AeroVax: study protocol for a randomised, double-blind, placebo-controlled, phase 2 trial to evaluate safety and immunogenicity of a next-generation COVID-19 vaccine delivered by inhaled aerosol to humans

Background: Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to have a significant impact worldwide, in part due to a reduction in neutralising antibody protection provided by vaccines targeting monovalent spike antigens related to immune escape. Development of vaccines amenable for respiratory mucosal delivery that provide broad and durable immunity are needed. This study aims to determine the safety and immunogenicity of a single inhaled dose of a replication-deficient chimpanzee adenovirus type 68 vector expressing a trivalent transgene cassette of SARS-CoV-2 S1 domain of spike, nucleocapsid and RNA polymerase genes (ChAd-triCoV/Mac). Methods: We plan to recruit 350 nonpregnant adults aged 18-65 who have previously received three intramuscular SARS-CoV-2 mRNA vaccines in this 24-week, multicentre, double-blind, parallel-group, phase II, two-sided superiority randomised controlled trial. Participants will be randomised 2:1 to receive either a single inhaled dose of ChAd-triCoV/Mac or placebo, both aerosolised via the AeroNeb® Solo vibrating mesh nebuliser. A subset of separately randomised participants will undergo bronchoalveolar lavage (BAL). The co-primary outcome to be analysed in the per-protocol population is SARS-CoV-2 antigen-specific CD4⁺ and CD8⁺ T-cell responses measured at 2 weeks in the peripheral blood; solicited adverse event frequency to day 7 and unsolicited to day 28. In the BAL sub-study, the co-primary outcome will also include BAL fluid SARS-CoV-2 antigen-specific CD4⁺ and CD8⁺ T-cell responses measured at 4 weeks. Conclusion: This placebo-controlled phase 2 randomised trial will test the safety and immunogenicity of an inhaled, nebulised ChAd-triCoV/Mac SARS-CoV-2 vaccine that is novel in its administration route and targeting of multiple viral epitopes. The results will provide further information regarding the mucosal T-cell response to immunisation.