Efficacy of RTS,S/AS01E Only Seen in Baseline Parasitemic and Not Baseline Aparasitemic Plasmodium falciparum-Exposed, Drug-Treated Kenyan Adults

Abstract

Background: RTS,S/AS01 vaccine efficacy (VE) was previously shown as lower in African adults than in malaria-naive US adults, potentially due to concurrent Plasmodium falciparum infections. We investigated whether treatment of infection prior to vaccination would lead to improved VE and immunogenicity.

Methods: A phase 2b study in Kenyan adults evaluated the efficacy of RTS,S/AS01E in conjunction with antimalarial chemopreventive drugs. Participants, grouped by baseline presence or absence of P. falciparum infections, were randomized to receive RTS,S/AS01E or rabies vaccine. Four groups received antimalarial drugs prior to immunization and were followed for 6 months to assess P. falciparum infection. We included an additional group not treated with antimalarial drugs for immunological assessment.

Results: VE (RTS,S/AS01E vs rabies vaccine) was 34.8% (95% confidence interval [CI], 8.9% to 53.4%) and -24.0% (95% CI, -97% to 22.4%) in baseline P. falciparum-positive and P. falciparum-negative participants, respectively. In RTS,S/AS01E recipients, there were no statistical differences in anticircumsporozoite (anti-CS) antibody titers in baseline P. falciparum-positive or P. falciparum-negative participants, or in susceptibility to infection during the postvaccination follow-up period. Drug treatment did not improve anti-CS antibody titers.

Conclusions: Treating P. falciparum infections during vaccination does not result in increased VE. Anti-CS antibody responses to vaccination do not differ with baseline P. falciparum infection status, drug treatment, or susceptibility to P. falciparum infections.

Clinical trials registration: NCT04661579; PACTR202006896481432.

Keywords: CSP antibody titers and infection; RTS,S/AS01; antimalarial drug treatment and malaria vaccine; malaria vaccine in African adults; vaccine-induced antibodies and infection.

Figure 1.

Study design. Abbreviations: ADI, active detection of infection; DHA, dihydroartemisinin; Pf, Plasmodium falciparum.

Figure 2.

Consort diagram. Abbreviation: ATP, according to protocol.

Figure 3.

Vaccine efficacy shown as Kaplan-Meier survival plots comparing the event-free survival between (A) groups 1 and 4 (primary end point), and (B) groups 2 and 5 (secondary end point). Lines represent proportion of subjects experiencing an event over days and the shaded areas represent the 95% confidence intervals. Abbreviation: Pf, Plasmodium falciparum.

Figure 4.

Anticircumsporozoite NANP and C-terminus antibody kinetics. A, Anti-NANP repeat titers from groups 1 and 2 who received RTS,S and antimalarial medications compared to (B) titers from group 3 who received RTS,S but no antimalarial medications. C, Anti–C-terminus titers from groups 1 and 2 who received RTS,S and antimalarial medications compared to (D) titers from group 3 who received RTS,S but no antimalarial medications. The dots represent the geometric mean titers at each sampling point and the error bars represent the 95% confidence intervals around the titers. Abbreviations: ELISA unit, enzyme-linked immunosorbent assay unit (equivalent to geometric mean titer); neg, negative; Pf, Plasmodium falciparum; pos, positive; Rx, medication.

Figure 5.

Anti-CS NANP and C-terminus titers in groups 1, 2, and 3 after dose 3 (day 225). Anti-NANP titers are shown as Box plots (A) and reverse cumulative distribution curve (B). Anti–C-terminus titers are shown as Box and whiskers plots (C) and reverse cumulative distribution curve (D). Box and whiskers plots show individual titers as dots. The box brackets the 1st and 3rd quartiles (25th to 75th percentile) with the median (50th percentile) in the middle. The vertical lines are known as whiskers, they are 1.5x the interquartile range (IQR), which is the difference between the 3rd and 1st quartile. The whiskers will end either at a point 1.5x IQR below or above a quartile or at the last observation, if it is less than 1.5 IQR away. The endpoints are denoted by horizontal lines. Abbreviations: CS, circumsporozoite; EU, enzyme-linked immunosorbent assay unit (equivalent to geometric mean titer); neg, negative; Pf; Plasmodium falciparum; pos, positive; Rx, medication.

Figure 6.

Box and whiskers plots showing anti-CS NANP and C-terminus titers after dose 3 (day 225), stratified by Plasmodium falciparum infection outcome during the active detection of infection phase: anti-NANP titers within group 1, P. falciparum PCR positive at baseline (A) and group 2, P. falciparum PCR negative at baseline (B); anti–C-terminus titers within group 1 (C) and group 2 (D). Box and whiskers plots show individual titers as dots. The box brackets the 1st and 3rd quartiles (25th to 75th percentile) with the median (50th percentile) in the middle. The vertical lines are known as whiskers, they are 1.5x the interquartile range (IQR), which is the difference between the 3rd and 1st quartile. The whiskers will end either at a point 1.5x IQR below or above a quartile or at the last observation, if it is less than 1.5 IQR away. The endpoints are denoted by horizontal lines. Abbreviations: CS, circumsporozoite; EU, enzyme-linked immunosorbent assay unit (equivalent to geometric mean titer); neg, negative; Pf, P. falciparum.