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Variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies

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Summary

Background

Influenza vaccine effectiveness (VE) can vary by type and subtype. Over the past decade, the test-negative design has emerged as a valid method for estimation of VE. In this design, VE is calculated as 100% × (1 – odds ratio) for vaccine receipt in influenza cases versus test-negative controls. We did a systematic review and meta-analysis to estimate VE by type and subtype.

Methods

In this systematic review and meta-analysis, we searched PubMed and Embase from Jan 1, 2004, to March 31, 2015. Test-negative design studies of influenza VE were eligible if they enrolled outpatients on the basis of predefined illness criteria, reported subtype-level VE by season, used PCR to confirm influenza, and adjusted for age. We excluded studies restricted to hospitalised patients or special populations, duplicate reports, interim reports superseded by a final report, studies of live-attenuated vaccine, and studies of prepandemic seasonal vaccine against H1N1pdm09. Two reviewers independently assessed titles and abstracts to identify articles for full review. Discrepancies in inclusion and exclusion criteria and VE estimates were adjudicated by consensus. Outcomes were VE against H3N2, H1N1pdm09, H1N1 (pre-2009), and type B. We calculated pooled VE using a random-effects model.

Findings

We identified 3368 unduplicated publications, selected 142 for full review, and included 56 in the meta-analysis. Pooled VE was 33% (95% CI 26–39; I2=44·4) for H3N2, 54% (46–61; I2=61·3) for type B, 61% (57–65; I2=0·0) for H1N1pdm09, and 67% (29–85; I2=57·6) for H1N1; VE was 73% (61–81; I2=31·4) for monovalent vaccine against H1N1pdm09. VE against H3N2 for antigenically matched viruses was 33% (22–43; I2=56·1) and for variant viruses was 23% (2–40; I2=55·6). Among older adults (aged >60 years), pooled VE was 24% (−6 to 45; I2=17·6) for H3N2, 63% (33–79; I2=0·0) for type B, and 62% (36–78; I2=0·0) for H1N1pdm09.

Interpretation

Influenza vaccines provided substantial protection against H1N1pdm09, H1N1 (pre-2009), and type B, and reduced protection against H3N2. Vaccine improvements are needed to generate greater protection against H3N2 than with current vaccines.

Funding

None.

Introduction

Influenza vaccines are licensed on the basis of findings from immunogenicity studies or randomised clinical trials (RCTs) showing efficacy and safety. In a previous meta-analysis1 of RCTs in healthy adults, we found that pooled vaccine efficacy was 59% against all strains. Although the RCT is the optimal design to minimise bias and confounding, it has important limitations. RCTs are often limited to one or two seasons, enrol healthy individuals, have low power to measure efficacy by subtype, and are not feasible to do annually. Placebo-controlled trials are not ethical in populations for whom vaccination is routinely recommended, and results from a single season might not predict efficacy in subsequent seasons.

Over the past decade, the test-negative design (TND) has emerged as a valid approach for estimation of influenza vaccine effectiveness (VE). In this design, VE is calculated as 100% × (1 – odds ratio [OR]) for vaccine receipt in influenza cases versus test-negative controls. The first TND study2 was published in 2005 by Canadian investigators who reported VE in British Columbia during the 2004–05 season. Since then, multiple TND studies have been done to estimate VE in both the northern and southern hemisphere. The TND is similar to a case-control study, but cases and controls are not identified at the time of enrolment. Instead, patients seeking medical care for an acute respiratory illness are enrolled and respiratory tract samples tested for influenza with RT-PCR. Findings from TND simulation studies3, 4 suggest that this method yields a valid estimate of VE in the source population under most scenarios.

Investigators of an increasing number of TND studies are reporting VE estimates separately by type and subtype. We did a systematic review and meta-analysis of published TND studies to estimate seasonal VE against illness caused by H3N2, H1N1pdm09, H1N1 (pre-2009), and type B.

Research in context

Evidence before this study

In March, 2014, we did an informal review of the literature by searching PubMed for original reports of influenza vaccine effectiveness (VE) published in English from 1990 to 2013. We restricted our review to studies that reported single-season VE against H3N2, H1N1, H1N1pdm09, or type B. To minimise potential bias, we further restricted our preliminary review to studies using the test-negative design with outpatient recruitment based on predefined criteria, those that had confirmation of influenza with RT-PCR or culture, and those that had age adjustment. We identified 43 publications that met these criteria, leading to a decision to do a formal meta-analysis. Our preliminary review indicated that the earliest test-negative design study of influenza VE was conducted in 2004–05, and the formal meta-analysis was therefore restricted to the period from Jan 1, 2004, to March 31, 2015.

Added value of this study

Findings from this study show substantial variation in VE across influenza types and subtypes. Influenza vaccine provided moderate to high protection against H1N1pdm09, H1N1 (pre-2009), and type B, and substantially lower protection against H3N2. Differences across age groups were minimal for H1N1pdm09 and type B. VE against H3N2 was highest in paediatric age groups and lowest in older adults. VE against H3N2 was low regardless of reported antigenic match, but this comparison was limited by the absence of standardised antigenic characterisation and information about antigenic distance. In this systematic review and meta-analysis, we found that relevant information about patient recruitment, symptom eligibility, and vaccine ascertainment was inconsistently reported, and we have made recommendations to optimise VE methods in the outpatient setting. These recommendations are consistent with draft recommendations being developed by WHO.

Implications of all the available evidence

H3N2 is associated with higher morbidity and mortality than are other subtypes, and vaccine improvements are needed to generate greater protection against H3N2 than against other subtypes. Alternatives to egg-based manufacturing should be pursued since egg-induced mutations in H3N2 vaccine strains contribute to antigenic mismatch.

Section snippets

Search strategy and selection criteria

In this systematic review and meta-analysis, published studies were eligible for inclusion if they met all of the following criteria: original analysis of influenza VE with the test-negative design; used RT-PCR to confirm influenza; reported VE (or corresponding OR) for one or more individual seasons against H3N2, H1N1, H1N1pdm09, or type B; recruited patients on the basis of predefined illness criteria; and reported results from age-adjusted logistic regression models or age-stratified VE

Results

We identified 3368 unduplicated publications, selected 142 for full review, and included 56 that met eligibility criteria in the meta-analysis (appendix).8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 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, 55, 56, 57, 58, 59, 60, 61, 62, 63 Most studies originated in the northern hemisphere, with a similar number of studies originating from Europe and North

Discussion

In this systematic review and meta-analysis, we found substantial variation in VE across types and subtypes. In the primary analysis that was not restricted by age, influenza vaccine provided moderate to high protection against H1N1pdm09, H1N1 (pre-2009), and type B, and substantially lower protection against H3N2. Monovalent pandemic vaccine yielded the highest pooled VE estimate. Pooled VE was higher for adjuvanted monovalent vaccines than for non-adjuvanted pandemic vaccines, but the small

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