A Phase IIa Controlled Human Malaria Infection and Immunogenicity Study of RTS,S/AS01E and RTS,S/AS01B Delayed Fractional Dose Regimens in Malaria-Naive Adults

Abstract

Background: A previous RTS,S/AS01B vaccine challenge trial demonstrated that a 3-dose (0-1-7-month) regimen with a fractional third dose can produce high vaccine efficacy (VE) in adults challenged 3 weeks after vaccination. This study explored the VE of different delayed fractional dose regimens of adult and pediatric RTS,S/AS01 formulations.

Methods: A total of 130 participants were randomized into 5 groups. Four groups received 3 doses of RTS,S/AS01B or RTS,S/AS01E on a 0-1-7-month schedule, with the final 1 or 2 doses being fractional (one-fifth dose volume). One group received 1 full (month 0) and 1 fractional (month 7) dose of RTS,S/AS01E. Immunized and unvaccinated control participants underwent Plasmodium falciparum-infected mosquito challenge (controlled human malaria infection) 3 months after immunization, a timing chosen to potentially discriminate VEs between groups.

Results: The VE of 3-dose formulations ranged from 55% (95% confidence interval, 27%-72%) to 76% (48%-89%). Groups administered equivalent formulations of RTS,S/AS01E and RTS,S/AS01B demonstrated comparable VE. The 2-dose group demonstrated lower VE (29% [95% confidence interval, 6%-46%]). All regimens were well tolerated and immunogenic, with trends toward higher anti-circumsporozoite antibody titers in participants protected against infection.

Conclusions: RTS,S/AS01E can provide VE comparable to an equivalent RTS,S/AS01B regimen in adults, suggesting a universal formulation may be considered. Results also suggest that the 2-dose regimen is inferior to the 3-dose regimens evaluated.

Clinical trial registration: NCT03162614.

Keywords: Plasmodium falciparum; 3-month challenge; RTS; S/AS01; controlled human malaria infection; delayed fractional dose; efficacy; immunogenicity; malaria; safety.

Figure 1.

Consolidated Standards of Reporting Trials flow diagram. Boxes in gray indicate treatment procedures. The intent-to-treat (ITT) set included all participants who received ≥1 dose of a study vaccine and the infectivity controls and was used for analyses of safety. The per-protocol set included all participants in the ITT set who received all vaccinations in accordance with procedures, requirements and limitations specified in the study protocol, who underwent the Plasmodium falciparum challenge, and for whom relevant data were available. AduFx, Adu2Fx, Adu1Fx, PedFx, and 2PedFx indicate study treatment groups. Treatment differences are presented in the individual boxed for months 0, 1, and 7. The protocol for controlled human malaria infection (CHMI) is presented in Methods. Reasons for withdrawal categorized as “Other” include travel, missed vaccination, exclusion criteria met, inability to participate in challenge, pregnancy, and family emergency. Two participants in the infectivity control group were administered presumptive antimalaria medication prohibited in the study protocol (prohibited medication).

Figure 2.

Vaccine efficacy (VE) and occurrence of parasitemia. A, VE in the prevention of confirmed Plasmodium falciparum parasitemia for all 5 study groups. Error bars indicate 95% confidence intervals (CIs). B, Kaplan-Meier survival curve for the time to onset of confirmed P. falciparum parasitemia. C, Mean times to onset of confirmed P. falciparum parasitemia in all study groups. P values represent comparison with the infectivity control group. Abbreviations: LL, lower limit of the 95% CI; UL, upper limit of the 95% CI.

Figure 3.

Reverse cumulative distribution curves for anti–circumsporozoite protein (CSP) (repeat region) antibodies, by treatment and protection status against the controlled human malaria infection (CHMI) challenge. A, Reverse cumulative curves for anti-CSP (repeat region) antibodies for all 5 treatment groups 1 month after administration of the delayed fractional dose. B, Reverse cumulative curves for anti-CSP (repeat region) antibodies for all participants stratified by protection status 1 month after administration of the delayed fractional dose. C, Reverse cumulative curves for anti-CSP (repeat region) antibodies for all 5 treatment groups on the day of CHMI challenge. D, Reverse cumulative curves for anti-CSP (repeat region) antibodies for all participants stratified by protection status on the day of CHMI challenge. Abbreviations: EU, enzyme-linked immunosorbent assay units; NP, stratified group of participants not protected against malaria in the CHMI challenge; P, stratified group of participants protected against malaria in the CHMI challenge.

Figure 4.

Anti–Plasmodium falciparum circumsporozoite protein (CSP) antibody response, by treatment and protection status against the controlled human malaria infection challenge. A, Anti-CSP (repeat region) antibody geometric mean concentrations (GMCs) for all 5 treatment groups. B, Anti-CSP (repeat region) antibody GMCs for all participants stratified by protection status. Abbreviations: Abbreviations: NP, stratified group of participants not protected against malaria in the CHMI challenge; P, stratified group of participants protected against malaria in the CHMI challenge; Pre(d1), prevaccination (day 1) sampling time point; PII(d59), day 59 (month 2) sampling time point; PII(d197), day 197 (month 7) sampling time point; PIII(d227), day 227 (month 8) sampling time point 1 month after administration of the delayed fractional dose; DoC (d287), day 287 (month 10) sampling time point (day of CHMI challenge); PIII(d315), day 315 (month 11) sampling time point; PIII(d377), day 377 (month 13) sampling time point.