Review 2: "Baseline Malaria Infection Status and RTS,S/AS01E Malaria Vaccine Efficacy"

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.

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Review: The RTS,S malaria vaccine has shown moderate protection against clinical malaria episodes (1). The present study now estimates the protective effect against any Plasmodium falciparum reinfection, with or without clinical manifestations. The study also explores if different vaccine dosing regimens may affect the vaccine efficacy (VE) differently. The study design was an open-label, phase 2b, randomized placebo-controlled trial with four different vaccine regimens in 1500 children aged 5-17 months (1). Blood samples were collected monthly throughout a one-year follow-up period after the third dose, for molecular identification and characterization of any P falciparum infection, by sequencing two regions coding for the sera-2 antigen.

Significant and comparable VE (25%-43%) against first new infection was observed for all four regimens which is similar to previous findings related to clinical episodes (1). The RTS,S vaccine also appeared to reduce complexity of infection. Interestingly the VE was significantly higher (68%) in participants who were malaria infected at the time of vaccination compared to uninfected participants (37%). This was considered unexpected since a number of mainly experimental studies have described immunosuppressive effect by malaria infection which may potentially compromise the immune response and thus effect of a vaccine. However a recent analysis of the previous RTS,S phase 3 clinical trial, quoted by the authors suggests that the VE was unaffected by infection status during vaccination. And more importantly, several studies, not quoted by the authors in the present study, have confirmed our early findings that asymptomatic P falciparum infections with multiple clones provide protection against new infections (2). It is therefore conceivable that a malaria vaccine may provide a stronger immune response when the protective immunity is already activated by a low-density infection but with multiple clones.

We also want to highlight another important issue which has not been considered in the analyses of the present study. In asymptomatic infections, there may be significant differences in parasite clones detected on two consecutive days, due to different synchronicity of parasite subpopulations (3). This implies that only a subset of clones may be detected in a single-day sample. A parasite population characterized in one sample may therefore falsely look different than in a sample one month later. If and how this may affect the analyses in the present study must be considered and discussed.

References 

1. Samuels et al. Lancet Infect Dis 2022;22(9):1329–42

2. Färnert et al Journal of Infectious Diseases.179:989-95, 1999

3. Färnert et al American Journal of Tropical Medicine and Hygiene. 56:538-547, 1997.