Elsevier

Vaccine

Volume 30, Issue 21, 2 May 2012, Pages 3209-3222
Vaccine

Impacts on influenza A(H1N1)pdm09 infection from cross-protection of seasonal trivalent influenza vaccines and A(H1N1)pdm09 vaccines: Systematic review and meta-analyses

https://doi.org/10.1016/j.vaccine.2012.02.048Get rights and content

Abstract

Cross-protection by seasonal trivalent influenza vaccines (TIVs) against pandemic influenza A H1N1 2009 (now known as A[H1N1]pdm09) infection is controversial; and the vaccine effectiveness (VE) of A(H1N1)pdm09 vaccines has important health-policy implications. Systematic reviews and meta-analyses are needed to assess the impacts of both seasonal TIVs and A(H1N1)pdm09 vaccines against A(H1N1)pdm09.We did a systematic literature search to identify observational and/or interventional studies reporting cross-protection of TIV and A(H1N1)pdm09 VE from when the pandemic started (2009) until July 2011. The studies fulfilling inclusion criteria were meta-analysed. For cross-protection and VE, respectively, we stratified by vaccine type, study design and endpoint.

Seventeen studies (104,781 subjects) and 10 studies (2,906,860 subjects), respectively, reported cross-protection of seasonal TIV and VE of A(H1N1)pdm09 vaccines; six studies (17,229 subjects) reported on both. Thirteen studies (95,903 subjects) of cross-protection, eight studies (859,461 subjects) of VE, and five studies (9,643 subjects) of both were meta-analysed and revealed: (1) cross-protection for confirmed illness was 19% (95% confident interval = 13–42%) based on 13 case–control studies with notable heterogeneity. A higher cross-protection of 34% (9–52%) was found in sensitivity analysis (excluding five studies with moderate/high risk of bias). Further exclusion of studies that recruited early in the pandemic (when non-recipients of TIV were more likely to have had non-pandemic influenza infection that may have been cross-protective) dramatically reduced heterogeneity. One RCT reported cross-protection of 38% (19–53%) for confirmed illness. One case–control study reported cross-protection of 50% (40–59%) against hospitalisation. (2) VE of A(H1N1)pdm09 for confirmed illness was 86% (73–93%) based on 11 case–control studies and 79% (22–94%) based on two cohort studies; VE against medically-attended ILI was 32% (8–50%) in one cohort study.

TIVs provided moderate cross-protection against both laboratory-confirmed A(H1N1)pdm09 illness (based on eight case–control studies with low risk of bias and one RCT) and also hospitalisation. A finding of increased risk from seasonal vaccine was limited to cases recruited early in the pandemic. A(H1N1)pdm09 vaccines were highly effective against confirmed A(H1N1)pdm09 illness. Although cross-protection was less than the direct effect of strain-specific vaccination against A(H1N1)pdm09, TIV was generally beneficial before A(H1N1)pdm09 vaccine was available.

Highlights

Systematic reviews of cross-protection of TIVs & A(H1N1)pdm09 vaccine effectiveness. ► TIVs provided moderate cross-protection against confirmed A(H1N1)pdm09 illness. ► A(H1N1)pdm09 vaccines were highly effective against confirmed illness.

Introduction

A novel influenza virus, A(H1N1)pdm09, was detected in April 2009 [1] and the World Health Organization (WHO) declared the first influenza pandemic of the 21st century 2 months later [2]. Cross-reacting antibodies against this virus were found in the elderly [3], [4], [5] while most of the younger population were at risk of the infection based on serology [6].

There are data suggesting that previous seasonal trivalent influenza vaccines (TIVs) could produce some cross-protection [7], [8], [9], [10], [11], [12]. However, a protective benefit was questioned by some health authorities [13], [14], and brought into doubt by other studies that showed no significant protection [13], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27] or even increased risk [28], [29] of acquiring the virus. Due to the substantial heterogeneities in study results, study designs, and quality of studies, it was difficult to draw a clear conclusion.

On the other hand, after the A(H1N1)pdm09 vaccines were widely distributed, the immunogenicity and short-term safety of various formulations of novel A(H1N1)pdm09 vaccines were clearly demonstrated [30]. Nevertheless, their clinical benefit in preventing disease has not yet been addressed in a systematic way. As several studies [8], [17], [24], [25], [26], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41] have already reported on vaccine effectiveness (VE), and given the important medical and health-policy implications, there is a need for a meaningful systematic review and meta-analyses to assess both the cross-protection of TIVs against A(H1N1)pdm09 infection and the VE of monovalent A(H1N1)pdm09 vaccines. Using the “Population, Intervention, Comparison, and Outcome” framework, our study was in human populations, given either TIVs or monovalent A(H1N1)pdm09 vaccines, comparing with subjects who were not vaccinated with TIV or A(H1N1)pdm09 vaccines and assessing the vaccine effect on preventing A(H1N1)pdm09 disease.

Section snippets

Literature search and selection criteria

Database searches, conducted by a medical librarian (CK), were limited to Humans. No date limits were applied, however, the searches were naturally limited to items reported beginning in 2009 when the pandemic commenced. The last search was undertaken on 18th July 2011. A copy of the full strategy used in OVID Medline is available if required. The searches were undertaken in Ovid MEDLINE (1948 to July Week 1 2011) and Ovid EMBASE (1980 to 2011 Week 28), The Cochrane Library databases – Cochrane

Results

Of the 2178 studies initially retrieved, we identified 34 relevant studies addressing either cross-protection of TIV and/or direct protection of A(H1N1)pdm09 vaccines against either confirmed A(H1N1)pdm09 infection or other relevant endpoints. Two publications reported the same study [20], [48] so we included 33 publications which covered 3,019,399 subjects (Fig. 1 and Table 2). The study by Skowronski published in 2010 [29] was divided into three case–control studies and one cohort study in

Discussion

Our systematic review and meta-analyses demonstrate moderate cross-protection of seasonal influenza vaccines of 34–38% against laboratory-confirmed 2009 A(H1N1)pdm09 illness (based on eight case–control studies [7], [10], [17], [23], [24], [25], [26], [29] and one RCT [12]) and perhaps protection from hospitalisation too (one case–control study) [11]. This finding is consistent with observations from a previous pandemic. No publication bias was identified [50].

No association was detected

Conclusions

Through our systematic review and meta-analyses, we are able to inform governments, academics, medical practitioners and others that, during the delay in A(H1N1)pdm09 vaccine production, seasonal influenza vaccination seemed to provide moderate protection of the population, perhaps less so initially but more later, and furthermore that, although limited by observational study design, the A(H1N1)pdm09 vaccines were generally highly effective against laboratory confirmed A(H1N1)pdm09 illness.

Acknowledgement

We gratefully thank Donna Armstrong for assistance with the literature review.

Contributors: All authors contributed significantly to the study. JKY and RB were involved in all phases of the study. CK conducted the literature search. MYKC assisted JKY in data extraction. PR provided the results of one unpublished RCT [12]. JKY led the statistical analysis. JKY and MYKC did the assessment of risk of bias. JKY, MYKC, GK, LH, PR and RB wrote the manuscript. Funding: None. Conflict of interest

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