Preclinical Development of GV-MVA-VLP Vaccines Against COVID-19

项目总结

PROJECT SUMMARY With unprecedented speed and scale, SARS-CoV-2 has caused a deadly global pandemic. A safe and effective vaccine to control this new pathogen is desperately needed. To address this need, GeoVax is leveraging its unique GV-MVA-VLPTM platform and advanced antigen design to develop multiple vaccine candidates against COVID-19. Unique among COVID-19 vaccines, the GeoVax candidates are specifically designed to provide highly protective immunity against SARS-CoV-2 while avoiding antibody-dependent enhancement (ADE) and immunopathology that have the potential to render vaccines not only ineffective but actually dangerous. In addition to the identification of the final vaccine candidate, the work proposed here will generate scientific data that are extremely valuable to the overall field of COVID-19 vaccine development, in that testing of our unique vaccines will determine whether application of our approach is able to overcome the ADE and immunopathology risks that plagued SARS vaccines. Under Specific Aim 1, we will complete the construction of GEO-CM02 through GEO-CM04 vaccine candidates. We will then test these candidates to demonstrate antigen expression, manufacturability, formation of VLPs, and genetic stability under conditions designed to simulate those in manufacturing, which will demonstrate the suitability of each vaccine construct as a candidate for full-scale production. Finally, we will produce adequate amount of each vaccine to enable the animal studies planned in Specific Aim 2 and ship the vaccines to our collaborators at the University of Texas Medical Branch. Under Specific Aim 2, we will then perform an immunogenicity and efficacy study in mice transgenic for human angiotensin converting enzyme 2 (hACE2). The hACE2 transgenic mouse model is a rigorous animal model developed for SARS that is well suited for testing of human coronaviruses. We will immunize animals, sample the animals for analysis of immune responses, challenge the animals with SARS-CoV-2, and monitor the animals post-challenge for development of clinical signs of disease. Under Specific Aim 3, we will analyze samples from the hACE2 mouse study to assess the immunogenicity, efficacy and safety (ADE and immunopathology) of our vaccine candidates. Immunogenicity analyses will include binding antibody (BAb) by ELISA, neutralizing antibody (NAb) by serum neutralization assay, antibody-dependent cellular cytotoxicity (ADCC) by cell-based assay, and T cell responses by intracellular cytokine screening (ICS). Efficacy analyses will include viral load and histopathology relative to unvaccinated controls. We will also analyze serum and tissue samples for evidence of ADE and immunopathology to test the hypothesis that our vaccines will avoid these risks associated with SARS vaccines. All these parameters will help to down select the most immunogenic (inducing broad Ab and T cell responses) and safe (lack of ADE and immunopathology upon challenge) vaccine candidate for further testing in non-human primates and Phase 1 human trials.