A Trial of a Next Generation COVID-19 Vaccine Delivered by Inhaled Aerosol

The global impact of the coronavirus disease 2019 (COVID-19) pandemic remains profound; COVID-19 continues to be one of the leading causes of death and hospitalization due to infectious disease, disproportionately affecting the elderly and immunocompromised. The continuous evolution of the virus has significantly challenged the effectiveness of first-generation and updated vaccination strategies. These variants of concern (VOCs) can evade neutralizing antibodies. Adequate and early lung mucosal immunity is critical for control of infection but current vaccines fail to induce robust mucosal immunity in the lungs, a major reason for the high rates of break-through infections. The respiratory mucosal route of immunization, however, can induce protective respiratory mucosal immunity consisting of trained innate immunity (via memory airway macrophages), mucosal antibodies, and tissue-resident memory CD4+/CD8+ T cells. A phase 1 study has been completed using a recombinant chimpanzee adenovirus (ChAd) vector, ChAd-CoV3/Mac in 23 healthy volunteers and has shown that the vaccine can be safely administered by aerosol and that immune responses against COVID-19 develop in the lung and T-cells and neutralizing antibodies are generated in the blood. The purpose of this placebo-controlled Phase 2 trial is to determine if this new COVID-19 vaccine, ChAd-triCoV/Mac, is safe to give by aerosol to people who have been vaccinated with at least three doses of a COVID mRNA vaccine and evaluate the immune responses generated. Specifically, the researchers want to see if T cell responses and antibody responses to the COVID virus proteins develop in the blood after receiving the vaccine. There is a lack of surrogate immune markers for vaccine-induced protection against antibody-evading VOCs of SARS-CoV-2. However, given the now recognized importance of respiratory mucosal T cell immunity in anti-SARS-CoV-2 host defense, this study will allow for a correlation of mucosal T cell immunity with the T cells in blood to help predict vaccine efficacy, and inform the design of phase 3 efficacy studies.