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

Abstract

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 Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV

“…Second, we show that the addition of the truncated shark class-II invariant chain (SIi) to the immunogen enhances the magnitude of the vaccine-induced T cell response, as has been reported in a recent study of ChAd and MVA viral vectored malaria vaccines in mice [13].…”

“…To generate a broad immune response targeting multiple HBV proteins, we designed a new HBV immunogen encompassing three full length HBV-antigens (precore/core, polymerase and preS1/preS2/surface) based on a patient genotype C sequence with maximum similarity to the genotype C consensus. The immunogen was linked to truncated shark class-II invariant chain (SIi) and tissue plasminogen activator (TPA) genetic sequences, and encoded into the chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors; these approaches have been shown to significantly enhance both CD8+ and CD4+ immune responses against encoded antigens [12,13]. We show that these vaccines can induce high magnitude polyfunctional T cells in immunocompetent uninfected mice against all major HBV immunogens, providing support for their clinical development in human trials.…”

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

“…A simian adenovirus (ChAdOx1) vector vaccine was constructed encoding nonstructural proteins of RHV linked to a truncated shark invariant chain known to enhance T‐cell responses (ChAd‐NS) (Fig. A) . A time course of CD4 + IFNγ + (Supporting Fig.…”

Preclinical Development and Assessment of Viral Vectors Expressing a Fusion Antigen of Plasmodium falciparum LSA1 and LSAP2 for Efficacy against Liver-Stage Malaria

“…To further maximize T cell responses, we chose to incorporate in the ChAdOx1 vectors the recently described shark and trout Ii chain TM domains, which we have shown to significantly enhance antigen-specific CD8 ϩ T cell responses after immunization with ME-TRAP-expressing viral vectors (16). We therefore generated the follow- ing ChAdOx1 vectors: single-antigen vectors expressing either PfLSA1 or PfLSAP2 and a dual-fusion antigen ChAdOx1 vector expressing a fusion (PfLSA1-PfLSAP2) (see Fig.…”

“…To increase the immunogenicity and efficacy of virus-vectored liver-stage malaria vaccines, different approaches could be employed, for example, including multiple parasite antigens in the viral vector to increase the breadth and number of malaria-specific T cells (14) or incorporating a molecular adjuvant in the viral vector to increase the overall size of the antigen-specific response (15). The latter approach been a rather difficult challenge, but truncated and xenogenized versions of the major histocompatibility complex (MHC) class II invariant chain as a molecular adjuvant have shown promising results in mice (16).…”