Development of adjuvanted multi-antigen liver-stage malaria vaccines

Abstract

Despite promising progress in malaria vaccine development in recent years, an efficacious subunit vaccine against P. falciparum remains to be licensed and deployed. The most advanced candidates in clinical development focus on two pre-erythrocytic antigens (CSP and ME-TRAP), but many more immunogenic antigens have been recently identified. The work described in this thesis aimed to improve on the immunogenicity and efficacy of the leading liver-stage vaccine candidate (ChAd63-MVA ME-TRAP), which is known to confer protection by eliciting high levels of antigen-specific CD8+ T cells. To achieve this, two different strategies were pursued. First, several prime-boost regimens with vectors encoding combinations of two liver-stage antigens were investigated. When mixed, vectors expressing LSA1 and LSAP2 conferred highest levels of protective efficacy in mice and were therefore considered for inclusion in the final second generation viral vectored liver-stage malaria vaccine. Second, the MHC class II invariant chain (Ii) was developed as a molecular adjuvant. Immunogenicity analyses of ChAd63 encoding ME-TRAP fused to several different versions of Ii showed that the transmembrane domain of Ii has the ability to strongly increase antigen-specific CD8+ T-cell responses, even in the absence of the rest of the Ii protein. This finding may lead to the discovery of numerous similar adjuvants (such as the transmembrane domain of the Newcastle disease virus fusion protein). Furthermore, experiments showed that the Ii chain sequence can also be xenogenised without losing adjuvanticity. Both strategies have been combined in numerous novel adjuvanted multi-antigen vaccines, which were ranked for immunogenicity and efficacy in inbred and outbred mice. The viral vectors of the best combination (ChAdOX1-sharkTM/Ii-LSA1-LSAP2 and MVA-tPA-LSA1-LSAP2) are currently being produced to GMP grade and will progress to initial clinical trials in early 2017.</p