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

Abstract

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.

Keywords: Malaria; Malaria vaccination; Plasmodium falciparum; RTS,S/AS01E; Seasonal malaria chemoprevention.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Schematic of the comparisons made in the analyses. Schematic of the comparisons made in the analyses. The analyses to estimate protection from the RTS,S/AS01E malaria vaccine (presented first in the paper) compare the combined intervention group with the SMC alone group. The analyses to estimate protection from SMC (presented second in the paper) compare the combined intervention group with the RTS,S alone group

Fig. 2

Timing of microscopically confirmed clinical malaria episodes after the final vaccination each year, among children in the SMC alone group and the combined group. Points show the timing of episodes of the primary outcome in the SMC alone group (who received SMC and control vaccines) and the Combined group (who received SMC and the RTS,S/AS01E malaria vaccine), in relation to the final dose of vaccination each year (dose 3 for year 1, dose 4 for year 2, and dose 5 for year 3). These groups were compared to estimate the protective efficacy of RTS,S/AS01E over time. The position relative to the y-axis indicates the age in months of the child at the time of the episode

Fig. 3

Protective efficacy of RTS,S/AS01E vaccine against clinical malaria, by time since vaccination, in each year of the study, using three methods. Footnotes: Protective efficacy was estimated using three methods by comparing children randomised to receive SMC and either control vaccines (SMC alone group) or RTS,S/AS01E vaccine (combined group). The left panels show results from piecewise Cox regression models. The middle panels show estimates from flexible parametric survival models. The right panels show results from Smoothed Schoenfeld Residuals from Cox regression models

Fig. 4

Protective efficacy of SMC in the first 30 days post-administration, among recipients of RTS,S/AS01E, according to adherence to SMC. Estimates of protective efficacy of SMC from Cox regression, as described in the text. SMC cycles 1, 2, 3 and 4 were administered in 2017, SMC cycles 5, 6, 7 and 8 in 2018, and SMC cycles 9, 10, 11 and 12 in 2019. ‘Scheduled SMC’ includes all children remaining in follow-up at the time of the SMC cycle, irrespective of whether any SMC was received. ‘Received SMC’, includes only children who received at least the first daily dose of the SMC cycle, but who may not have received subsequent doses. ‘Full SMC’ includes only children for whom all 3 daily doses of SMC or placebo SMC were successfully administered and documented. ‘First daily SMC dose only (pooled)’ includes only children who were confirmed to have received the day 1 dose of SP+AQ, but not the day 2 or day 3 doses of AQ, pooled across all 12 cycles given during the study period

Fig. 5

Timing of microscopically confirmed clinical malaria episodes after the final SMC cycle in each year of the study, among recipients of RTS,S/AS01E, randomised to receive either placebo SMC (RTS,S alone group) or active SMC (Combined group). Points show the timing of episodes of the primary outcome in the RTS,S/AS01E alone group (who received placebo SMC and the RTS,S vaccine) and the Combined group (who received active SMC and the RTS,S vaccine), in relation to the final SMC cycle administered each year (SMC 4 in year 1, SMC 8 in year 2, and SMC 12 in year 3). The position relative to the y-axis indicates the age in months of the child at the time of the episode

Fig. 6

Profile of protective efficacy of SMC against clinical malaria, among recipients of RTS,S/AS01E. Footnotes: Protective efficacy of SMC against clinical malaria over time, among children randomised to receive the RTS,S/AS01E malaria vaccine. Results are presented up to 30 days post-SMC (left panels), combining data from all 12 SMC cycles; and up to 60 days post-SMC (right panels), combining data from the final SMC cycle in each year of the study. The top panels show results from flexible parametric survival models, and the bottom panels show results from smoothed Schoenfeld residuals from Cox regression models