Abstract
BackgroundApical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63) and orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1).Methodology/Principal FindingsAdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA) against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63) vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8+ and CD4+ T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice.Conclusions/SignificanceOptimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials.
Highlights
It is estimated that in Africa alone there are 200 million cases and 0.8 million deaths due to malaria every year [1]
All mice seroconverted after the AdHu5-Plasmodium falciparum AMA1 (PfAMA1) (3D7) prime and these responses significantly increased (P#0.05) by day 55, in agreement with murine data for similar AdHu5 vectors encoding the P. yoelii and P. falciparum MSP1 antigens [28,32]
The first generation AdHu5-modified vaccinia virus Ankara (MVA) mono-allelic Apical membrane antigen 1 (AMA1) (3D7) vaccines induced cross-reactive antibodies to the heterologous FVO allele of AMA1 both in mice and rabbits as measured by ELISA, there was a better correlation in rabbits than in mice between the 3D7 and FVO antibodies at the peak day 70 time-point
Summary
It is estimated that in Africa alone there are 200 million cases and 0.8 million deaths due to malaria every year [1]. Vaccine-induced immunity in an endemic area could help to significantly reduce overall transmission by inducing herd immunity when combined with pre-existing partially effective control interventions including insecticide-treated bednets, artemisinin-based combination therapies and indoor residual spraying [2]. Individuals living in malaria endemic countries develop immunity by repeated exposure to the parasite and a significant proportion of this immunity is directed to antigens expressed on the blood-stage parasites or infected erythrocytes. This immunity is mostly antibody mediated [4], more recently the importance of cellular immunity has begun to be recognized in mice [5,6] and humans [7,8]. We describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63) and orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1)
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