Protective immunity induced by an inhaled SARS-CoV-2 subunit vaccine

Targeting the site of infection is a promising strategy for improving vaccine effectivity. To date, licensed COVID-19 vaccines have been administered intramuscularly despite the fact that SARS-CoV-2 is a respi-ratory virus. Here, we aim to induce local protective mucosal immune responses with an inhaled subunit vaccine candidate, ISR52, based on the SARS-CoV-2 Spike S1 protein. When tested in a lethal challenge hACE2 transgenic SARS-CoV-2 mouse model, intranasal and intratracheal administration of ISR52 provided superior protection against severe infection, compared to the subcutaneous injection of the vac-cine. Interestingly for a protein-based vaccine, inhaled ISR52 elicited both CD4 and CD8 T-cell Spike -specific responses that were maintained for at least 6 months in wild-type mice. Induced IgG and IgA responses cross-reacting with several SARS-CoV-2 variants of concern were detected in the lung and in serum and protected animals displayed neutralizing antibodies. Based on our results, we are develop-ing ISR52 as a dry powder formulation for inhalation, that does not require cold-chain distribution or the use of needle administration, for evaluation in a Phase I/II clinical trial. & COPY; 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

Automated summary

Targeting the site of infection, inhalation of the subunit vaccine ISR52 based on SARS-CoV-2 Spike S1 protein can induce local protective mucosal immune responses, providing superior protection against severe infection compared to subcutaneous injection. Inhalation of ISR52 also induces sustained Spike-specific CD4 and CD8 T-cell responses, cross-reactive IgG and IgA antibodies against various SARS-CoV-2 variants, and neutralizing antibodies. A dry powder formulation of ISR52 for inhalation is being developed for evaluation in a Phase I/II clinical trial.