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

Abstract

BackgroundOur 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.Methods6203 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.ResultsTIV 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%).ConclusionDue 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 RegistrationClinical trial registery: NCT00197223.

Expected cost effectiveness of high-dose trivalent influenza vaccine in US seniors

“…However, accurately predicting which B-lineage strain will predominate in the upcoming season has proven to be a challenging task resulting in frequent mismatches with the vaccine strain [4]. During mismatch seasons, efficacy and effectiveness against the opposite B lineage have been reduced [5][6][7][8][9][10][11]. To address the issue of co-circulating B lineages, several manufacturers have developed new seasonal influenza vaccines that include both influenza B virus strains.…”

Genetic and Antigenic Typing of Seasonal Influenza Virus Breakthrough Cases from a 2008-2009 Vaccine Efficacy Trial

“…Determining whether influenza viruses isolated from clinical breakthrough cases are drifted or mismatched to the vaccine strains is therefore necessary to appropriately estimate vaccine effectiveness (7, 9, 10), but it is challenging because of the requirement to use culture-based methods (26). Moreover, in the context of a vaccine efficacy clinical trial, the number of breakthrough cases detected through culture-based methods may be relatively small, especially if the attack rate is unusually low in a given season (38). The use of PCR is highly attractive because of its sensitivity and ease of application (7,36,37,39).…”

Assessing vaccine efficacy in influenza clinical trials: challenges and difficulties

“…In case of homogeneous length of follow-up, the risk is defined as the proportion of subjects with an event [6][7][8][9][10][11][12][13][14] (ClinicalTrials.gov identifiers: NCT00192413, NCT00133523, NCT00128167, NCT00133523, NCT00197223, NCT00216242, NCT00363870, NCT00538512 in Table 1) and the ratio ψ as a relative risk [15]. A variety of methods can be used to estimate ψ and one of the most frequently used is the logistic regression that produces an estimated odds ratio which can be used to approximate the relative risk when the risks are sufficiently small [16].…”