Efficacy of parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine as a single dose primer and booster against SARS-CoV-2 variants.

Immunization with COVID-19 vaccines has greatly reduced COVID-19-related deaths and hospitalizations from SARS-CoV-2 infection, but waning immunity and the emergence of variants capable of immune escape indicate the need for annual vaccine updates or development of different SARS-CoV-2 vaccine platforms. Parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine with the ancestral spike (S) protein (CVXGA1) has been shown to be a promising next-generation COVID-19 vaccine preclinically and is currently being evaluated in humans. This work investigates the immunogenicity and efficacy of CVXGA1 and other PIV5-vectored vaccine candidates expressing additional SARS-CoV-2 nucleoprotein (N) antigen or SARS-CoV-2 variant S proteins of beta, delta, gamma, and omicron variants against homologous and heterologous challenges in hamsters. A single intranasal dose of CVXGA1 induces neutralizing antibodies (nAbs) against SARS-CoV-2 WA1 (ancestral), delta variant, and omicron variant and protects against both homologous and heterologous virus challenges. Compared to mRNA COVID-19 vaccine, neutralizing antibody titers induced by CVXGA1 were well maintained over time. When administered as a booster following two doses of an mRNA COVID-19 vaccine, PIV5-vectored vaccines expressing the S protein from WA1 (CVXGA1), delta, or omicron variants generate higher levels of cross-reactive nAbs than three doses of mRNA vaccine. Our data indicate that an intranasal PIV5-vectored COVID-19 vaccine can serve as a booster vaccine against emerging variants. IMPORTANCE: With emerging new variants of concern (VOC), SARS-CoV-2 continues to be a major threat to human health. Approved COVID-19 vaccines have been less effective against these emerging VOCs. This work demonstrates the protective efficacy and strong boosting effect of an intranasal viral-vectored vaccine against SARS-CoV-2 variants in hamsters. Our intranasal vaccine can act as an effective booster for individuals already 58 vaccinated against SARS-CoV-2.