Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02 A administered alone or concurrently in rhesus monkeys

Abstract

In an effort to broaden the immune response induced by the RTS,S/AS02 A,vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1 42 and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1 42 and AMA1 vaccines formulated with the AS02 A Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1 42 or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1 42 and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-γ and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1 42 and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1 42 lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1 42 significantly reduced AMA1 IFN-γ and IL-5 responses. MSP1 42 suppression of AMA1 IFN-γ responses was not seen in animals receiving RTS,S + AMA1 + MSP1 42 suggesting that RTS,S restored IFN-γ responses. Conversely, AMA1 had no effect on MSP1 42 antibody and IFN-γ and IL-5 responses. Neither AMA1 alone or combined with MSP1 42 affected RTS,S antibody or IFN-γ and IL-5 responses. Immune interference by MSP1 42 on AMA1 antibody responses was also evident when AMA1, MSP1 42 and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.