A parainfluenza virus 5 (PIV5)-vectored intranasal SARS-CoV-2 vaccine (CVXGA1) elicits protective and long-lasting immunity in nonhuman primates.

Waning immunity from approved COVID-19 vaccines and emerging variants of SARS-CoV-2 necessitate the need to develop alternative COVID-19 vaccines for improved durability and broader protection. This work investigates the efficacy and mucosal, humoral, and cellular immunogenicity of intranasal, parainfluenza virus 5 (PIV5)-vectored COVID-19 vaccine CVXGA1 in an African green monkey (AGM) nonhuman primate model. A single intranasal dose of CVXGA1 induced robust and sustained humoral and cellular immune responses in AGMs and protected against SARS-CoV-2 ancestral WA1 strain and alpha variant challenge infection in the respiratory tracts as demonstrated by lack of viral load and greatly decreased histopathology. Mucosal IgA antibodies were detected in the upper and lower respiratory tracts of immunized AGMs. CVXGA1-vaccinated AGMs maintained serum anti-S IgG and IgA antibody titers for over 245 days. S-specific CD4⁺ and CD8⁺ T cells producing predominantly IFN-γ, TNF-α, MIP-β, and CD107α cytokines peaked on day 28 and could be detected on day 180 by intracellular cytokine staining of peripheral blood mononuclear cells (PBMC). IL13-secreting CD4⁺ and CD8⁺ T cells were minimally detected, indicative of a dominant type 1 immune response. These data supported the clinical evaluation of CVXGA1 intranasal COVID-19 vaccine. These data demonstrate that intranasal immunization with CVXGA1 induces long-lasting protective SARS-CoV-2 S-specific mucosal, humoral, and cellular responses in AGMs.IMPORTANCEThe continued threat of SARS-CoV-2 indicates the need for a novel vaccine that induces long-lasting mucosal, cellular, and humoral immunity, as well as block transmission. This work demonstrates that intranasal, PIV5 viral-vectored SARS-CoV-2 vaccine CVXGA1 induces mucosal immunity and long-lasting cellular and humoral immunity that protects African green monkeys from SARS-CoV-2 challenge. The ability of our intranasal vaccine to elicit long-lasting mucosal, cellular, and humoral immunity against SARS-CoV-2 indicates great promise of the PIV5-vectored COVID-19 vaccine for further clinical development.