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Clinical Trial
doi: 10.1186/s12936-015-0969-8.

The time-course of protection of the RTS,S vaccine against malaria infections and clinical disease

Affiliations
Clinical Trial

The time-course of protection of the RTS,S vaccine against malaria infections and clinical disease

Melissa A Penny et al. Malar J. .

Abstract

Background: Recent publications have reported follow-up of the RTS,S/AS01 malaria vaccine candidate Phase III trials at 11 African sites for 32 months (or longer). This includes site- and time-specific estimates of incidence and efficacy against clinical disease with four different vaccination schedules. These data allow estimation of the time-course of protection against infection associated with two different ages of vaccination, both with and without a booster dose.

Methods: Using an ensemble of individual-based stochastic models, each trial cohort in the Phase III trial was simulated assuming many different hypothetical profiles for the vaccine efficacy against infection in time, for both the primary course and boosting dose and including the potential for either exponential or non-exponential decay. The underlying profile of protection was determined by Bayesian fitting of these model predictions to the site- and time-specific incidence of clinical malaria over 32 months (or longer) of follow-up. Using the same stochastic models, projections of clinical efficacy in each of the sites were modelled and compared to available observed trial data.

Results: The initial protection of RTS,S immediately following three doses is estimated as providing an efficacy against infection of 65 % (when immunizing infants aged 6-12 weeks old) and 91 % (immunizing children aged 5-17 months old at first vaccination). This protection decays relatively rapidly, with an approximately exponential decay for the 6-12 weeks old cohort (with a half-life of 7.2 months); for the 5-17 months old cohort a biphasic decay with a similar half-life is predicted, with an initial rapid decay followed by a slower decay. The boosting dose was estimated to return protection to an efficacy against infection of 50-55 % for both cohorts. Estimates of clinical efficacy by trial site are consistent with those reported in the trial for all cohorts.

Conclusions: The site- and time-specific clinical observations from the RTS,S/AS01 trial data allowed a reasonably precise estimation of the underlying vaccine protection against infection which is consistent with common underlying efficacy and decay rates across the trial sites. This calibration suggests that the decay in efficacy against clinical disease is more rapid than that against infection because of age-shifts in the incidence of disease. The dynamical models predict that clinical effectiveness will continue to decay and that likely effects beyond the time-scale of the trial will be small.

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Figures

Fig. 1
Fig. 1
Posterior distributions of parameters for vaccine efficacy profiles (assuming Weibull decay function, fitted to trial data at 3-monthly periods). Colour green indicates 6–12 weeks cohort, and pink the 5–17 months cohort. a Vaccine initial efficacy against infection; b half-life of decay in efficacy against infection; c Weibull decay function shape parameters; d boost efficacy against infection
Fig. 2
Fig. 2
Observed and predicted efficacy against clinical disease for 3-monthly periods. Field and predicted estimates of clinical efficacy at each 3-month follow-up for a the 6–12 weeks without booster; b 5–17 months cohort without booster, by the 9 trial site used in the fitting (excludes Kilifi and Manhica). Reported efficacy (mean and 95 % CI) in the trial site is indicated by black circles. Prediction estimates (mean and 95 % prediction intervals) are shown in colour for different fitted models, orange assuming exponential decay and blue fitting for decay shape
Fig. 3
Fig. 3
Predicted and observed efficacy against clinical disease by 3-monthly periods by trial site for the 5–17 months cohort using best-fitted vaccine profile. Reported efficacy (mean and 95 % CI) in the trial site is indicated by black circles. Prediction estimates in purple (median and 95 % CI)
Fig. 4
Fig. 4
Predicted and observed efficacy against clinical disease by 3-monthly periods by trial site for the 5–17 months cohort with booster using best-fitted vaccine profile. Reported efficacy (mean and 95 % CI) in the trial site is indicated by black circles. Prediction estimates in purple (median and 95 % CI)
Fig. 5
Fig. 5
Predicted and observed efficacy against clinical disease by three-monthly periods by trial site for the 6–12 weeks cohort using best-fitted vaccine profile. Reported efficacy (mean and 95 % CI) in the trial site is indicated by black circles. Prediction estimates in purple (median and 95 % CI)
Fig. 6
Fig. 6
Predicted and observed efficacy against clinical disease by three-monthly periods by trial site for the 6–12 weeks cohort with booster using best-fitted vaccine profile. Reported efficacy (mean and 95 % CI) in the trial site is indicated by black circles. Prediction estimates in purple (median and 95 % CI)
Fig. 7
Fig. 7
Predicted cumulative vaccine efficacy against clinical disease over time (in years post dose 3) over all trial sites for the a 5–17 months cohort and b 6–12 weeks cohort with and without booster. The solid lines show the predicted efficacy with the booster schedule and the dashed lines the predicted efficacy with the non-booster schedule

References

    1. World Health Organization . World Malaria Report 2013. Geneva: World Health Organization; 2014.
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