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Despite promising progress in malaria vaccine development, an efficacious subunit vaccine against P. falciparum remains to be licensed and deployed. This study aimed to improve on the immunogenicity of the leading liver-stage vaccine candidate (ChAd63-MVA ME-TRAP), known to confer protection by eliciting high levels of antigen-specific CD8 + T cells. We previously showed fusion of ME-TRAP to the human MHC class II invariant chain (Ii) could enhance CD8 + T cell responses in non-human primates, but did not progress to clinical testing due to potential risk of auto-immunity by vaccination of humans with a self-antigen. Initial immunogenicity analyses of ME-TRAP fused to subdomains of the Ii showed that the Ii transmembrane domain alone can enhance CD8 + T cell responses. Subsequently, truncated Ii sequences with low homology to human Ii were developed and shown to enhance CD8 + T cell responses. By systematically mutating the TM domain sequence, multimerization of the Ii chain was shown to be important for immune enhancement. We subsequently identified several proteins from a variety of microbial pathogens with similar characteristics, that also enhance the CD8 + T cell response and could therefore be used in viral vector vaccines when potent cell mediated immunity is required.

The orthodox role of the invariant chain (CD74; Ii) is in antigen presentation to CD4+ T cells, but enhanced CD8+ T cells responses have been reported after vaccination with vectored viral vaccines encoding a fusion of Ii to the antigen of interest. In this study we assessed whether fusion of the malarial antigen, ME-TRAP, to Ii could increase the vaccine-induced CD8+ T cell response. Following single or heterologous prime-boost vaccination of mice with a recombinant chimpanzee adenovirus vector, ChAd63, or recombinant modified vaccinia virus Ankara (MVA), higher frequencies of antigen-specific CD4+ and CD8+ T cells were observed, with the largest increases observed following a ChAd63-MVA heterologous prime-boost regimen. Studies in non-human primates confirmed the ability of Ii-fusion to augment the T cell response, where a 4-fold increase was maintained up to 11 weeks after the MVA boost. Of the numerous different approaches explored to increase vectored vaccine induced immunogenicity over the years, fusion to the invariant chain showed a consistent enhancement in CD8+ T cell responses across different animal species and may therefore find application in the development of vaccines against human malaria and other diseases where high levels of cell-mediated immunity are required.