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

John Clemens, Sunheang Shin, Mohammad Ali
Lancet Infect Dis 2011; 11: 48287 International Vaccine Institute, Kwanak-gu, Seoul, South Korea (J Clemens MD, S Shin MSc, M Ali PhD) Correspondence to: Dr John Clemens, International Vaccine Institute, SNU Research Park, San 4-8 Bongcheon-7 dong, Kwanak-gu 151-919, Seoul, South Korea jclemens@ivi.int

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 eects 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 eect of a vaccine in a population that exceeds the eect expected on the basis of the known protective ecacy 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.212 Interest in herd protective eects 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.1317 In some cases, the cost-eectiveness prole of such vaccines becomes favourable only if herd protective eects are considered.18 Second, some new generation vaccines, such as orally administered vaccines against cholera, confer moderate degrees of protective ecacy within individuals, and the demonstration of herd protective eects might establish whether the use of such vaccines in populations will be sucient for disease control.19 Third, the herd protective eects 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.2022 Evidence about a vaccines herd protective eects generated by clinical studies of a vaccine done at an early stage, even before licensure, would benet 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 dierent evaluative approaches.

Vaccine herd protection

Vaccine-induced herd eects 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
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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 whether the target infection is transmitted from person to person, or by some other route. By contrast, vaccine herd protection results from the reduction of the intensity of transmission of the targeted infection in a population, owing to the presence of people who are made immune to the infection by vaccination. This reduced intensity of transmission stems from the reduced transmission from exposed vaccinees to their subsequent contacts.25 Herd protection can be induced by live vaccines, such as the measles vaccine, or by non-live vaccines, such as the whole-cell pertussis vaccine. By contrast with vaccine herd immunity, vaccine herd protection occurs only for target infections that are transmitted from person to person, either directly or indirectly. Reduction in the intensity of transmission of the target pathogen in a population can result in protection of nonvaccinated neighbours, termed indirect protection, by contrast with the direct protection of a vaccinated person owing only to vaccine-induced immunity in that person. Moreover, reduction in the intensity of transmission can also result in improved protection of vaccinees, because of a reduction in exposure to the pathogen and sometimes because of the greater ability of vaccine-induced immunity to protect against a light challenge with the pathogen than against a heavy challenge. This enhanced protection of vaccinees attributable to direct vaccine protection plus additional protection attributable to reduced transmission is termed total protection.25,26 A commonly cited variable in relation to vaccine herd protection is the herd immunity threshold, or the proportion of the population that must be immune because of vaccination or natural immunity (sometimes referred to as community immunity)for herd protection to eliminate person-to-person transmission.27 However, vaccine herd protection of a population, short
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of elimination of the pathogen, may be achieved with lower levels of vaccine coverage or with use of moderately eective vaccines that cannot achieve the threshold for herd immunity even with nearly complete coverage.27

Traditional assessments after vaccine licensure

Traditionally, the herd protective eects of vaccines have been studied only after their licensure and use in public health practice. Both concurrent and nonconcurrent 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 dierent 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 inversely related to the level of coverage of children given the measles vaccine, a nding that is consistent with vaccine herd protection of non-vaccinated children. A more common design to assess vaccine herd protection compares secular trends of the incidence of the target disease with secular trends of vaccine coverage of the targeted population. This design assesses whether the secular decrease of disease incidence is more than what could be expected on the basis of level of coverage of the population targeted for vaccination. Such an analysis assessed the secular decrease of invasive pneumococcal disease attributable to vaccine serotypes in the USA after the introduction of a seven-valent pneumococcal-CRM 197 protein conjugate vaccine in childhood immunisation programmes.29 The analysis showed a striking fall in incidence in targeted age groups that was much higher than could be explained on the basis of levels of vaccine coverage and the known individual-level protective ecacy of the vaccine. Moreover, the investigators reported a major decrease in disease in elderly peoplea group that was not targeted for the vaccine.29

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 inuenzae type b polysaccharide-protein conjugate vaccines are known to provide protection to vaccinees against nasopharyngeal colonisation with vaccine-targeted organisms, and this diminished colonisation is thought to bring about the herd protective eects against invasive disease conferred by these vaccines.3034 However, although such data can suggest that a vaccine confers herd protection against disease, they are not sucient to conrm that a vaccine will confer such protection. Furthermore, these studies do not allow assessment of the relation between the extent of vaccine coverage and the extent of anticipated vaccine herd protection.
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Phase 3 individually randomised trials of vaccine ecacy, which are typically needed by national regulatory agencies as pivotal trials for vaccine licensure, are designed to measure only direct vaccine protection of vaccineesa variable that, in theory, should make the results of the assessment generalisable to other populations. The logic behind this assertion is that individual randomisation will usually create sucient geographical dispersion of vaccinees in a population that levels of coverage will not be sucient to reduce transmission. And even if the levels of coverage do reduce transmission, this eect should benet vaccinees and non-vaccinees equally, so that the ratio of the incidence of disease in vaccinees and non-vaccinees, which forms the basis for calculation of vaccine protective ecacy for individuals, will be similar to that recorded had transmission not been reduced. In view of the importance of evidence about vaccineinduced herd eects to decisions about the introduction of new vaccines into routine public health programmes, it has been proposed that clinical trials of vaccines should be designed to assess not only direct vaccine protection, but also vaccine-induced herd eects.35 Methodological advances in the design and analysis of vaccine trials, with clinical disease as an endpoint, now provide an indication of a vaccines ability to confer herd protective eects against important clinical outcomes, even before a vaccine is licensed. A trial design that randomises clusters of individuals, rather than individuals per se, can assess both direct and herd vaccine protective eects for a vaccine designed to prevent an infection that is transmitted from person to person.36 In cluster-randomised trials, eligible consenting individuals within a cluster receive the agent (vaccine or an alternative, often a control agent with no protective eect against the target infection) assigned to the cluster. Various choices of clusters are availableeg, households have served as clusters in a trial of vaccines against pertussis, geographical regions have dened clusters in a trial of pneumococcal conjugate vaccine, and clusters of people in direct or indirect (via common partners) sexual contact have been proposed for trials of vaccines against sexually transmitted infections.3640 In these trials, randomisation of clusters is typically done before enrolment of individuals in the clusters, and longitudinal follow-up for target outcomes provides estimates of incidence rates to assess vaccine protective eects. Within a cluster-randomised trial, indirect vaccine protection can be estimated by a comparison of attack rates of the target infection among non-vaccinated members of vaccinated clusters versus rates among nondosed individuals in the control clusters. Comparison of rates among recipients of the study vaccine versus recipients of the control agent estimates total vaccine protection. Comparison of rates among all members of
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Overall protection Cluster randomised to the control agent Cluster randomised to the vaccine

Indirect protection Received control agent Did not receive control agent

Total protection Received vaccine Did not receive vaccine

Figure: Measurement of vaccine-induced herd protective eects in a cluster-randomised vaccine trial Two hypothetical clusters are shown, and the individuals contrasted for measurement of overall, total, and indirect vaccine protection are identied.

vaccinated versus control clusters estimates overall vaccine protection.26 Each of these estimates is based on concurrent, randomised comparisons, which is an important methodological strength that strengthens the credibility of inferences made from cluster-randomised trials (gure gure). Direct vaccine protection can be estimated with this design by comparison of attack rates among vaccinated and non-vaccinated members of vaccinated clusters.26 In conventional cluster-randomised trials, such comparisons are not randomised and are therefore subject to the biases of observational studies. A hybrid so-called double randomisation design has been proposed to remedy this limitation, in which individuals in clusters randomly assigned to the vaccine are also individually randomly assigned to either the vaccine or the control agent, and direct protection is measured from the comparative attack rates in these vaccinees and controls.41 Several factors have to be considered in the design and analysis of cluster-randomised trials of vaccines.42 First, the clusters should be selected so that transmission of the target infection between individuals occurs within clusters, and there is little transmission to the clusters from the outsideeither from other clusters or from the surrounding, non-participating population. Such transmission could attenuate measured estimates of vaccine-induced herd eects. Second, there has to be little migration of participants between clusters; such migration can aect the composition of the clusters with respect to vaccinees and non-vaccinees and thereby change measured herd eects. Third, multiple clusters are needed for these trials, not only to safeguard against chance imbalances in baseline factors between vaccinated and control clusters, but also to allow for appropriate statistical inferences.42 Fourth, because of the
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intercorrelation of outcome events between members of a specic cluster, sample sizes have to be appropriately inated for these design eects and special analytical methods need to be used to analyse these trials. Although individually randomised trials are the standard for phase 3 trials of vaccines, there is precedent for use of phase 3 cluster-randomised trials. In the clinical development of seven-valent pneumococcal polysaccharide-CRM 197 conjugate vaccine, now licensed in the USA, the US Food and Drug Administration sanctioned inclusion of a cluster-randomised trial as a pivotal phase 3 trial. This trial randomised geographical clusters of Native American children younger than 2 years to the pneumococcal conjugate vaccine or a meningococcal A conjugate vaccine. 8091 children in 38 geographically distinct clusters were enrolled, with 19 clusters in each arm of the trial. The primary analysis was of total vaccine protection, which was 83% (95% CI 2196) in an intention-to-treat analysis.39 In another example of the use of cluster-randomised trials, investigators undertook a phase 4 trial that randomised 80 geographical clusters of individuals aged 2 years and older, living in urban Kolkata, India, to one of two licensed vaccines: Vi polysaccharide typhoid vaccine or hepatitis A vaccine. After 2 years of follow-up a signicantly lower incidence of typhoid fever was detected in non-vaccinees in the Vi clusters than in the control clusters, indicating that Vi polysaccharide typhoid vaccine had conferred indirect protection (table 1 43 table 1). Recent methodological developments have enabled measurement of vaccine herd protective eects in individually randomised trials,44 taking advantage of the fact that vaccine coverage might dier between clusters of the target population because of chance variations in randomised assignments and dierent rates of eligibility and participation. If suitable clusters can be identied and if variation in vaccine coverage between these clusters is sucient, vaccine-induced herd eects can be assessed by evaluation of the correlation of disease incidence with levels of vaccine coverage in these clusters. Thus, an inverse relation between the incidence of the target disease among non-vaccinees and the level of vaccination coverage of the cluster would indicate indirect protective eects. Similarly, an inverse relation between the incidence of the target disease among vaccinees and the level of vaccine coverage of the cluster would be an indicator of total vaccine protection. Considerations for selection of clusters in such analyses are identical to those for cluster-randomised trials. Furthermore, because the level of vaccine coverage of clusters in individually randomised trials is aected by many non-random factors, such as choices to participate in the trial, the analyses are observational, and care should be taken to adjust analyses for factors that might bias the association between levels of vaccine coverage and disease rates.44
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Vi Total protection Number of participants Typhoid episodes Typhoid incidence* Protective eectiveness (95% CI) Simple Adjusted Indirect protection Number of participants Typhoid episodes Typhoid incidence* Protective eectiveness (95% CI) Simple Adjusted Overall protection Number of participants Typhoid episodes Typhoid incidence* Protective eectiveness (95% CI) Simple Adjusted 60% (3974) 57% (3771) 31 075 50 023 45% (170) 44% (269) 12 206 16 019 65% (4279) 61% (4175) 18 869 34 026

Hepatitis A

Conclusions
Data on herd protection are important in the assessment of the public health eect and cost-eectiveness 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 factors, waiting for results of studies done after vaccine introduction could mean that the vaccine will not be introduced. Methodological advances in the analysis of individually randomised trials now allow estimation of vaccine herd protective eects. Moreover, cluster-randomised trials can oer a straightforward and unbiased approach to measurement of indirect, total, and overall vaccine protection. Both these approaches allow not only assessment of whether or not a vaccine can confer herd protective eects, but also estimation of dose-response relations between levels of vaccine coverage and the magnitude of these eects. Estimation of dose-response relations are very useful to inform models designed to predict vaccine eect, and cost-eectiveness analyses that aim to account for both direct and herd protective eects. Both of these proposed approaches have limitations. Herd protective eects for a particular vaccine might dier between populations dependent on levels and patterns of vaccine coverage, dierences in host immune responses to a vaccine, and dierences in the transmission patterns of the target disease. Thus demonstration of vaccine herd protection before vaccine licensure merely indicates the potential for the vaccine to induce herd protection, and does not guarantee that the vaccine will confer herd protection wherever and whenever it is used. Conversely, the absence of herd protective eects in prelicensure trials does not necessarily exclude the potential for a vaccine to confer herd protection. Whereas double-blind individually randomised trials are the gold standard to measure direct vaccine protection in an unbiased manner, analysis of vaccine-induced herd eects in these trials, which rely on non-randomised and
Target population (%) Vaccine group n <28% 2835% 3640% 4150% >50% Total 24 954 (206%) 25 059 (207%) 24 583 (203%) 24 159 (199%) 22 394 (185%) 121 149 (100%) 5627 8883 10 772 11 513 12 541 49 336 Cases 15 22 17 26 16 96 Risk per 1000* 266 247 157 225 127 194 Placebo group n 2852 4429 5503 5801 6082 24 667 Cases 20 26 26 27 9 108 Risk per 1000 701 587 472 465 147 437

18 804 96 073 .. .. 12 877 31 035 .. .. 31 681 127 058 .. ..

Adapted from reference 43. *Episodes per 100 000 person-days of follow-up. Protective eectiveness estimated in simple analyses that adjusted for variables used to dene strata for randomisation and for the design eect of cluster randomisation, but not for other baseline covariates. p<0001. Protective eectiveness adjusted for variables used to dene strata for randomisation, for the design eect of cluster randomisation, and for other baseline covariates associated with the risk of typhoid fever. p=004.

Table 1: Occurrence of typhoid fever in analyses of total, indirect, and overall protection by Vi vaccine against typhoid fever, during 2 years of follow-up

This approach was used in a reanalysis of the 1985 trial of killed oral cholera vaccines in Bangladesh.44 Findings from this placebo-controlled individually randomised trial showed that the two vaccines under assessment, a cholera toxin B subunit-killed whole-cell vaccine and a very similar killed whole-cell vaccine, conferred 5363% individual level protective ecacy against treated episodes of cholera during the rst year of surveillance. Because the study population of 89 596 people resided in 6423 baris, patrilineally linked groups of houses that correspond to the geographical unit of person-to-person transmission of Vibrio cholerae 01 in this setting, baris were selected as clusters for the analysis.45,46 Findings from the analysis showed signicant inverse relations between vaccine coverage of the baris and the incidence of cholera in recipients of both placebo and vaccine, indicating indirect and total protection, respectively (table 2). Furthermore, these ndings were conrmed in multivariable models to adjust for potential confounders. These results were then used to calibrate models to assess the likely vaccine eect and cost-eectiveness of these vaccines under dierent vaccine introduction scenarios.19,47
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Adapted from reference 44. *p=005 for trend and p<00001 for trend in adjusted analyses.

Table 2: Cholera risk by the level of cholera vaccine coverage of baris, Matlab, Bangladesh 198586

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non-blinded comparisons of clusters according to the level of vaccine coverage, might be susceptible to bias. Although double-blind cluster-randomised trials enable unbiased measurement of indirect, total, and overall vaccine protection, they are susceptible to bias when used to estimate direct vaccine protection unless individuals in the vaccinated clusters are additionally randomly assigned to vaccine or a suitable control agent.41 Furthermore, the requirements for denition of appropriate clusters mean that assessment of vaccine herd protection will not be possible in every trial, and a suitable cluster-randomised design might not be possible in every setting. Pre-licensure assessments of vaccine herd protection should not be seen as a replacement for post-licensure assessments. Only post-licensure studies in diverse populations can provide a comprehensive picture of a vaccines herd protective eects. Moreover, in this paper we have addressed only the measurement of vaccineinduced herd protective eects and have not discussed other less benecial eects that can occur when transmission of the target pathogen is reduced, such as an increase in the average age of infection, which could result in more severe disease for some infections, and replacement of the prevented pathogen by related pathogens that could diminish or even negate the preventive eect of vaccination.22 Although there is little experience in the use of randomised trials to assess these pernicious outcomes of vaccine herd protection, the short durations of clinical trials might not be well suited for assessment of these eects. Despite the public health desirability of being able to assess the potential herd protective eects of a vaccine before its licensure, there are some disadvantages to use of trials for this purpose. Because of the cluster-based analysis, sample size requirements for these studies will often be substantially higher than for conventional individually randomised trials. Furthermore, regulatory agencies have been reluctant to approve the inclusion of cluster-randomised trials in dossiers submitted by producers for licensure. Nevertheless, the ability of randomised trials to yield important information about vaccine herd protective eects, and the desirability of assessment of these eects early in the course of vaccine development and implementation, lend support to the greater use of these new approaches in trials done both before and after licensure, as complements to conventional pre-licensure individually randomised trials.
Contributors All authors contributed equally to this Personal View. Conicts of interest We are employees of the International Vaccine Institute, which has transferred the manufacturing technology for killed oral cholera vaccine to VaBiotech (Vietnam) and Shantha Biotechnics (India) and for Vi typhoid vaccine to Shantha Biotechnics (India). Acknowledgments This work was supported by the Bill & Melinda Gates Foundation, and by the governments of Korea, Sweden, and Kuwait. We thank A Donner and M Emch for many illuminating discussions on this topic.

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