Abstract Summary/Description
The response to the global COVID-19 pandemic by public health entities and the vaccine industry was unprecedented and highly successful. The primary focus of the first-generation vaccines was on the use of the SARS-CoV-2 spike (S) protein as the primary vaccine immunogen with the goal of inducing high levels of neutralizing antibodies. However, multiple limitations associated with this approach are now evident due to the emergence of variants of concerns, VOCs, with notable mutations in the Spike protein sequence. Consequently, vaccine efficacy was disrupted due to the diminished neutralizing capacity of vaccine-induced antibodies and hence vaccine protection against reinfection. Evaluation of immune responses in COVID-19 convalescent patients demonstrated numerous viral proteins to be highly immunogenic including S and N proteins, suggesting their primary role as immunodominant antigens for humoral and cellular immunity. Therefore, the inclusion of multiple SARS-CoV-2 antigens has the potential to broaden immunity and mitigate the impact of variants on vaccine efficacy. In response, GeoVax developed a clinical vaccine candidate GEO-CM04S1, a modified vaccinia Ankara vector (MVA) co-expressing spike and nucleocapsid antigens based on the Wuhan-Hu-1 reference strain. Here, we report GEO-CM04S1 vaccine efficacy against the ancestral Wuhan strain B.1 and the Omicron subvariant XBB.1.5 in K18-hACE-2 mouse model. We demonstrate that intramuscular vaccination of hACE2 mice with GEO-CM04S1 protects against weight loss, upper and lower respiratory tract infection, lung injury and viral neuroinvasion following intranasal challenge with B.1 and XBB.1.5. We also report the efficacy of MVA-vectored vaccines expressing only S or N protein termed MVA-S and MVA-N, respectively. In MVA-S-vaccinated mice, full protective efficacy against B.1 was observed; however, the vaccine had diminished protection against XBB.1.5 variant. Minimal protection against B.1 was observed in MVA-N-immunized mice. These results demonstrate the efficacy of GEO-CM04S1 that confers full cross-protective immunity against SARS-CoV-2 and its emerging VOCs.
