Intranasal self-amplifying RNA SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission

Abstract While mRNA vaccines have been effective in combating SARS-CoV-2, waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 self-amplifying RNA (saRNA) vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident IgG-secreting cells, and robust lymphoid tissue T cell immune responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory and lung-homing T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m. and i.n. administered vaccines protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naive cagemates. This saRNA vaccine’s potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens. One Sentence Summary Intranasal SARS-CoV-2 saRNA vaccination induces systemic and mucosal immunity in mice, and prevents morbidity and blocks viral transmission in hamsters.