing ILI could be included; the only available evidence comes from studies carried out during the 1968 to 1969 pandemic (Analyses 12 to 16).

The efficacy of inactivated aerosol vaccine in preventing laboratory‐confirmed influenza (Analysis 3.1.1) is assessed in one RCT (aa Langley 2011), whose results do not show a statistically significant protective effect (RR 0.38, 95% CI 0.14 to 1.02).

Harms

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

Inactivated parenteral vaccines ‐ cohort studies (Analysis 04)

In this analysis, we have considered the effects of vaccine administration in pregnant women and their newborns.

Based on unadjusted data from a cohort study (high risk of bias), 2009/2010 H1N1 monovalent pandemic vaccines (Analysis 4.1.1) provide a significant protective effect against ILI in pregnant women (Vaccine Effectiveness 89%, 95% CI 79% to 94%; NNV 54, 95% CI 51 to 61). Seasonal inactivated vaccine is not effective against ILI (RR 0.54, 95% CI 0.22 to 1.32; Analysis 4.1.2). Sensitivity analysis performed using the fixed‐effect model showed statistical significance, even for a modest, protective effect (RR 0.76, 95% CI 0.65 to 0.89; NNV 92, 95% CI 63 to 201; VE 24%, 95% CI 11% to 35%).

The effectiveness of vaccination with seasonal inactivated vaccine during pregnancy for preventing ILI in newborns is not statistically significant, as it results from two cohort studies using either hazard ratio (HR) or RR adjusted estimates (Analysis 4.2.1 and Analysis 4.3.1, respectively). Efficacy against confirmed influenza (Analysis 4.3.2) is really modest but has statistical significance (adjusted RR 0.59, 95% CI 0.37 to 0.94; NNV 27, 95% CI 18 to 185; VE 41%, 95% CI 6% to 63%).

It seems that vaccination with the 2009/2010 H1N1 monovalent pandemic vaccine during pregnancy is not associated with a higher risk of abortion (Analysis 4.4.1 and Analysis 4.4.2), congenital malformation (Analysis 4.4.3) or neonatal death (Analysis 4.4.5).

Cases of neonatal death and abortion have been observed less frequently among women immunised with seasonal influenza vaccine (Analysis 4.5.1 and Analysis 4.5.4, both unadjusted estimates).

The results of pcb Deinard 1981 are based on the follow‐up results of 189 pregnant women immunised with monovalent pandemic A/New Jersey/8/76 (either in split or whole virus formulation) and 517 pregnant women who did not receive vaccination. The time of observation was extended up to the first eight weeks of life of the newborns. No statistically different incidence of maternal pregnancy outcomes and infant deaths was observed between vaccinated and unvaccinated groups. Statistical analysis (Chi2 test) shows no relation between immunisation history and presence of anomalities at the 8th week of life. This cohort study has not been included in the analysis as the vaccine studied is no longer in use.

Inactivated parenteral vaccines ‐ case‐control studies (Analysis 05)

This analysis only includes studies assessing the effect of vaccination against influenza during pregnancy. The incidence of ILI in pregnant women who were immunised with inactivated seasonal vaccine during pregnancy was not statistically different when compared with that observed among unvaccinated pregnant women (Analysis 5.1.1). However, in sensitivity analysis using the fixed‐effect model, the results of the analysis become statistically significant. In conclusion, the results of this comparison were affected by the model used to perform the analysis.

One further case‐control study did not find a statistically significant association between exposure to seasonal inactivated vaccine in pregnancy and abortion cases (Analysis 5.2.1).

One retrospective cohort study tried to assess the effect of live attenuated vaccine during pregnancy, based on data from a health insurance database during six subsequent influenza seasons (pcb Toback 2012). A total of 834,999 pregnant women were identified, out of whom 138 received live attenuated vaccine at any time during pregnancy. Claims for hospitalisation or visits to the emergency department within 42 days after immunisation were searched for but all observed events were considered to be related to a normal physiological pregnancy and not to immunisation. The system used (claim data) would be unable to detect birth outcomes.

Serious adverse events ‐ Guillain‐Barré syndrome ‐ cohort studies (Analysis 06)

The possible association between exposure to seasonal inactivated vaccine in healthy adults and Guillain‐Barré syndrome onset within six weeks following immunisation was investigated by two cohort studies performed during two subsequent epidemic seasons. No significant association was found Analysis 6.1.1). Administration of seasonal inactivated vaccine during pregnancy was not associated with Guillain‐Barré syndrome onset within six weeks from immunisation (Analysis 6.1.2).

The cohort of cb Shonberger 1979 was the first study that compared Guillain‐Barré syndrome cases by vaccination status and the national incidence in vaccinated and unvaccinated national cohorts after the suspension of the National Influenza Immunisation Program in the winter of 1976 to 1977. At that time the monovalent inactivated swine vaccine A/New Jersey/8/76 had been administered. The attributable risk from vaccination was just below one case of Guillain‐Barré syndrome in every 100,000 vaccinations. This cohort study has not been included in the analysis as the vaccine studied is no longer in use.

Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control studies (Analysis 07)

In an analysis performed using the mean of unadjusted data relative to six data sets, exposure to monovalent H1N1 pandemic inactivated vaccine resulted in an apparent statistically significant association with Guillain‐Barré syndrome onset when administration took place within six weeks before symptoms occurred (odds ratio (OR) 2.22, 95% CI 1.14 to 4.31, Analysis 7.1.1). Thus, it should be taken into account that only one out of the six data sets showed a statistically significant association between vaccine exposure and Guillain‐Barré syndrome onset (bb Dieleman 2011e). When we performed a sensitivity analysis excluding this data set from the pooled estimate, the result was no longer significant. When the analysis was performed considering that vaccine exposure occurred at any time before disease onset, there was no significant association (Analysis 7.1.2).

The analyses performed by pooling authors' estimates adjusted for several confounders (i.e. receipt of other vaccines, family history of autoimmune diseases, physician consultation during the previous year and use of antibiotic, antiviral or antipyretic agents) do not show a statistical association for exposure within six weeks (Analysis 7.2.1) before disease onset or for exposure at any time (Analysis 7.2.2).

Data from one other case‐control study confirm that immunisation with seasonal inactivated vaccine is not significantly associated with the onset of Guillain‐Barré syndrome within six weeks after inoculation (bb Galeotti 2013) (Analysis 7.3).

Serious adverse events ‐ demyelinating diseases ‐ cohort studies (Analysis 08)

In one cohort study the authors tried to assess whether there is an association between exposure to inactivated trivalent seasonal influenza vaccine during pregnancy and several pathologies (e.g. Guillain‐Barré syndrome, demyelinating diseases, immune thrombocytopaenic purpura) within six weeks after immunisation. Unadjusted estimates were calculated for an association with demyelinating diseases by using the number of cases observed among exposed and unexposed hemi‐cohorts and indicate that there is no association (Analysis 8.1.2).

One cohort study assessed the safety of the H1N1 vaccine. No statistical association was found between vaccination with H1N1 monovalent pandemic vaccine and demyelinating diseases.

Serious adverse events ‐ demyelinating diseases ‐ case‐control studies (Analysis 09)

An association between exposure to seasonal inactivated vaccine and demyelinating diseases (including both multiple sclerosis and optic neuritis case definitions) in a healthy adult population was not statistically significant when we pooled unadjusted data from four case‐control studies (OR 0.96, 95% CI 0.79 to 1.17) (Analysis 9.1). Also, when we analysed adjusted data for each of the case definitions separately, the estimates remained non‐statistically significant for multiple sclerosis (Analysis 9.2) and for optic neuritis (Analysis 9.3).

Serious adverse events ‐ immune thrombocytopenic purpura ‐ cohort studies (Analysis 10)

One cohort study aimed to assess whether there is an association between exposure to inactivated trivalent seasonal influenza vaccine during pregnancy and several pathologies (e.g. Guillain‐Barré syndrome, demyelinating diseases, immune thrombocytopaenic purpura) within six weeks after immunisation. Neither the unadjusted (Analysis 10.2.2) nor adjusted estimates (Analysis 10.1.2) for an association with immune thrombocytopenic purpura were statistically significant.

Serious adverse events ‐ immune thrombocytopenic purpura ‐ case‐control studies (Analysis 11)

Data analysis of two case‐control studies (bb Garbe 2012; bb Grimaldi‐Bensouda 2012) did not show a statistically significant association between immune thrombocytopaenic purpura and seasonal influenza vaccine in any of the time frames considered (i.e. less than two months, six or 12 months between immunisation and disease onset), or when the data were pooled together (Analysis 11.2). The same conclusions could be drawn when analysis was performed by using estimates adjusted for confounders (Analysis 11.1) and are further confirmed by the fact that a sensitivity analysis carried out by using either a random‐effects or fixed‐effect model did not change them in any way. It should be observed that no data sets included in this comparison, with the exception of bb Garbe 2012, showed a statistical association between disease and influenza vaccination. It is possible that the ages of the participants (cases and controls) were different in these two studies and that some elderly participants could have been included. Unlike bb Grimaldi‐Bensouda 2012, the case‐control study (bb Garbe 2012) considered as exposed those cases that were immunised up until 28 days before immune thrombocytopaenic purpura onset.

Serious and rare harms
Oculo‐respiratory syndrome

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

Bell's palsy

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

Rheumatoid arthritis

One case‐control study used the register of the Northern California Kaiser Permanente Health Plan (NCKPHP) in order to identify cases of rheumatoid arthritis diagnosed during a three‐year period (1 January 1997 to 31 December 1999) among members of NCKPHP for at least two years (i.e. since 1 January 1995) and aged between 15 and 59 (bb Ray 2011). After reviewing clinical cards, 415 cases of definite or probable rheumatoid arthritis were included together with 1245 randomly selected controls matched for age within one year and for a categorical utilisation variable based on the number of clinic visits during the year prior to the rheumatoid arthritis symptom onset date (none, one to two, three to five, six to nine or 10+ visits). The Kaiser Immunisation Tracking System and chart review were used to determine vaccination status of cases and controls. Different time intervals between immunisation and rheumatoid arthritis onset were considered for analysis: 90, 180, 365 and 730 days. No significant association between vaccination and rheumatoid arthritis could be determined for any time interval, even after adjustment for confounders (sex, race and exact number of utilisation visits). The authors of this study performed a data analysis by using a person‐time cohort design, in which vaccinated cases contributed to the unexposed follow‐up time until they were immunised and to the exposed follow‐up time thereafter. Unlike case‐control analysis, person‐time cohort analysis was performed by excluding cases who showed symptoms in 1996. Even if a significant association for exposure to vaccine occurred within 180 and 365 days before disease onset was found (OR adjusted for race, sex and number of clinic visits 1.36, 95% CI 1.03 to 1.80 and 1.34, 95% CI 1.06 to 1.69, respectively), the authors point out that it is very difficult to estimate with sufficient precision the true onset date of rheumatoid arthritis, as the first symptoms could already be present some time before participants present for medical care. This is the most important limitation of this study and could have affected the estimates in a significant manner.

Neurological and autoimmune disorders

The study of cb Bardage 2011 is a large, prospective cohort study carried out in a Stockholm population (n = 1,945,024) during the vaccination campaign with monovalent A (H1N1) pandemic vaccine Pandemrix (GlaxoSmithKline, containing adjuvants AS03 and squalene) to evaluate the presence of an association between Pandemrix and neurological and/or autoimmune diseases (Guillain‐Barré syndrome, multiple sclerosis, Bell's palsy, narcolepsy, polyneuropathy, an/hypoaesthesia, paraesthesia, rheumatological disease and inflammatory bowel disease). During the first 45 days, participants with high‐risk conditions were preferentially vaccinated; vaccination was then offered to the remainder of the population in a second phase of the campaign (see description for more details).

The analysis of the hazard ratio (HR) adjusted for age, sex, socioeconomic status and healthcare consumption (number of hospital admissions and visits to specialist care one year before the pandemic period) showed that in participants immunised during the early phase of the campaign there was a significantly increased risk of Bell's palsy (HR 1.34, 95% CI 1.11 to 1.64), paraesthesia (HR 1.25, 95% CI 1.10 to 1.41) and inflammatory bowel disease (HR 1.25, 95% CI 1.04 to 1.50). For the participants vaccinated in the late phase of the campaign (> 45 days), HR estimates showed that the investigated diseases had been observed with no statistically different incidence between the vaccinated and unvaccinated participants.

A further stratification was performed, considering the time since first vaccination (six weeks or less and more than six weeks). This showed that in participants immunised during the first phase of the campaign, an increased incidence of Bell's palsy and paraesthesia was most pronounced, as well as within six weeks of vaccination (HR 1.74, 95% CI 1.16 to 2.59 for Bell's palsy and HR 1.60, 95% CI 1.25 to 2.05 for paraesthesia) and thereafter (HR 1.26, 95% CI 1.01 to 1.57 for Bell's palsy and 1.17, 95% CI 1.02 to 1.34 for paraesthesia). The increased risk of inflammatory bowel disease among those vaccinated in the early phase was only observed more than six weeks after vaccination (HR 1.29, 95% CI 1.06 to 1.58). Formal tests to determine whether risks further differed between those within and more than six weeks from vaccination were only statistically significant for paraesthesia (P = 0.005). In participants immunised during the second phase of the campaign, polyneuropathy was significantly more common within six weeks of immunisation (HR 1.79, 95% CI 1.16 to 2.77).

Cutaneous melanoma

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

Primary cardiac arrest

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

Pulmonary function

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

Other serious adverse events

The study of cb Baxter 2012 is a large, retrospective cohort performed among members of Kaiser Permanente Health Plans of Northern California, Hawaii and Colorado aged between 18 and 59 years, who were immunised with live attenuated, inactivated influenza vaccine or did not receive vaccination. The study retrospectively investigated the occurrence of adverse events (see description) during five subsequent epidemics, but did not identify any unexpected serious risks when the live attenuated vaccine was used in approved populations.

Vaccines for the 1968 to 1969 (H3N2) influenza pandemic (Analyses 12 to 16)

Five studies yielded 12 data sets (aa Eddy 1970; aa Mogabgab 1970a; aa Mogabgab 1970b; aa Sumarokow 1971; aa Waldman 1969a; aa Waldman 1969b; aa Waldman 1969c; aa Waldman 1969d; aa Waldman 1972a; aa Waldman 1972b; aa Waldman 1972c; aa Waldman 1972d). As one would expect, vaccine performance was poor when the content did not match the pandemic strain (Analysis 12.1; Analysis 12.2). However, one‐dose or two‐dose monovalent whole virion (i.e. containing dead complete viruses) vaccines achieved a VE of 65% (95% CI 52% to 75%) protection against ILI (NNV 16, 95% CI 14 to 20), a VE of 93% (95% CI 69% to 98%; NNV 35, 95% CI 33 to 47) protection against influenza and a VE of 65% (95% CI 6% to 87%) with NNV 94 (95% CI 70 to 1022) against hospitalisation (Analysis 13.1; Analysis 13.2; Analysis 13.3).

Approximately half a working day and half a day of illness (Analysis 13.5; Analysis 13.6) were saved but no effect was observed on pneumonia (Analysis 13.4). All comparisons except for ILI are based on a single study (Analysis 13.4). The large effect on ILI is coherent with the high proportion of these illnesses caused by influenza viruses in a pandemic (i.e. the gap between the efficacy and effectiveness of the vaccines is narrow). Aerosol polyvalent or monovalent vaccines had a modest effect.

Discussion

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Summary of main results

The overall effectiveness of inactivated parenteral vaccine against influenza‐like illness (ILI) is 16% (95% confidence interval (CI) 5% to 25%), with a corresponding number needed to vaccinate (NNV) of 40 (95% CI 26 to 128). The overall efficacy of inactivated vaccines in preventing influenza is 60% (95% CI 53% to 66%) with a NNV of 71 (95% CI 64 to 80). When vaccine content matches the circulating strain the efficacy is 62% (95% CI 52% to 69%) and the NNV is 58 (95% CI 52 to 69). Based on the results from one single study (aa Bridges 2000b), physician visits appear to be 42% less frequent (95% CI 9% to 63%) in participants immunised with vaccines prepared with strains matching circulating viruses, whereas no significant differences are found when the degree of matching is unknown or absent (risk ratio (RR) 1.28, 95% CI 0.90 to 1.83). The overall effect is again not significant (RR 0.87, 95% CI 0.40 to 1.89). There seems to be no effect on the time an antibiotic or a drug is prescribed. Four trials evaluated time off work, estimating that vaccination saves on average around 0.04 working days. This result is affected by high levels of heterogeneity and changes depending on whether a fixed‐effect (mean difference (MD) ‐0.04, 95% CI ‐0.06 to ‐0.01) or random‐effects model (MD ‐0.04, 95% CI ‐0.14 to 0.06) is used.

Live aerosol vaccines have an overall effectiveness of 10% (95% CI 4% to 16%) and a NNV of 46 (95% CI 29 to 115), and content and matching appear not to affect their performance significantly. The overall efficacy is 53% (95% CI 38% to 65%) and the NNV is 39 (95% CI 32 to 54). Again, neither content nor matching appear to affect their performance significantly. Many more recipients experienced local symptoms after vaccine administration than placebo administration.

No randomised controlled trials (RCTs) assessing the effectiveness of inactivated aerosol vaccines in preventing ILI could be included. The only available evidence comes from studies carried out during the 1968 to 1969 pandemic. The efficacy of inactivated aerosol vaccine in preventing laboratory‐confirmed influenza (Analysis 3.1.1) was assessed in one RCT (aa Langley 2011) whose results did not show a statistically significant protective effect (RR 0.38, 95% CI 0.14 to 1.02).

The effects of influenza vaccine administration in pregnant women and their newborns has been investigated in a RCT (Zaman 2008) in which 23 valent pneumococcal vaccine was administered to the control group. For this reason, the RCT was excluded from the review and the evidence for effectiveness and efficacy is based only on observational studies (case‐control and cohort studies).

The effectiveness of vaccination with seasonal inactivated parenteral vaccine during pregnancy for preventing ILI in newborns was not statistically significant. The evidence comes from two cohort studies using either HR or RR adjusted estimates. However, it seems that vaccination has a modest effect against ILI in pregnant women (NNV 92, 95% CI 63 to 201) and against laboratory‐confirmed influenza in newborns from vaccinated women (NNV 27, 95% CI 18 to 185).

No evidence of an association was found between seasonal inactivated vaccines and Guillain‐Barré syndrome or H1N1 pandemic vaccine and Guillain‐Barré syndrome.

There was no evidence of an association between exposure to seasonal inactivated influenza vaccine and other serious adverse events (multiple sclerosis, optic neuritis and immune thrombocytopaenic purpura).

Overall completeness and applicability of evidence

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

  1. Methods of vaccine standardisation have changed significantly.

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

  3. Different doses and schedules were pooled in the analysis.

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

Quality of the evidence

We found evidence from more than 70,000 people in 69 randomised studies. Regardless of quality, all studies failed to report any evidence of an effect on complications. The safety evidence base from randomised trials of inactivated vaccines is very small, probably indicating less concern with harms. Inactivated vaccines cause rare, major harms that appear to be mostly linked to specific products or lots.

Potential biases in the review process

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

An earlier review of 274 influenza vaccine studies in all age groups (including most of the studies in this review) showed an inverse relationship between risk of bias and the direction of study conclusions. Conclusions favourable to the use of influenza vaccines were associated with a higher risk of bias. In these studies, the authors made claims and drew conclusions that were unsupported by the data they presented. In addition, industry‐funded studies are more likely to have favourable conclusions, to be published in significantly higher‐impact factor journals and to have higher citation rates than non‐industry‐funded studies. This difference is not explained by either their size or methodological quality (Jefferson 2009a). Any interpretation of the body of evidence in this review should be made with these findings in mind.

Agreements and disagreements with other studies or reviews

Systematic reviews estimating the efficacy of influenza vaccination

DiazGranados 2012 performed a meta‐analysis that included RCTs on seasonal inactivated or live attenuated influenza vaccines with laboratory‐confirmed influenza (with either polymerase chain reaction (PCR) or serological confirmation of infection) as the efficacy outcome. Thirty studies in children and adults were included. The authors provided efficacy estimates (RR with 95% CI) stratified by the degree of matching between the vaccine and circulating strains (good, poor, no matching, matching) and by strain type (A H1N1, A H3N2, B). DiazGranados 2012 estimated that in an adult population the efficacy of inactivated vaccine against laboratory‐confirmed influenza is 59% (95% CI 50% to 66%). The efficacy estimate for live attenuated vaccine is 39% (95% CI 16% to 55%).

The systematic review by Osterholm 2012 included evidence of the efficacy of both live attenuated and inactivated vaccines in preventing laboratory‐confirmed influenza infection assessed exclusively by either PCR or a positive culture. Considering studies carried out in adults only, the pooled estimate of efficacy from six studies (eight data sets) was 59% (95% CI 51% to 67%). Even though three RCTs estimating the efficacy of live attenuated vaccines were included, the authors did not perform an analysis for the reason that none of the single estimates was statistically significant. Observational studies were also included and discussed.

Systematic reviews assessing the efficacy/effectiveness and/or safety issues of influenza vaccines when administered during pregnancy

The review by Skowronski 2009 is the first comprehensive publication in which the evidence for the effectiveness and safety aspects of vaccination during pregnancy has been exhaustively discussed. In the first part of the paper the authors consider the burden of disease during pregnancy, the risk of death and the influenza‐related risk for the fetus and summarise how the US Advisory Committee on Immunization Practice (ACIP) recommendations have changed over the last four decades. The available evidence on protection (in mother and newborns) and vaccination safety issues are descriptively illustrated, discussed and compared with the statements in the current vaccination policies reported. In the authors' opinion, immunisation against influenza at any stage of pregnancy may be warranted during pandemics or for women with co‐morbidities. Seasonal immunisation with TIV may be warranted in pregnancy, without potential complications during the second half of the pregnancy. Finally, the available evidence is insufficient to recommend standard routine vaccination in the early stages of pregnancy.

Systematic reviews of evidence of severe harms

Farez 2011 evaluates the risk of developing multiple sclerosis or experiencing relapsing multiple sclerosis following immunisation with several vaccinations, including influenza. Meta‐analysis performed by pooling the results of four case‐control studies (bb DeStefano 2003; bb Hernan 2004; Ramagopalan 2009; bb Zorzon 2003) would exclude an increased risk of developing multiple sclerosis following influenza vaccine administration (odds ratio (OR) 0.97, 95% CI 0.77 to 1.23).

Other issues

In Toback 2012, there is evidence supporting the introduction of a new quadrivalent live attenuated vaccine (Q‐LAIV, already licensed in the USA where it will be available for the 2013 to 2014 season) containing two different B strains of different lineage (B/Yamagata/16/88 and B/Victoria/2/87). This evidence comes from two RCTs comparing immunogenicity and local and systemic reactions after administration of either Q‐LAIV, trivalent inactivated or trivalent live attenuated vaccines. One of them was performed in adults, the other in a paediatric population. The presence of two B strains would not significantly affect the antibody response against each B strain. Local and systemic adverse events induced by Q‐LAIV administration did not differ significantly from those recorded after receiving other vaccines already in use.

Study flow diagram
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Figure 1

Study flow diagram

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'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 1 Influenza‐like illness.
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Analysis 1.1

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 2 Influenza.
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Analysis 1.2

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 3 Physician visits.
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Analysis 1.3

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 4 Days ill.
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Analysis 1.4

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 5 Times any drugs were prescribed.
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Analysis 1.5

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 6 Times antibiotic was prescribed.
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Analysis 1.6

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 7 Working days lost.
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Analysis 1.7

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 8 Hospitalisations.
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Analysis 1.8

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

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 9 Clinical cases (clinically defined without clear definition).
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Analysis 1.9

Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 9 Clinical cases (clinically defined without clear definition).

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 10 Local harms.
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Analysis 1.10

Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 10 Local harms.

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Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 11 Systemic harms.
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Analysis 1.11

Comparison 1 Inactivated parenteral vaccine versus placebo or 'do nothing', Outcome 11 Systemic harms.

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Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 1 Influenza‐like illness.
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Analysis 2.1

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

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Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 2 Influenza.
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Analysis 2.2

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

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Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 3 Influenza cases (clinically defined without clear definition).
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Analysis 2.3

Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 3 Influenza cases (clinically defined without clear definition).

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Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 4 Local harms.
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Analysis 2.4

Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 4 Local harms.

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Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 5 Systemic harms.
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Analysis 2.5

Comparison 2 Live aerosol vaccine versus placebo or 'do nothing', Outcome 5 Systemic harms.

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Comparison 3 Inactivated aerosol vaccine versus placebo or 'do nothing', Outcome 1 Influenza.
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Analysis 3.1

Comparison 3 Inactivated aerosol vaccine versus placebo or 'do nothing', Outcome 1 Influenza.

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Comparison 3 Inactivated aerosol vaccine versus placebo or 'do nothing', Outcome 2 Local harms.
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Analysis 3.2

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

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Comparison 3 Inactivated aerosol vaccine versus placebo or 'do nothing', Outcome 3 Systemic harms.
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Analysis 3.3

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

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Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 1 Seasonal inactivated vaccine effectiveness in mothers ‐ pregnant women.
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Analysis 4.1

Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 1 Seasonal inactivated vaccine effectiveness in mothers ‐ pregnant women.

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Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 2 Seasonal inactivated vaccine effectiveness in newborns ‐ pregnant women.
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Analysis 4.2

Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 2 Seasonal inactivated vaccine effectiveness in newborns ‐ pregnant women.

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Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 3 Seasonal inactivated vaccine effectiveness in newborns ‐ pregnant women.
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Analysis 4.3

Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 3 Seasonal inactivated vaccine effectiveness in newborns ‐ pregnant women.

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Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 4 H1N1 vaccine ‐ safety ‐ pregnancy‐related outcomes ‐ pregnant women.
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Analysis 4.4

Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 4 H1N1 vaccine ‐ safety ‐ pregnancy‐related outcomes ‐ pregnant women.

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Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 5 Seasonal vaccine ‐ safety ‐ pregnancy‐related outcomes ‐ pregnant women.
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Analysis 4.5

Comparison 4 Inactivated parenteral vaccine versus placebo ‐ cohort studies, Outcome 5 Seasonal vaccine ‐ safety ‐ pregnancy‐related outcomes ‐ pregnant women.

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Comparison 5 Inactivated parenteral vaccine versus placebo ‐ case‐control, Outcome 1 Effectiveness in newborns ‐ pregnant women (adjusted data).
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Analysis 5.1

Comparison 5 Inactivated parenteral vaccine versus placebo ‐ case‐control, Outcome 1 Effectiveness in newborns ‐ pregnant women (adjusted data).

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Comparison 5 Inactivated parenteral vaccine versus placebo ‐ case‐control, Outcome 2 Seasonal vaccine safety ‐ pregnancy‐related outcomes (adjusted data).
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Analysis 5.2

Comparison 5 Inactivated parenteral vaccine versus placebo ‐ case‐control, Outcome 2 Seasonal vaccine safety ‐ pregnancy‐related outcomes (adjusted data).

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Comparison 6 Serious adverse events ‐ Guillain‐Barré syndrome ‐ cohort studies, Outcome 1 Seasonal influenza vaccination and Guillain‐Barré syndrome.
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Analysis 6.1

Comparison 6 Serious adverse events ‐ Guillain‐Barré syndrome ‐ cohort studies, Outcome 1 Seasonal influenza vaccination and Guillain‐Barré syndrome.

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Comparison 7 Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control, Outcome 1 2009 to 2010 A/H1N1 ‐ general population (unadjusted data).
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Analysis 7.1

Comparison 7 Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control, Outcome 1 2009 to 2010 A/H1N1 ‐ general population (unadjusted data).

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Comparison 7 Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control, Outcome 2 2009 to 2010 A/H1N1 ‐ general population (adjusted data).
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Analysis 7.2

Comparison 7 Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control, Outcome 2 2009 to 2010 A/H1N1 ‐ general population (adjusted data).

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Comparison 7 Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control, Outcome 3 Seasonal influenza vaccination general population (adjusted data).
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Analysis 7.3

Comparison 7 Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control, Outcome 3 Seasonal influenza vaccination general population (adjusted data).

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Comparison 8 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies, Outcome 1 Influenza vaccination (seasonal) ‐ demyelinating diseases (unadjusted data).
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Analysis 8.1

Comparison 8 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies, Outcome 1 Influenza vaccination (seasonal) ‐ demyelinating diseases (unadjusted data).

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Comparison 8 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies, Outcome 2 Influenza vaccination (H1N1) ‐ demyelinating diseases (unadjusted).
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Analysis 8.2

Comparison 8 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies, Outcome 2 Influenza vaccination (H1N1) ‐ demyelinating diseases (unadjusted).

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Comparison 9 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies, Outcome 1 Influenza vaccination (seasonal) ‐ general population ‐ demyelinating diseases (unadjusted data).
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Analysis 9.1

Comparison 9 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies, Outcome 1 Influenza vaccination (seasonal) ‐ general population ‐ demyelinating diseases (unadjusted data).

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Comparison 9 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies, Outcome 2 Influenza vaccination (seasonal) ‐ general population ‐ multiple sclerosis (adjusted data).
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Analysis 9.2

Comparison 9 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies, Outcome 2 Influenza vaccination (seasonal) ‐ general population ‐ multiple sclerosis (adjusted data).

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Comparison 9 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies, Outcome 3 Influenza vaccination (seasonal) ‐ general population ‐ optic neuritis (adjusted data).
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Analysis 9.3

Comparison 9 Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies, Outcome 3 Influenza vaccination (seasonal) ‐ general population ‐ optic neuritis (adjusted data).

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Comparison 10 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies, Outcome 1 Seasonal influenza vaccine ‐ HR (adjusted data).
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Analysis 10.1

Comparison 10 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies, Outcome 1 Seasonal influenza vaccine ‐ HR (adjusted data).

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Comparison 10 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies, Outcome 2 Seasonal influenza vaccine (unadjusted data).
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Analysis 10.2

Comparison 10 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies, Outcome 2 Seasonal influenza vaccine (unadjusted data).

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Comparison 11 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control studies, Outcome 1 Seasonal influenza vaccine ‐ general population (adjusted data).
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Analysis 11.1

Comparison 11 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control studies, Outcome 1 Seasonal influenza vaccine ‐ general population (adjusted data).

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Comparison 11 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control studies, Outcome 2 Seasonal influenza vaccine ‐ general population (unadjusted data).
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Analysis 11.2

Comparison 11 Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control studies, Outcome 2 Seasonal influenza vaccine ‐ general population (unadjusted data).

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Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 1 Influenza‐like illness.
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Analysis 12.1

Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 1 Influenza‐like illness.

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Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 2 Influenza.
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Analysis 12.2

Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 2 Influenza.

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Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 3 Hospitalisations.
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Analysis 12.3

Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 3 Hospitalisations.

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Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 4 Pneumonia.
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Analysis 12.4

Comparison 12 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo, Outcome 4 Pneumonia.

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Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 1 Influenza‐like illness.
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Analysis 13.1

Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 1 Influenza‐like illness.

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Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 2 Influenza.
Figures and Tables -
Analysis 13.2

Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 2 Influenza.

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Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 3 Hospitalisations.
Figures and Tables -
Analysis 13.3

Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 3 Hospitalisations.

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Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 4 Pneumonia.
Figures and Tables -
Analysis 13.4

Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 4 Pneumonia.

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Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 5 Working days lost.
Figures and Tables -
Analysis 13.5

Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 5 Working days lost.

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Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 6 Days ill.
Figures and Tables -
Analysis 13.6

Comparison 13 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo, Outcome 6 Days ill.

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Comparison 14 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo, Outcome 1 Influenza‐like illness.
Figures and Tables -
Analysis 14.1

Comparison 14 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo, Outcome 1 Influenza‐like illness.

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Comparison 15 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo, Outcome 1 Influenza‐like illness.
Figures and Tables -
Analysis 15.1

Comparison 15 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo, Outcome 1 Influenza‐like illness.

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Comparison 16 1968 to 1969 pandemic: live aerosol vaccine versus placebo, Outcome 1 Influenza cases (clinically defined without clear definition).
Figures and Tables -
Analysis 16.1

Comparison 16 1968 to 1969 pandemic: live aerosol vaccine versus placebo, Outcome 1 Influenza cases (clinically defined without clear definition).

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Comparison 16 1968 to 1969 pandemic: live aerosol vaccine versus placebo, Outcome 2 Complications (bronchitis, otitis, pneumonia).
Figures and Tables -
Analysis 16.2

Comparison 16 1968 to 1969 pandemic: live aerosol vaccine versus placebo, Outcome 2 Complications (bronchitis, otitis, pneumonia).

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Table 1. Risk of bias in included studies

Study design

High risk

Low risk

Unclear risk

Total

Case‐control

3

2

15

20

Cohort

14

0

13

27

RCT/CCT

6

9

54

69

Total

23

11

82

116

Table 1 dispalys the overall methodological quality assessment of the included studies described in the text and represented in extended form (with all items of the tools) in Figure 1.

Figures and Tables -
Table 1. Risk of bias in included studies
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Table 2. Funding source of included studies

Study design

Government, institutional or public

Industry

Mixed

Total

Case‐control

13

1

1

15

Cohort

22

3

2

27

RCT/CCT

31

12

5

48

Total

66

16

8

90
Figures and Tables -
Table 2. Funding source of included studies
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Comparison 1. Inactivated parenteral vaccine versus placebo or 'do nothing'

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza‐like illness Show forest plot

16

25795

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.78, 0.87]

1.1 WHO recommended ‐ matching vaccine

7

4760

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.77, 0.89]

1.2 WHO recommended ‐ vaccine matching absent or unknown

7

20942

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.75, 0.90]

1.3 Monovalent not WHO recommended ‐ vaccine matching

1

59

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.28, 3.70]

1.4 Monovalent not WHO recommended ‐ vaccine matching ‐ high dose

1

34

Risk Ratio (M‐H, Fixed, 95% CI)

0.46 [0.09, 2.30]

2 Influenza Show forest plot

22

51724

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.33, 0.44]

2.1 WHO recommended ‐ matching vaccine

12

26947

Risk Ratio (M‐H, Fixed, 95% CI)

0.37 [0.31, 0.45]

2.2 WHO recommended ‐ vaccine matching absent or unknown

7

15068

Risk Ratio (M‐H, Fixed, 95% CI)

0.44 [0.35, 0.56]

2.3 Monovalent not WHO recommended ‐ vaccine matching

2

9675

Risk Ratio (M‐H, Fixed, 95% CI)

0.23 [0.10, 0.54]

2.4 Monovalent not WHO recommended ‐ vaccine matching ‐ high dose

1

34

Risk Ratio (M‐H, Fixed, 95% CI)

0.11 [0.00, 2.49]

3 Physician visits Show forest plot

2

2308

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.40, 1.89]

3.1 WHO recommended ‐ matching vaccine

1

1178

Risk Ratio (M‐H, Random, 95% CI)

0.58 [0.37, 0.91]

3.2 WHO recommended ‐ vaccine matching absent or unknown

1

1130

Risk Ratio (M‐H, Random, 95% CI)

1.28 [0.90, 1.83]

4 Days ill Show forest plot

3

3133

Mean Difference (IV, Random, 95% CI)

‐0.21 [‐0.98, 0.56]

4.1 WHO recommended ‐ matching vaccine

2

2003

Mean Difference (IV, Random, 95% CI)

‐0.58 [‐0.85, ‐0.32]

4.2 WHO recommended ‐ matching absent or unknown

1

1130

Mean Difference (IV, Random, 95% CI)

0.66 [0.16, 1.16]

5 Times any drugs were prescribed Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.03, 0.01]

5.1 WHO recommended ‐ matching vaccine

1

1178

Mean Difference (IV, Random, 95% CI)

‐0.02 [‐0.04, ‐0.00]

5.2 WHO recommended ‐ matching absent or unknown

1

1130

Mean Difference (IV, Random, 95% CI)

0.0 [‐0.00, 0.00]

6 Times antibiotic was prescribed Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.02 [‐0.03, ‐0.01]

6.1 WHO recommended ‐ matching vaccine

1

1178

Mean Difference (IV, Random, 95% CI)

‐0.02 [‐0.03, ‐0.01]

6.2 WHO recommended ‐ matching absent or unknown

1

1130

Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.03, 0.01]

7 Working days lost Show forest plot

4

3726

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐0.14, 0.06]

7.1 WHO recommended ‐ matching vaccine

3

2596

Mean Difference (IV, Random, 95% CI)

‐0.09 [‐0.19, 0.02]

7.2 WHO recommended ‐ matching absent or unknown

1

1130

Mean Difference (IV, Random, 95% CI)

0.09 [0.00, 0.18]

8 Hospitalisations Show forest plot

3

11924

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.85, 1.08]

8.1 WHO recommended ‐ matching vaccine

1

1178

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

8.2 WHO recommended ‐ vaccine matching absent or unknown

1

1130

Risk Ratio (M‐H, Random, 95% CI)

2.89 [0.12, 70.68]

8.3 Monovalent not WHO recommended ‐ vaccine matching

1

9616

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.85, 1.08]

9 Clinical cases (clinically defined without clear definition) Show forest plot

3

4259

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.72, 1.05]

9.1 WHO recommended ‐ matching vaccine

2

2056

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.64, 1.25]

9.2 WHO recommended ‐ vaccine matching absent or unknown

1

2203

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.69, 0.99]

10 Local harms Show forest plot

20

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

10.1 Local ‐ tenderness/soreness

20

35655

Risk Ratio (M‐H, Random, 95% CI)

3.13 [2.44, 4.02]

10.2 Local ‐ erythema

9

29499

Risk Ratio (M‐H, Random, 95% CI)

2.59 [1.77, 3.78]

10.3 Local ‐ induration

3

7786

Risk Ratio (M‐H, Random, 95% CI)

4.28 [1.25, 14.67]

10.4 Local ‐ arm stiffness

1

50

Risk Ratio (M‐H, Random, 95% CI)

1.62 [0.54, 4.83]

10.5 Local ‐ combined endpoint (any or highest symptom)

11

12307

Risk Ratio (M‐H, Random, 95% CI)

2.44 [1.82, 3.28]

11 Systemic harms Show forest plot

16

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1 Systemic ‐ myalgia

10

30360

Risk Ratio (M‐H, Random, 95% CI)

1.77 [1.40, 2.24]

11.2 Systemic ‐ fever

12

19202

Risk Ratio (M‐H, Random, 95% CI)

1.54 [1.22, 1.95]

11.3 Systemic ‐ headache

13

31351

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.01, 1.36]

11.4 Systemic ‐ fatigue or indisposition

11

31140

Risk Ratio (M‐H, Random, 95% CI)

1.23 [1.07, 1.42]

11.5 Systemic ‐ nausea/vomiting

3

1667

Risk Ratio (M‐H, Random, 95% CI)

2.68 [0.55, 13.08]

11.6 Systemic ‐ malaise

3

26111

Risk Ratio (M‐H, Random, 95% CI)

1.51 [1.18, 1.92]

11.7 Systemic ‐ combined endpoint (any or highest symptom)

6

2128

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.87, 1.53]
Figures and Tables -
Comparison 1. Inactivated parenteral vaccine versus placebo or 'do nothing'
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Comparison 2. Live aerosol vaccine versus placebo or 'do nothing'

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza‐like illness Show forest plot

6

12688

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.84, 0.96]

1.1 WHO recommended ‐ matching vaccine

2

4254

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.76, 1.12]

1.2 WHO recommended ‐ vaccine matching absent or unknown

3

8150

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.82, 0.97]

1.3 Non WHO recommended ‐ vaccine matching absent or unknown

1

284

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.73, 1.16]

2 Influenza Show forest plot

9

11579

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.35, 0.62]

2.1 WHO recommended ‐ matching vaccine

4

6584

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.37, 0.82]

2.2 WHO recommended ‐ vaccine matching absent or unknown

3

4568

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.27, 0.68]

2.3 Non WHO recommended ‐ vaccine matching absent or unknown

2

427

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.08, 0.56]

3 Influenza cases (clinically defined without clear definition) Show forest plot

3

23900

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.71, 1.11]

3.1 WHO recommended ‐ matching vaccine

1

1931

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.49, 0.80]

3.2 WHO recommended ‐ vaccine matching absent or unknown

1

2082

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.88, 1.25]

3.3 Non WHO recommended ‐ vaccine matching absent or unknown

1

19887

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.92, 1.05]

4 Local harms Show forest plot

13

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Local ‐ upper respiratory infection symptoms

6

496

Risk Ratio (M‐H, Random, 95% CI)

1.66 [1.22, 2.27]

4.2 Local ‐ cough

6

2401

Risk Ratio (M‐H, Random, 95% CI)

1.51 [1.08, 2.10]

4.3 Local ‐ coryza

2

4782

Risk Ratio (M‐H, Random, 95% CI)

1.56 [1.26, 1.94]

4.4 Local ‐ sore throat

7

6940

Risk Ratio (M‐H, Random, 95% CI)

1.66 [1.49, 1.86]

4.5 Local ‐ hoarseness

1

306

Risk Ratio (M‐H, Random, 95% CI)

1.21 [0.51, 2.83]

4.6 Local ‐ combined endpoint (any or highest symptom)

3

4921

Risk Ratio (M‐H, Random, 95% CI)

1.56 [1.31, 1.87]

5 Systemic harms Show forest plot

7

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Systemic ‐ myalgia

4

1318

Risk Ratio (M‐H, Random, 95% CI)

2.47 [1.26, 4.85]

5.2 Systemic ‐ fever

4

1318

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.54, 1.92]

5.3 Systemic ‐ fatigue or indisposition

3

1018

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.93, 2.07]

5.4 Systemic ‐ headache

2

975

Risk Ratio (M‐H, Random, 95% CI)

1.54 [1.09, 2.18]

5.5 Systemic ‐ combined endpoint (any or highest symptom)

5

1018

Risk Ratio (M‐H, Random, 95% CI)

1.40 [0.82, 2.38]
Figures and Tables -
Comparison 2. Live aerosol vaccine versus placebo or 'do nothing'
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Comparison 3. Inactivated aerosol vaccine versus placebo or 'do nothing'

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza Show forest plot

1

1348

Odds Ratio (M‐H, Random, 95% CI)

0.38 [0.14, 1.02]

1.1 WHO recommended ‐ vaccine matching absent or unknown

1

1348

Odds Ratio (M‐H, Random, 95% CI)

0.38 [0.14, 1.02]

1.2 WHO recommended ‐ matching vaccine

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Local harms Show forest plot

3

1578

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.71, 1.27]

2.1 Local ‐ sore throat

3

1500

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.54, 1.33]

2.2 Local ‐ combined endpoint (any or highest symptom)

1

78

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.71, 1.48]

3 Systemic harms Show forest plot

3

1880

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.71, 1.62]

3.1 Systemic ‐ myalgia

2

151

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.36, 2.25]

3.2 Systemic ‐ fatigue or indisposition

2

151

Risk Ratio (M‐H, Random, 95% CI)

1.40 [0.52, 3.75]

3.3 Systemic ‐ headache

2

151

Risk Ratio (M‐H, Random, 95% CI)

1.52 [0.85, 2.72]

3.4 Systemic ‐ fever

1

1349

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.03, 7.80]

3.5 Systemic ‐ combined endpoint (any or highest symptom)

1

78

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.12, 1.04]
Figures and Tables -
Comparison 3. Inactivated aerosol vaccine versus placebo or 'do nothing'
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Comparison 4. Inactivated parenteral vaccine versus placebo ‐ cohort studies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Seasonal inactivated vaccine effectiveness in mothers ‐ pregnant women Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 H1N1 ‐ vaccine ‐ effectiveness ILI (unadjusted data)

1

7328

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.06, 0.21]

1.2 Seasonal ‐ vaccine ‐ effectiveness ILI ‐ (unadjusted data)

2

50129

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.22, 1.32]

2 Seasonal inactivated vaccine effectiveness in newborns ‐ pregnant women Show forest plot

2

Hazard Ratio (Random, 95% CI)

Subtotals only

2.1 Seasonal vaccine effectiveness ILI (HR adjusted data)

2

Hazard Ratio (Random, 95% CI)

0.96 [0.90, 1.03]

3 Seasonal inactivated vaccine effectiveness in newborns ‐ pregnant women Show forest plot

1

Risk Ratio (Random, 95% CI)

Subtotals only

3.1 Seasonal vaccine effectiveness ILI (RR adjusted data)

1

Risk Ratio (Random, 95% CI)

0.92 [0.73, 1.16]

3.2 Seasonal vaccine efficacy influenza ‐ laboratory‐confirmed

1

Risk Ratio (Random, 95% CI)

0.59 [0.37, 0.94]

4 H1N1 vaccine ‐ safety ‐ pregnancy‐related outcomes ‐ pregnant women Show forest plot

9

Odds Ratio (Random, 95% CI)

Subtotals only

4.1 Abortion (OR ‐ adjusted data)

5

Odds Ratio (Random, 95% CI)

0.75 [0.62, 0.90]

4.2 Abortion (HR ‐ adjusted data)

2

Odds Ratio (Random, 95% CI)

0.88 [0.67, 1.16]

4.3 Congenital malformation (OR ‐ adjusted data)

5

Odds Ratio (Random, 95% CI)

1.06 [0.90, 1.25]

4.4 Prematurity (< 37 weeks) (OR adjusted data)

8

Odds Ratio (Random, 95% CI)

0.86 [0.76, 0.97]

4.5 Neonatal death (OR adjusted data)

1

Odds Ratio (Random, 95% CI)

1.81 [0.16, 20.35]

5 Seasonal vaccine ‐ safety ‐ pregnancy‐related outcomes ‐ pregnant women Show forest plot

4

Odds Ratio (Random, 95% CI)

Subtotals only

5.1 Abortion (OR ‐ unadjusted data)

1

Odds Ratio (Random, 95% CI)

0.60 [0.41, 0.86]

5.2 Congenital malformation (OR unadjusted data)

2

Odds Ratio (Random, 95% CI)

0.55 [0.08, 3.73]

5.3 Prematurity (OR unadjusted data)

4

Odds Ratio (Random, 95% CI)

0.96 [0.79, 1.17]

5.4 Neonatal death (OR unadjusted data)

1

Odds Ratio (Random, 95% CI)

0.55 [0.35, 0.88]
Figures and Tables -
Comparison 4. Inactivated parenteral vaccine versus placebo ‐ cohort studies
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Comparison 5. Inactivated parenteral vaccine versus placebo ‐ case‐control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Effectiveness in newborns ‐ pregnant women (adjusted data) Show forest plot

2

Odds Ratio (Random, 95% CI)

0.24 [0.04, 1.40]

1.1 Seasonal vaccine ‐ effectiveness ‐ ILI ‐ pregnant women

2

Odds Ratio (Random, 95% CI)

0.24 [0.04, 1.40]

2 Seasonal vaccine safety ‐ pregnancy‐related outcomes (adjusted data) Show forest plot

1

Odds Ratio (Random, 95% CI)

0.80 [0.36, 1.78]

2.1 Abortion

1

Odds Ratio (Random, 95% CI)

0.80 [0.36, 1.78]
Figures and Tables -
Comparison 5. Inactivated parenteral vaccine versus placebo ‐ case‐control
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Comparison 6. Serious adverse events ‐ Guillain‐Barré syndrome ‐ cohort studies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Seasonal influenza vaccination and Guillain‐Barré syndrome Show forest plot

3

Risk Ratio (Random, 95% CI)

1.28 [0.85, 1.93]

1.1 General population (adjusted data)

2

Risk Ratio (Random, 95% CI)

1.29 [0.83, 2.02]

1.2 Pregnant women (unadjusted data)

1

Risk Ratio (Random, 95% CI)

0.65 [0.03, 15.95]
Figures and Tables -
Comparison 6. Serious adverse events ‐ Guillain‐Barré syndrome ‐ cohort studies
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Comparison 7. Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 2009 to 2010 A/H1N1 ‐ general population (unadjusted data) Show forest plot

6

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 < 7 weeks

6

1528

Odds Ratio (M‐H, Random, 95% CI)

2.22 [1.14, 4.31]

1.2 At any time

6

1656

Odds Ratio (M‐H, Random, 95% CI)

1.69 [0.87, 3.29]

2 2009 to 2010 A/H1N1 ‐ general population (adjusted data) Show forest plot

4

Odds Ratio (Random, 95% CI)

0.83 [0.39, 1.75]

2.1 < 7 weeks

4

Odds Ratio (Random, 95% CI)

0.92 [0.35, 2.40]

2.2 > 6 weeks

3

Odds Ratio (Random, 95% CI)

0.71 [0.22, 2.32]

3 Seasonal influenza vaccination general population (adjusted data) Show forest plot

1

Odds Ratio (Random, 95% CI)

1.38 [0.18, 10.43]
Figures and Tables -
Comparison 7. Serious adverse events ‐ Guillain‐Barré syndrome ‐ case‐control
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Comparison 8. Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza vaccination (seasonal) ‐ demyelinating diseases (unadjusted data) Show forest plot

1

223898

Odds Ratio (M‐H, Random, 95% CI)

0.16 [0.02, 1.25]

1.1 General population

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Pregnant women

1

223898

Odds Ratio (M‐H, Random, 95% CI)

0.16 [0.02, 1.25]

2 Influenza vaccination (H1N1) ‐ demyelinating diseases (unadjusted) Show forest plot

1

144252

Risk Ratio (M‐H, Random, 95% CI)

2.06 [0.51, 8.22]
Figures and Tables -
Comparison 8. Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ cohort studies
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Comparison 9. Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza vaccination (seasonal) ‐ general population ‐ demyelinating diseases (unadjusted data) Show forest plot

4

8009

Odds Ratio (M‐H, Random, 95% CI)

0.96 [0.79, 1.17]

2 Influenza vaccination (seasonal) ‐ general population ‐ multiple sclerosis (adjusted data) Show forest plot

2

(Random, 95% CI)

0.76 [0.54, 1.08]

3 Influenza vaccination (seasonal) ‐ general population ‐ optic neuritis (adjusted data) Show forest plot

2

Odds Ratio (Random, 95% CI)

1.03 [0.82, 1.30]
Figures and Tables -
Comparison 9. Serious adverse events ‐ demyelinating diseases (multiple sclerosis, optic neuritis) ‐ case‐control studies
Navigate to table in Review
Comparison 10. Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Seasonal influenza vaccine ‐ HR (adjusted data) Show forest plot

1

Hazard Ratio (Random, 95% CI)

Subtotals only

1.1 General population

0

Hazard Ratio (Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Pregnant women

1

Hazard Ratio (Random, 95% CI)

0.90 [0.68, 1.19]

2 Seasonal influenza vaccine (unadjusted data) Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 General population

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Pregnant women

1

223898

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.70, 1.20]
Figures and Tables -
Comparison 10. Serious adverse events ‐ immune thrombocytopaenic purpura ‐ cohort studies
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Comparison 11. Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control studies

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Seasonal influenza vaccine ‐ general population (adjusted data) Show forest plot

2

Odds Ratio (Random, 95% CI)

Subtotals only

1.1 < 2 months

2

Odds Ratio (Random, 95% CI)

1.87 [0.43, 8.06]

1.2 < 6 months

1

Odds Ratio (Random, 95% CI)

0.90 [0.55, 1.47]

1.3 < 12 months

1

Odds Ratio (Random, 95% CI)

0.70 [0.47, 1.04]

2 Seasonal influenza vaccine ‐ general population (unadjusted data) Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 < 2 months

2

1926

Odds Ratio (M‐H, Random, 95% CI)

1.72 [0.48, 6.15]

2.2 < 6 months

1

1065

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.59, 1.43]

2.3 < 12 months

1

1066

Odds Ratio (M‐H, Random, 95% CI)

0.72 [0.50, 1.05]
Figures and Tables -
Comparison 11. Serious adverse events ‐ immune thrombocytopaenic purpura ‐ case‐control studies
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Comparison 12. 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza‐like illness Show forest plot

3

3065

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.57, 0.88]

1.1 Standard recommended parenteral ‐ non‐matching ‐ 1 dose

3

2715

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.57, 0.95]

1.2 Standard recommended parenteral ‐ non‐matching ‐ 2 doses

1

350

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.44, 0.98]

2 Influenza Show forest plot

1

2072

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.26, 0.87]

2.1 Standard recommended parenteral ‐ non‐matching

1

2072

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.26, 0.87]

3 Hospitalisations Show forest plot

1

2072

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.41, 1.68]

3.1 Standard recommended parenteral ‐ non‐matching

1

2072

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.41, 1.68]

4 Pneumonia Show forest plot

1

2072

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.14, 7.17]

4.1 Standard recommended parenteral ‐ non‐matching

1

2072

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.14, 7.17]
Figures and Tables -
Comparison 12. 1968 to 1969 pandemic: inactivated polyvalent parenteral vaccine versus placebo
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Comparison 13. 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza‐like illness Show forest plot

4

4580

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.25, 0.48]

1.1 WHO recommended parenteral ‐ matching vaccine ‐ 1 dose

4

4226

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.23, 0.53]

1.2 WHO recommended parenteral ‐ matching vaccine ‐ 2 doses

1

354

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.22, 0.57]

2 Influenza Show forest plot

1

1923

Risk Ratio (M‐H, Random, 95% CI)

0.07 [0.02, 0.31]

2.1 WHO recommended parenteral ‐ matching vaccine

1

1923

Risk Ratio (M‐H, Random, 95% CI)

0.07 [0.02, 0.31]

3 Hospitalisations Show forest plot

1

1923

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.13, 0.94]

3.1 WHO recommended parenteral ‐ matching vaccine

1

1923

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.13, 0.94]

4 Pneumonia Show forest plot

1

1923

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.05, 6.51]

4.1 WHO recommended parenteral ‐ matching vaccine

1

1923

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.05, 6.51]

5 Working days lost Show forest plot

1

1667

Mean Difference (IV, Random, 95% CI)

‐0.45 [‐0.60, ‐0.30]

5.1 WHO recommended parenteral ‐ matching vaccine

1

1667

Mean Difference (IV, Random, 95% CI)

‐0.45 [‐0.60, ‐0.30]

6 Days ill Show forest plot

1

1667

Mean Difference (IV, Random, 95% CI)

‐0.45 [‐0.60, ‐0.30]

6.1 WHO recommended ‐ matching vaccine

1

1667

Mean Difference (IV, Random, 95% CI)

‐0.45 [‐0.60, ‐0.30]
Figures and Tables -
Comparison 13. 1968 to 1969 pandemic: inactivated monovalent parenteral vaccine versus placebo
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Comparison 14. 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza‐like illness Show forest plot

2

1000

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.46, 0.95]

1.1 Inactivated polyvalent aerosol vaccine versus placebo ‐ non‐matching ‐ 1 dose

2

644

Risk Ratio (M‐H, Random, 95% CI)

0.64 [0.32, 1.27]

1.2 Inactivated polyvalent aerosol vaccine versus placebo ‐ non‐matching ‐ 2 doses

1

356

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.44, 0.97]
Figures and Tables -
Comparison 14. 1968 to 1969 pandemic: inactivated polyvalent aerosol vaccine versus placebo
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Comparison 15. 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza‐like illness Show forest plot

2

1009

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.32, 0.91]

1.1 Inactivated monovalent aerosol vaccine versus placebo ‐ matching ‐ 1 dose

2

650

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.17, 1.41]

1.2 Inactivated monovalent aerosol vaccine versus placebo ‐ matching ‐ 2 doses

1

359

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.38, 0.86]
Figures and Tables -
Comparison 15. 1968 to 1969 pandemic: inactivated monovalent aerosol vaccine versus placebo
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Comparison 16. 1968 to 1969 pandemic: live aerosol vaccine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Influenza cases (clinically defined without clear definition) Show forest plot

1

19887

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.92, 1.05]

1.1 Non‐matching

1

19887

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.92, 1.05]

2 Complications (bronchitis, otitis, pneumonia) Show forest plot

1

19887

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.03, 2.24]

2.1 Non‐matching

1

19887

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.03, 2.24]
Figures and Tables -
Comparison 16. 1968 to 1969 pandemic: live aerosol vaccine versus placebo
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