Intranasal PIV5-vectored SARS-COV-2 KP.2 vaccine protects against homologous and heterologous challenge in mice and hamsters

Despite currently available commercial COVID-19 vaccines, a COVID-19 vaccine that can offer greater and broader protection with minimal side effects is needed. The parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine (CVXGA) expressing the spike (S) protein is a promising next generation COVID-19 vaccine that has been shown to be safe and efficacious in Phase 1 and 2a clinical studies. Here, we conducted the preclinical studies to evaluate the immunogenicity and efficacy of CVXGA50, an updated PIV5-vectored COVID-19 vaccine expressing the S protein of the Omicron KP.2 variant. In contrast to the PIV5-based CVXGA1 COVID vaccine expressing the WA1 S protein, which induced high levels of IgG and neutralizing antibodies (nAb) in mice, CVXGA50 elicited lower levels of serum S-specific IgG and undetectable nAb in naïve and pre-immune mouse models. However, a robust cellular immune response was detected in CVXGA50 immunized mouse models. Despite the poor serum antibody responses, CVXGA50 completely protected against homologous KP.2 challenge virus replication in the lungs of K18-hACE2 mice, as well as heterologous WA1 lethal challenge, suggesting that the nAb response is not the major protective mechanism for CVXGA50 intranasal vaccine. KP.2 mRNA vaccine elicited a high level of serum S-specific IgG and nAb response, but it was not superior to CVXGA50 in preventing challenge virus replication. In contrast to the mouse model, CVXGA50 elicited high levels of serum S-IgG and nAb in naïve and pre-immune hamsters and offered complete protection against KP.2 challenge, reflecting species-specific antibody responses. One Sentence Summary: PIV5-vectored SARS-CoV-2 KP.2 intranasal vaccine protects against homologous and heterologous challenge in the mouse and hamster animal models even though it did not generate a robust serum antibody response in the mouse models.