Phase 1, Open Label Study to Evaluate the Safety and Immunogenicity of ChAd68 and AdHu5 Vector-based Trivalent COVID-19 Vaccines Delivered Via Inhaled Aerosol

This is a phase 1, dose-escalating study to evaluate the safety and immunogenicity of a single dose of either Ad5-triCoV/Mac, a replication deficient human adenovirus vector, or ChAd-triCoV/Mac, a replication deficient chimpanzee adenovirus 68 vector, delivered to the respiratory tract by aerosol, in healthy volunteers who have received at least three doses of an mRNA COVID-19 vaccine. Both vectors have been engineered to express the spike, nucleocapsid and RNA polymerase proteins.

Up to 36 healthy volunteers will be enrolled in this dose escalation study. The first cohort (n=6) will receive Ad5-triCoV/Mac (n=3) or ChAd-triCoV/Mac (n=3) at the lowest dose of 10e5 TCID50, administered using the AeroNeb Solo Vibrating Mesh Nebulizer. Assuming no safety concerns, participants will then be administered Ad5-triCoV/Mac (n=3) or ChAd-triCoV/Mac (n=3) at a dose of 10e6. Assuming no safety signals we will move to vaccinate at the next dose level of 1x10e7 TCID50. Decisions about dose escalation will be made independently for each vaccine based on safety and immunogenicity profile. If the immunogenicity endpoints are not reached, in the absence of a safety signal, at the 10e7 dose level, we will move to the next dose level of 3x10e7 TCID50 and enrol three participants/vaccine group. Similarly, if all of the immunogenicity endpoints in the BAL are not met at 3x10e7, and in the absence of any safety signal, we will further escalate to 6x10e7, then 1x10e8 TCID50 and enrol three participants/vaccine group, if required. Once safety has been shown in participants without a history of COVID, we will proceed to enrol participants with a history of COVID infection to receive ChAd-triCoV/Mac, beginning with a dose of 3x10e7 (n=3) and, in the absence of any safety signal, escalating to 6x10e7 and, if required, 1x10e8 and, once the optimal dose has been determined based on immunogenicity outcomes, continue to enrol participants at this dose level to complete enrolment of the cohort (n=6).

Antibody and specific T cell responses will be measured in lung from bronchoalveolar lavage fluid collected at bronchoscopy at baseline and at 4 weeks following vaccination and in blood at several time points up to week 48 following vaccination.

Safety endpoints will include the nature of any adverse events, their severity and the probability of a relationship to study procedures and administration of vaccine.