A phase IIA extension study evaluating the effect of booster vaccination with a fractional dose of RTS,S/AS01E in a controlled human malaria infection challenge.

BACKGROUND: We previously demonstrated that RTS,S/AS01B and RTS,S/AS01E vaccination regimens including at least one delayed fractional dose can protect against Plasmodium falciparum malaria in a controlled human malaria infection (CHMI) model, and showed inferiority of a two-dose versus three-dose regimen. In this follow-on trial, we evaluated whether fractional booster vaccination extended or induced protection in previously protected (P-Fx) or non-protected (NP-Fx) participants. METHODS: 49 participants (P-Fx: 25; NP-Fx: 24) received a fractional (1/5th dose-volume) RTS,S/AS01E booster 12 months post-primary regimen. They underwent P. falciparum CHMI three weeks later and were then followed for six months for safety and immunogenicity. RESULTS: Overall vaccine efficacy against re-challenge was 53% (95% CI: 37-65%), and similar for P-Fx (52% [95% CI: 28-68%]) and NP-Fx (54% [95% CI: 29-70%]). Efficacy appeared unaffected by primary regimen or previous protection status. Anti-CS (repeat region) antibody geometric mean concentrations (GMCs) increased post-booster vaccination. GMCs were maintained over time in primary three-dose groups but declined in the two-dose group. Protection after re-challenge was associated with higher anti-CS antibody responses. The booster was well-tolerated. CONCLUSIONS: A fractional RTS,S/AS01E booster given one year after completion of a primary two- or three-dose RTS,S/AS01 delayed fractional dose regimen can extend or induce protection against CHMI. CLINICAL TRIAL REGISTRATION: NCT03824236. linked to this article can be found on the Research Data as well as Figshare https://figshare.com/s/ee025150f9d1ac739361.

An open label study of the safety and efficacy of a single dose of weekly chloroquine and azithromycin administered for malaria prophylaxis in healthy adults challenged with 7G8 chloroquine-resistant Plasmodium falciparum in a controlled human malaria infection model.

BACKGROUND: Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. METHODS: In this open label study, 18 healthy volunteers, aged 18-50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. RESULTS: All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28-41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. CONCLUSION: Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808.

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.

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.