A phase IIa controlled human malaria infection and immunogenicity study of RTS,S/AS01_E and RTS,S/AS01_B delayed fractional dose regimens in malaria-naive adults

Background. A previous RTS,S/AS01_B 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/AS01_B or RTS,S/ AS01_E 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/AS01_E. 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/AS01_E and RTS,S/AS01_B 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/AS01_E can provide VE comparable to an equivalent RTS,S/AS01_B 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.