In an attempt to improve the efficacy of the candidate
malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum
thrombospondin-related anonymous
protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination
vaccine had an acceptable safety profile and was acceptably tolerated.
Antigen-specific
antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination
vaccine were qualitatively similar to those generated by the single component
vaccines. However, post-dose 2 anti-CS
antibodies in the RTS,S+TRAP/AS02
vaccine recipients were lower than in the RTS,S/AS02
vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed
parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of
parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate
vaccine. The absence of significant protection or delay of
parasitemia in the 11 RTS,S+TRAP/AS02
vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP
antigen may have interfered with the
vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based
vaccines should consider employing alternative
vaccine platforms.