Analysis of varicella vaccine breakthrough rates: implications for the effectiveness of immunisation programmes
Introduction
In clinical trials vaccine efficacy is measured as the relative risk of infection in the vaccinated group compared with unvaccinated individuals [1]. In general, vaccine efficacy is comprised of three components [2]: the proportion of individuals who acquire protection; the degree to which they are protected; and the duration of that protection. It can be difficult to estimate the contribution of each effect to the overall vaccine efficacy measured in controlled trials, because these often have a short time span relative to the period over which the vaccine is intended to offer protection (often life-time). Clearly, however, it is critical to have good estimates of these parameters to allow accurate long-term predictions of the impact of vaccination programs to be made.
Halloran et al. attempted to estimate vaccine efficacy parameters for varicella zoster (VZV) vaccine by reviewing the literature available at the time and employing a Delphi process [3]. These parameter values have been used in subsequent studies (such as Coudeville et al. [4]). Since many countries are in the process of evaluating the cost-effectiveness of varicella vaccination it is now timely to re-examine these estimates and amend them if necessary.
In this paper, we re-evaluate Halloran et al.’s estimates in the light of new data. Additionally, Halloran et al. used the standard approach of estimating each parameter separately. This approach can result in a poor fit to the data when all the parameters are combined even though each individual estimate seems plausible. Our approach differs in that we estimate the parameters simultaneously from the observed breakthrough rates (varicella infection in seroconverted vaccinees [3]) over time.
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Selection of studies
Most of the published studies of vaccine immunogenicity and efficacy have involved the Oka/Merck product (Varivax®, Merck Research Laboratories). Published data using the other manufacturer’s vaccines were too few to include in the analysis.
The pre-licensure studies of Varivax® involved four different lots prepared in 1982, 1984, 1987 and 1991 [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. These lots differed in the relative amounts of both live virus and non-viable viral antigen as
Results
Fig. 2 shows the data and the best fit model for the best, worst and base-cases (best fit parameter values are given in Table 1). For comparative purposes the annual proportion of the cohort with breakthrough infections as predicted using Halloran et al.’s base-case and worst-case (“low-efficacy”) parameter combinations (see Table 1) are also shown in Fig. 2. It is clear that none of Halloran et al.’s parameter sets fit the data: even the least optimistic vaccine assumptions give far fewer
Discussion
We have updated Halloran et al.’s vaccine efficacy parameters. Our estimates yield higher breakthrough rates, which give a better fit to the observed data. Indeed, the annual number of breakthrough cases with Halloran et al.’s worst-case scenario is lower than that of the lowest observed breakthrough data (lot 1982, with passive reporting). Thus studies using Halloran et al.’s parameter sets may be overestimating the predicted effectiveness of varicella immunisation.
This study also shows that
Acknowledgements
We wish to acknowledge Merck Research Laboratories for generously providing us with previously unpublished data.
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