Development of a Molecular Adjuvant to Enhance Antigen-Specific CD8 + T Cell Responses

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.