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New approaches to the assessment of vaccine herd protection in clinical trials

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Summary

Criteria for the introduction of new vaccines into routine public health practice are becoming increasingly stringent. For vaccines that are expensive and those that provide moderate protection, the ability to confer herd protection could be crucial to policy deliberations about vaccine introduction. Traditionally, herd protection has been assessed after a vaccine is introduced, delaying the availability of data on herd effects to inform decisions about vaccine introduction. New methodological developments now provide the possibility to assess herd protection before the introduction of a vaccine into public health programmes. One approach is a cluster-randomised trial, which allows assessment of herd protection in a way that minimises biases. Analysis of individually randomised trials by appropriately selected clusters created post hoc can also provide measurements of herd protection. Here we discuss the use of these designs, which can generate an improved evidence base at an early stage for making decisions about the introduction of new vaccines.

Introduction

Herd protection is the protective effect of a vaccine in a population that exceeds the effect expected on the basis of the known protective efficacy within individuals and the level of vaccine coverage.1 Herd protection has been suggested for a diverse array of vaccines used in public health practice.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12

Interest in herd protective effects of newly developed vaccines has increased for several reasons. First, recently developed and licensed vaccines, such as those against rotavirus, pneumococcus, and human papillomavirus, are substantially more expensive than are traditional childhood vaccines.13, 14, 15, 16, 17 In some cases, the cost-effectiveness profile of such vaccines becomes favourable only if herd protective effects are considered.18 Second, some new generation vaccines, such as orally administered vaccines against cholera, confer moderate degrees of protective efficacy within individuals, and the demonstration of herd protective effects might establish whether the use of such vaccines in populations will be sufficient for disease control.19 Third, the herd protective effects of vaccines could change the epidemiology and ecology of microbial pathogens, sometimes with deleterious consequences such as shifting the average age of infection by a pathogen or helping to set the stage for replacement of the targeted pathogen by a related pathogen.20, 21, 22

Evidence about a vaccine's herd protective effects generated by clinical studies of a vaccine done at an early stage, even before licensure, would benefit policy decisions about deployment of a vaccine. Here we discuss the notion of vaccine herd protection, ways to measure vaccine herd protection both before and after licensure, and the relative strengths of the different evaluative approaches.

Section snippets

Vaccine herd protection

Vaccine-induced herd effects include vaccine herd immunity and vaccine herd protection, and these two terms are often used interchangeably. We use the term vaccine herd immunity to describe the protection of non-vaccinated people exposed to live vaccine organisms transmitted by shedding of these organisms by vaccinees, leading to a protective immune response,23 as happens with live oral polio vaccine.24 Herd immunity, used in this way, applies only to live vaccines and does not depend on

Traditional assessments after vaccine licensure

Traditionally, the herd protective effects of vaccines have been studied only after their licensure and use in public health practice. Both concurrent and non-concurrent study designs have been used. An example of a concurrent study design was a study of the incidence of measles in non-vaccinated children residing in different regions of Milwaukee, WI, USA.28 In this study, the investigators showed that the incidence of measles among non-vaccinated children who were concurrently followed up was

New approaches

Small clinical trials are often done before licensure to assess whether a vaccine reduces mucosal colonisation by the target pathogen among vaccinees, reasoning that prevention of colonisation by vaccination might translate into vaccine herd protection. Both pneumococcal polysaccharide-protein and Haemophilus influenzae type b polysaccharide-protein conjugate vaccines are known to provide protection to vaccinees against nasopharyngeal colonisation with vaccine-targeted organisms, and this

Conclusions

Data on herd protection are important in the assessment of the public health effect and cost-effectiveness of many vaccines. Studies of vaccine herd protection are often needed to inform policy decisions about vaccine introduction. Previously, assessments of vaccine herd protection had typically been deferred until a vaccine had been used in practice. For some vaccines, especially those for which introduction into practice might be impeded by cost, less than optimum direct protection, or other

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