In the Phase 2 study, the highest anti-TRAP GMTs were observed post Dose 2 (DOC) in both the TRAP/AS02 and RTS,S + TRAP/AS02 groups; GMTs were similar in both groups. At 134 days post DOC, anti-TRAP GMTs had decreased but were still above post Dose 1 values
in both vaccine groups. In the Phase 1 study, antigen specific Alectinib proliferative responses to RTS,S in recipients of RTS,S/AS02 or RTS,S + TRAP/AS02 and to TRAP in recipients of TRAP/AS02 or RTS,S + TRAP/AS02 were markedly elevated over baseline values. Proliferation to RTS,S was similar in both the RTS,S/AS02 and RTS,S + TRAP/AS02 groups and to TRAP in both the TRAP/AS02 and RTS,S + TRAP/AS02 groups (see Supplementary Appendix). Cellular responses were boosted
by the third vaccination and responses persisted at day 360. Measurements of IFN-γ and IL-5 in culture supernatant in response to antigen-specific stimulation showed substantial induction post second vaccination; no meaningful increase was observed post third vaccination. No real differences in RTS,S stimulated responses were observed between RTS,S and RTS,S/TRAP vaccinated groups (see Supplementary Appendix). In the Phase 2 study, RTS,S stimulated IFN-γ responses in PBMC cultures derived from subjects vaccinated with RTS,S + TRAP/AS02 greatly exceeded baseline responses (Fig. 2). RTS,S did not elicit IFN-γ responses in PBMC cultures from subjects vaccinated with TRAP/AS02. TRAP-specific IFN-γ responses were observed in PBMC cultures from RTS,S + TRAP as well as TRAP vaccinated subjects, check details but not in pre-vaccination PBMC cultures. Analysis of IL-4 responses in parallel cultures of PBMC from pre- and post-vaccinated subjects showed a similar pattern of reactivity (Fig. 3). Pre-immune PBMC showed no notable responses to either RTS,S or to TRAP. Post vaccination IL-4 responses elicited with RTS,S and TRAP were antigen-specific in that TRAP recalled responses in TRAP and RTS,S + TRAP recipients,
whereas RTS,S recalled responses only in RTS,S + TRAP vaccinees. Of note, while PBMC from RTS,S + TRAP recipients showed higher IFN-γ responses to RTS,S than TRAP, results for IL-4 responses PAK6 to both antigens were similar. Of the 24 volunteers who underwent challenge, patent parasitemia developed in 10 of 11 RTS,S + TRAP/AS02 vaccinees, all 5 TRAP/AS02 vaccinees, and all 8 infectivity controls (Fig. 4). Fisher’s exact tests of the proportion of subjects infected indicated that neither vaccinated group differed from control (p = 1.0). The median pre-patent period from challenge to infection was 13.0, 11.0 and 12.0 days for the RTS,S + TRAP/AS02, TRAP/AS02 and infectivity control groups, respectively (log rank test: p = 0.096 RTS,S + TRAP/AS02 vs control, p = 0.661 TRAP/AS02 vs control). Both studies demonstrated the combination vaccine RTS,S + TRAP/AS02 had an acceptable safety profile and was generally well tolerated.