ReviewVaccine effects and impact of vaccination programmes in post-licensure studies
Introduction
Before licensure, a vaccine must demonstrate its immunogenicity and/or protective efficacy in clinical trials, as well as its quality and safety [1], [2]. Once the vaccine is authorized by regulatory authorities and used in the population at large, post-licensure studies are required to assess vaccine safety and effectiveness, as well as impact of vaccination programmes [3]. This monitoring of the benefit–risk balance is currently an integral part of the life cycle of vaccines [4].
Vaccine efficacy, and the study designs used to measure it, are clearly defined [3], [5], [6]. But the distinction from vaccine effectiveness is often ignored [3], [5], [6]. The term impact of a vaccination programme is widely used in the literature and by international agencies but what it exactly means and how to measure it is usually not described and certainly not standardized [1], [2], [7], [8], [9]. Overall, post-licensure vaccine studies use diverging terms to describe different types of effect. This confusion in terminology implies that the type of post-licensure effects that is expected from a vaccine – or a vaccination programme – is rarely clarified at the level of decision-makers.
Post-licensure studies are mainly observational because the real-life effects of a vaccine administered in a public health programme are difficult to measure in an experimental design. Observational designs are based on a number of assumptions that are rarely met, and their findings are thus prone to biases. Decision-makers in the vaccine world need to know which effect is measured and which are the methodological limitations to be able to interpret and use the findings of post-licensure studies.
Our objective is to review and delineate, among the various evaluations of vaccine intervention, what applies to the effectiveness of vaccines and to the impact of vaccination programmes. We propose a bridge between the effects of vaccine, as defined in previous work [10], [11], and epidemiological measures of public health impact. We describe relevant methods to measure these effects and discuss the assumptions and potential biases that are involved.
Section snippets
Definitions
Vaccine efficacy is commonly defined as the direct effect of a vaccine measured in pre-licensure randomized clinical trials, where vaccination is allocated under optimal conditions (Table 1) [3], [10]. It is estimated by comparing disease occurrence between vaccinated and non-vaccinated individuals in a population. When vaccination is randomly administered and blinding is ensured, it is assumed that any differences in disease occurrence can be attributed to the direct effect of the vaccine [3],
Study designs
Post-licensure vaccine-related effects are measured in observational studies. These may involve confounding and biases that random allocation and blinding ideally control in pre-licensure randomized trials [3]. Table 3 describes the study designs to measure vaccine effectiveness and vaccination programme impact as well as the population groups that are compared.
Assumptions and requirements
Several assumptions have to be made in vaccine studies. The main types of bias and confounding factors are described in Table 4.
Greenwood and Yules stated three conditions for valid inference in vaccine studies [60]: (1) the persons must be alike in all relevant material aspects, including equal susceptibility to the disease; (2) the probability to be exposed to infection must be identical in the vaccinated and unvaccinated groups; and (3) the probability of being vaccinated must be independent
Conclusions
Authorization of new vaccines is increasingly based on surrogates of protection and information on the clinical benefit is often lacking when national authorities must decide on vaccine policies. As placebo-controlled clinical trials are no longer considered ethical when the benefit of an intervention is proven, effectiveness and impact measures provided by post-licensure observational studies are becoming crucial for decision-making.
Observational studies measure different effects of the
Acknowledgments
We thank Pierre Van Damme and Koen Van Herck for their useful input on a previous version of this manuscript, as well as the organizers and participants to the workshop “Current challenges and new methodological approaches to assess vaccine effectiveness and vaccination impact” held in Veyrier-du-Lac in September 2009.
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