Open Access Highly Accessed Research article

Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example

Jiří Beran12*, Veronika Wertzova1, Karel Honegr2, Eva Kaliskova4, Martina Havlickova3, Jiří Havlik1, Helena Jirincova3, Pascale Van Belle5, Varsha Jain6, Bruce Innis6 and Jeanne-Marie Devaster5

Author Affiliations

1 The Vaccination and Travel Medicine Center, Hradec Kralove, Czech Republic

2 Department of Infectious Diseases, University Hospital, Hradec Kralove, Czech Republic

3 National Institute of Public Health, National Reference Laboratory for Influenza, Praha, Czech Republic

4 GlaxoSmithKline Biologicals, Praha, Czech Republic

5 GlaxoSmithKline Biologicals, Rixensart, Belgium

6 GlaxoSmithKline Biologicals, King of Prussia, USA

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BMC Infectious Diseases 2009, 9:2  doi:10.1186/1471-2334-9-2

Published: 17 January 2009

Abstract

Background

Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine (TIV) against culture-confirmed influenza A and/or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic.

Methods

6203 subjects were randomized to receive TIV (N = 4137) or placebo (N = 2066). The sample size was based on an assumed attack rate of 4% which provided 90% power to reject the hypothesis that vaccine efficacy (VE) was ≥ 45%. Cases of influenza like illness (defined as fever (oral temperature ≥37.8°C) plus cough and/or sore throat) were identified both by active (biweekly phone contact) and passive (self reporting) surveillance and nasal and throat swabs were collected from subjects for viral culture.

Results

TIV was well tolerated and induced a good immune response. The 2005/2006 influenza season was exceptionally mild in the study area, as it was throughout Europe, and only 46 culture-confirmed cases were found in the study cohort (10 influenza A and 36 influenza B). Furthermore among the B isolates, 35 were identified as B/Hong Kong 330/2001-like (B/Victoria/2/87 lineage) which is antigenically unrelated to the vaccine B strain (B/Yamagata/16/88 lineage). The attack rate in the vaccine group (0.7%) was not statistically significantly different from the attack rate in the placebo group (0.9%).

Conclusion

Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy. This experience illustrates the challenge of conducting a prospective influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance.

Trial Registration

Clinical trial registery: NCT00197223.