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Effectiveness of seasonal influenza vaccine in community-dwelling elderly people: a meta-analysis of test-negative design case-control studies

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Summary

Background

The application of test-negative design case-control studies to assess the effectiveness of influenza vaccine has increased substantially in the past few years. The validity of these studies is predicated on the assumption that confounding bias by risk factors is limited by design. We aimed to assess the effectiveness of influenza vaccine in a high-risk group of elderly people.

Methods

We searched the Cochrane library, Medline, and Embase up to July 13, 2014, for test-negative design case-control studies that assessed the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling people aged 60 years or older. We used generalised linear mixed models, adapted for test-negative design case-control studies, to estimate vaccine effectiveness according to vaccine match and epidemic conditions.

Findings

35 test-negative design case-control studies with 53 datasets met inclusion criteria. Seasonal influenza vaccine was not significantly effective during local virus activity, irrespective of vaccine match or mismatch to the circulating viruses. Vaccination was significantly effective against laboratory confirmed influenza during sporadic activity (odds ratio [OR] 0·69, 95% CI 0·48–0·99) only when the vaccine matched. Additionally, vaccination was significantly effective during regional (match: OR 0·42, 95% CI 0·30–0·60; mismatch: OR 0·57, 95% CI 0·41–0·79) and widespread (match: 0·54, 0·46–0·62; mismatch: OR 0·72, 95% CI 0·60–0·85) outbreaks.

Interpretation

Our findings show that in elderly people, irrespective of vaccine match, seasonal influenza vaccination is effective against laboratory confirmed influenza during epidemic seasons. Efforts should be renewed worldwide to further increase uptake of the influenza vaccine in the elderly population.

Funding

None.

Introduction

Because of the changing nature of influenza viruses and the consequent need for an annual update of the influenza vaccine, the effectiveness of seasonal influenza vaccines should be assessed every year. Seasonal influenza vaccination is regarded as the main preventive strategy in adults aged 60 years and older in most developed countries; as such, undertaking of a randomised controlled trial such as that done by Govaert and colleagues1 is no longer ethical.2 Therefore, the main strategy to assess the effectiveness of influenza vaccine in this age group is to do observational studies—ie, variations on case-control and cohort designs. One of the major drawbacks of such designs is confounding by indication, also referred to as the healthy user effect or selection bias, due to poor allocation concealment and differences in baseline characteristics between vaccinated and non-vaccinated groups.3, 4 Several studies have shown that estimates of influenza vaccine effectiveness in elderly people could be affected by the presence of selection bias in observational studies.4, 5, 6 Furthermore, in most observational studies, influenza vaccine effectiveness has been assessed against non-specific outcomes. Findings have shown that use of non-specific endpoints, such as influenza-like illness, underestimates vaccine effectiveness.7

A type of case-control design known as test-negative design has been developed to assess the effectiveness of seasonal influenza vaccine.8 Vaccine status in test-negative design studies is compared between patients presenting with influenza-like symptoms who test positive for influenza with laboratory tests (laboratory-confirmed cases) and those who test negative (controls). Because both cases and controls are recruited in the same process and have similar health care-seeking behaviour, their validity is predicated on the assumption that confounding by possible risk factors is reduced by design.9, 10 Moreover, because vaccine effectiveness is estimated against a specific outcome confirmed by a sensitive and specific laboratory test, the provided estimate can be assumed to be more accurate than are estimates from non-specific outcomes.7, 9

In the past few years the number of test-negative design studies has increased substantially. Within the I-MOVE programme—a European programme to monitor the effectiveness of seasonal and pandemic influenza vaccine—test-negative design case-control studies provide much evidence about the effectiveness of annual influenza vaccination in the European Union and European Economic Area. As a result, investigators of a systematic review assessing the efficacy and effectiveness of influenza vaccine included several test-negative design studies.11 Although the investigators attempted to reduce bias by including studies that solely assessed the vaccine effectiveness against virologically confirmed influenza outcomes, only a few test-negative design studies were included. Therefore, the pooled vaccine effectiveness against laboratory confirmed influenza could not be estimated, and a clear conclusion about the protectiveness of influenza vaccine in the elderly population could not be made.

We therefore did this study to assess the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling elderly people.

Section snippets

Definitions and outcome

We defined the effectiveness of influenza vaccine as a relative reduction in risk of laboratory confirmed influenza endpoints attributed to vaccination from test-negative design studies given by odds ratios (ORs).12 We defined laboratory confirmed influenza as that confirmed by at least one of several laboratory tests: culture testing, rapid antigen testing, fluorescent antibody assays, or PCR tests. To assess vaccine effectiveness we considered the effect of vaccine match and epidemic

Results

The systematic literature search resulted in 3875 potentially relevant articles. After exlusion of duplicates, 2975 titles and abstracts were screened of which 35 studies met the inclusion criteria for the meta-analysis (figure 1).7, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 These 35 studies resulted in 49 datasets because some reported data for more than one influenza season (table 1). In 12 studies,

Discussion

Our findings show that seasonal influenza vaccine was effective against laboratory confirmed illness during regional and widespread outbreaks, irrespective of vaccine match or mismatch to the circulating viruses, although the effect was stronger when the vaccine matched. Additionally, vaccination showed significant effectiveness against outcome during sporadic virus activity when the vaccine matched the circulating viruses. However, vaccine was not significantly effective against laboratory

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