Estimation of vaccine efficacy in a repeated measures study under heterogeneity of exposure or susceptibility to infection

Valim, Clarissa; Mezzetti, Maura; Maguire, James H.; Urdaneta, Margarita; Wypij, David

doi:10.1098/rsta.2008.0044

Cited by 7 publications

(7 citation statements)

References 44 publications

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“…However, when infection rather than blood-stage disease is the primary outcome this may be problematic given that infection is generally the most reliable marker of exposure. In addition Valim et al [ 34 ] recently proposed a statistical estimator of individual vaccine efficacy that corrects for the effects of heterogeneity in exposure by taking account of multiple exposures. Whilst the authors are not aware of comparable estimators that account for heterogeneity in response, this may in fact not be a major problem for the RTS, S vaccine because in one of the Phase II trials of RTS, S [ 5 ], nearly all of the vaccinated group became infected with P. falciparum at some stage during the monitoring period.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

White

Griffin

Drakeley

et al. 2010

Malar J

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BackgroundPhase III trials of the malaria vaccine, RTS, S, are now underway across multiple sites of varying transmission intensity in Africa. Heterogeneity in exposure, vaccine response and waning of efficacy may bias estimates of vaccine efficacy.MethodsTheoretical arguments are used to identify the expected effects of a) heterogeneity in exposure to infectious bites; b) heterogeneity in individual's response to the vaccine; and c) waning efficacy on measures of vaccine efficacy from clinical trials for an infection-blocking vaccine.ResultsHeterogeneity in exposure and vaccine response leads to a smaller proportion of trial participants becoming infected than one would expect in a homogeneous setting. This causes estimates of vaccine efficacy from clinical trials to be underestimated if transmission heterogeneity is ignored, and overestimated if heterogeneity in vaccine response is ignored. Waning of vaccine efficacy can bias estimates of vaccine efficacy in both directions.ConclusionsFailure to account for heterogeneities in exposure and response, and waning of efficacy in clinical trials can lead to biased estimates of malaria vaccine efficacy. Appropriate methods to reduce these biases need to be used to ensure accurate interpretation and comparability between trial sites of results from the upcoming Phase III clinical trials of RTS, S.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

White

Griffin

Drakeley

et al. 2010

Malar J

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“…Heterogeneity in malaria exposure may bias estimates of malaria vaccine efficacy over time in longitudinal studies [8] , [9] . This is predicted by simulations of populations under heterogeneous malaria exposure, where vaccine efficacy is underestimated as a consequence of heterogeneity and apparent waning of efficacy over time is seen even if vaccine protection is maintained [10] .…”

Section: Introductionmentioning

confidence: 99%

“…Although a randomized controlled trial may ensure equal distributions of malaria exposure at the start of the trial, if the vaccine is protective then the more highly susceptible individuals will experience earlier clinical malaria episodes in the control group than in the active vaccination group. Their subsequent removal from the “at risk set” will subsequently unsettle the comparability of vaccinees and non-vaccinees and produce inaccurate estimates of efficacy [8] , [9] . This effect will become more marked as time since randomization increases.…”

Section: Introductionmentioning

confidence: 99%

Estimating Individual Exposure to Malaria Using Local Prevalence of Malaria Infection in the Field

et al. 2012

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BackgroundHeterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level.Method and FindingsWe studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1142 were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1142 antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66–0.73), 0.71 (95%CI: 0.69–0.73) and 0.82 (95%CI: 0.80–0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1142 antibody levels provided an AUC of 0.83 (95%CI: 0.79–0.88).ConclusionWe have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria.

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“…Other factors might influence the pattern of malaria disease in a population and may be taken into account as covariates for data analyses. The importance to controlling for heterogeneity in malaria risk to avoid underestimating vaccine efficacy has been highlighted earlier [ 21 ].…”

Section: Covariatesmentioning

confidence: 99%

Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS,S/AS01 malaria vaccine in African children

Lievens

Aponte

Williamson

et al. 2011

Malar J

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BackgroundThere has been much debate about the appropriate statistical methodology for the evaluation of malaria field studies and the challenges in interpreting data arising from these trials.MethodsThe present paper describes, for a pivotal phase III efficacy of the RTS, S/AS01 malaria vaccine, the methods of the statistical analysis and the rationale for their selection. The methods used to estimate efficacy of the primary course of vaccination, and of a booster dose, in preventing clinical episodes of uncomplicated and severe malaria, and to determine the duration of protection, are described. The interpretation of various measures of efficacy in terms of the potential public health impact of the vaccine is discussed.ConclusionsThe methodology selected to analyse the clinical trial must be scientifically sound, acceptable to regulatory authorities and meaningful to those responsible for malaria control and public health policy.Trial registrationClinicaltrials.gov NCT00866619

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Estimation of vaccine efficacy in a repeated measures study under heterogeneity of exposure or susceptibility to infection

Cited by 7 publications

References 44 publications

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

Estimating Individual Exposure to Malaria Using Local Prevalence of Malaria Infection in the Field

Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS,S/AS01 malaria vaccine in African children

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