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Review 1: "Baseline Malaria Infection Status and RTS,S/AS01E Malaria Vaccine Efficacy"

Reviewers highlighted that the study challenges previous findings by suggesting pre-existing malaria infection enhances immune response, contradicting studies indicating immunosuppressive effects of malaria on vaccine efficacy.

Published onJun 01, 2024
Review 1: "Baseline Malaria Infection Status and RTS,S/AS01E Malaria Vaccine Efficacy"
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key-enterThis Pub is a Review of
Baseline malaria infection status and RTS,S/AS01E malaria vaccine efficacy
Baseline malaria infection status and RTS,S/AS01E malaria vaccine efficacy

Abstract Background The only licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy (VE).Methods 1,500 children aged 5–17 months were randomized to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b clinical trial in Ghana and Kenya. We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods in over 36K participant specimens. We performed a post hoc analysis of VE based on malaria infection status at first vaccination and force of infection.Results We observed significant and comparable VE (25–43%, 95% CI union 9–53%) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 and 20 months). Each RTS,S/AS01E regimen significantly reduced the number of new infections in the 20-month follow-up period (control mean 4.1 vs. RTS,S/AS01E mean 2.6–3.0). VE against first new infection was significantly higher in participants who were malaria-infected (68%; 95% CI, 50 to 80%) versus uninfected (37%; 95% CI, 23 to 48%) at the first vaccination (P=0.0053) and in participants experiencing greater force of infection between dose 1 and 3 (P=0.059).Conclusions All tested dosing regimens blocked some infections to a similar degree. Improved VE in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. ( number, NCT03276962)

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.


Review: This post-hoc analysis of an RTS,S/AS01E vaccine trial in 1500 children in Kenya and Ghana assessed four different vaccine regimens, including full and fractional doses and a delayed third dose. Overall, the study is highly interesting in that it provides evidence that RTS,S reduces the complexity of infection, and that participants who are parasite-positive at baseline and/or at time points during vaccination exhibit enhanced vaccine efficacy compared to participants who are not infected. This has significant programmatic implications in that it suggests that children do not need to be treated for malaria before routine vaccinations with RTS,S. On the other hand, it somewhat contradicts what was reported in the Phase 3 RTS,S trial employing standard dosing regimens-- that children living in the most highly endemic areas demonstrated decreased efficacy compared to children living in areas of lower endemicity, and what has been reported in adult and mouse studies regarding the immunosuppressive effect of blood stage malaria on vaccination. As the authors state, results need to be validated in other studies, perhaps in other malaria transmission settings. 

  1. Although the sample size was small and not powered to detect small differences between groups, they genotyped infection endpoints in participants, and found no differences between the three dosing regimens. Here, the authors should clearly state the magnitude of difference in vaccine efficacy they would have been able to detect and the power they had to detect this difference. 

  2. The authors report no evidence for differential vaccine efficacy against first new infection with a perfect amino acid residue match compared to mismatch to the vaccine strain, though this has been reported in other studies of RTS,S. What explanation do the authors give for this finding?

  3. Findings of enhanced vaccine efficacy in the presence of malaria parasitemia would be interesting to look at by site, as the Ghana site would be expected to have a much lower background of antimalarial immune responses in children versus Kenya.

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