Vaccines based on replication incompetent Ad26 viral vectors: standardized template with key considerations for a risk/benefit assessment

Abstract Replication-incompetent adenoviral vectors have been under investigation as a platform to carry a variety of transgenes, and express various antigens as a basis for preventive or therapeutic vaccine development. A replication incompetent adenoviral vector based on human adenovirus type 26 (Ad26) has been evaluated in several clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and features of recombinant viral vector vaccines. This paper reviews the biological features of the Ad26 vectors, including tabulation of safety and risk assessment characteristics of Ad26 vector-based vaccines. Substantial information on immunogenicity, clinical safety, biological characteristics and manufacturing are reported. In the Ad26 vector, deletion of the E1 gene, rendering the vector replication incompetent and providing space for transgene insertion, is combined with additional genetic engineering for vaccine manufacturability and transgene expression optimization. These vaccines are manufactured using the E1-complementing PER.C6® cell line, a continuous, human cell-line that can be cultured in serum-free medium in a suspension to high cell densities, providing an effective and flexible system for high-yield manufacturing. Ad26 vector vaccines have favorable thermostability profiles, compatible with vaccine supply chains. Safety data are compiled in the Ad26 vaccine safety database version 4.0, with unblinded data from 23 ongoing and completed clinical studies for a total of 3912 participants in Ebola, HIV, Malaria, RSV and Filovirus Ad26-based vaccine programs. Overall, all Ad26-based vaccines have been well tolerated, with no significant safety issues identified from the available data in the current Ad26 vaccine safety database. Evaluation of Ad26-based vaccines to further characterize the safety profile is continuing, with more than 90,000 participants vaccinated as of 1st July 2020 (cut-off date). Extensive evaluation of immunogenicity in humans shows strong and durable humoral and cellular immune responses. Clinical trials have not shown meaningful impact of pre-existing immunity to Ad26 on vaccine immunogenicity, even in the presence of Ad26 neutralizing antibody titers or Ad26-targeting T cell responses at baseline. The first vaccine, against Ebola virus, that makes use of the Ad26 vector, received marketing authorization from EC on 1st July 2020, as part of the Ad26.ZEBOV, MVA BN Filo vaccine regimen. New developments based on the Ad26 vector are underway, including a COVID-19 vaccine, which is currently in clinical evaluation.