Estimation of the primary, secondary and composite effects of malaria vaccines using data on multiple clinical malaria episodes

Cheung, Yin Bun; Ma, Xiangmei; Lam, Kwok Fai; Milligan, Paul

doi:10.1016/j.vaccine.2020.05.086

Cited by 4 publications

(11 citation statements)

References 29 publications

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“…However, recent research has shown that this assumption is not required in the estimation of the overall effect of an intervention. 12,21 As previously discussed, the AG model is suitable for estimation of the overall intervention effect, and the overall effect is important from a public health perspective. 12,21,22 Hence the choice we made here.…”

Section: Discussionmentioning

confidence: 99%

“…12,21 As previously discussed, the AG model is suitable for estimation of the overall intervention effect, and the overall effect is important from a public health perspective. 12,21,22 Hence the choice we made here. One alternative approach for modeling recurrent events is the frailty model.…”

Section: Discussionmentioning

confidence: 99%

“…One approach is to divide person-time into intervals and estimate a step function. 8,[11][12][13] It can work well if the number of events is very large. Otherwise, it may encounter volatility in PE estimates if the intervals are narrow, or loss of information if the intervals are wide.…”

Section: Introductionmentioning

confidence: 99%

“…There is emerging consensus on its usefulness in clinical and public health research. 12,[21][22][23][24] In the analysis of the first or single event, it is known that Cox model is biased towards the null value as time goes by due to unobserved heterogeneity. 25,26 This bias distorts the trajectory.…”

Section: Introductionmentioning

confidence: 99%

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Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times

Cheung,

Ma,

Lam

et al. 2024

Statistics in Medicine

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In studies of infectious disease prevention, the level of protective efficacy of medicinal products such as vaccines and prophylactic drugs tends to vary over time. Many products require administration of multiple doses at scheduled times, as opposed to one‐off or continual intervention. Accurate information on the trajectory of the level of protective efficacy over time facilitates informed clinical recommendations and implementation strategies, for example, with respect to the timing of administration of the doses. Based on concepts from pharmacokinetic and pharmacodynamic modeling, we propose a non‐linear function for modeling the trajectory after each dose. The cumulative effect of multiple doses of the products is captured by an additive series of the function. The model has the advantages of parsimony and interpretability, while remaining flexible in capturing features of the trajectories. We incorporate this series into the Andersen‐Gill model for analysis of recurrent event time data and compare it with alternative parametric and non‐parametric functions. We use data on clinical malaria disease episodes from a trial of four doses of an anti‐malarial drug combination for chemoprevention to illustrate, and evaluate the performance of the methods using simulation. The proposed method out‐performed the alternatives in the analysis of real data in terms of Akaike and Bayesian Information Criterion. It also accurately captured the features of the protective efficacy trajectory such as the area under curve in simulations. The proposed method has strong potential to enhance the evaluation of disease prevention measures and improve their implementation strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times

Cheung,

Ma,

Lam

et al. 2024

Statistics in Medicine

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“…Ideally, comparisons between studies should be based on the profile of efficacy over time, adjusted for transmission intensity (i.e. the primary effect [29]), rather than average efficacy, or estimates based on the total effect. Finally, since there are relatively few cases beyond 6 months after the final dose each year, it is unclear how efficacy changes beyond this point, making it unclear to what extent this would increase risk in children if they were to be vaccinated earlier in the year.…”

Section: Discussionmentioning

confidence: 99%

The duration of protection against clinical malaria provided by the combination of seasonal RTS,S/AS01E vaccination and seasonal malaria chemoprevention versus either intervention given alone

Cairns

Zongo²,

Sagara³

et al. 2022

BMC Med

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Background A recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria. Methods In order to help optimise the timing of these two interventions, trial data were reanalysed to estimate the duration of protection against clinical malaria provided by RTS,S/AS01E when deployed seasonally, by comparing the group who received the combination of SMC and RTS,S/AS01E with the group who received SMC alone. The duration of protection from SMC was also estimated comparing the combined intervention group with the group who received RTS,S/AS01E alone. Three methods were used: Piecewise Cox regression, Flexible parametric survival models and Smoothed Schoenfeld residuals from Cox models, stratifying on the study area and using robust standard errors to control for within-child clustering of multiple episodes. Results The overall protective efficacy from RTS,S/AS01E over 6 months was at least 60% following the primary series and the two seasonal booster doses and remained at a high level over the full malaria transmission season. Beyond 6 months, protective efficacy appeared to wane more rapidly, but the uncertainty around the estimates increases due to the lower number of cases during this period (coinciding with the onset of the dry season). Protection from SMC exceeded 90% in the first 2–3 weeks post-administration after several cycles, but was not 100%, even immediately post-administration. Efficacy begins to decline from approximately day 21 and then declines more sharply after day 28, indicating the importance of preserving the delivery interval for SMC cycles at a maximum of four weeks. Conclusions The efficacy of both interventions was highest immediately post-administration. Understanding differences between these interventions in their peak efficacy and how rapidly efficacy declines over time will help to optimise the scheduling of SMC, malaria vaccination and the combination in areas of seasonal transmission with differing epidemiology, and using different vaccine delivery systems. Trial registration The RTS,S-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT03143218

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Modelling non-linear patterns of time-varying intervention effects on recurrent events in infectious disease prevention studies

Cheung

Lam

et al. 2022

Journal of Biopharmaceutical Statistics

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Estimation of the primary, secondary and composite effects of malaria vaccines using data on multiple clinical malaria episodes

Cited by 4 publications

References 29 publications

Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times

Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times

The duration of protection against clinical malaria provided by the combination of seasonal RTS,S/AS01E vaccination and seasonal malaria chemoprevention versus either intervention given alone

Modelling non-linear patterns of time-varying intervention effects on recurrent events in infectious disease prevention studies

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