A replication-incompetent adenovirus type 55 vaccine induces broad and durable protective immunity against pathogenic adenoviruses

Human adenovirus types 55, 11, and 14 (HAdV-55, -11, and -14) are pathogenic respiratory viruses for which no drugs or vaccines are currently available. We report the generation of a replication-incompetent rAd55-5E4 with deleted E1 and E3 genes, which only replicates in cells that provide E1 proteins in trans. In mice and non-human primates, vaccination with live non-replicating rAd55-5E4 elicited robust and durable neutralizing antibody (nAb) and cell-mediated immune responses against HAdV-55, as well as cross-reactivity against HAdV-11 and HAdV-14. Furthermore, vaccination with the live non-replicating rAd55-5E4 elicited much stronger immune responses than inactivated rAd55-5E4. In transgenic mice that express human desmoglein-2, the cellular receptor for HAdV-55, -11 and -14, vaccination with rAd55-5E4 or passive transfer of macaque immune sera collected at 66 weeks post vaccination effectively protected against challenges with HAdV-55, HAdV-11, and HAdV-14. Epitope profiling revealed that nAbs mainly recognize epitopes on hexon hypervariable regions 1, 2, 5, and 7, as well as the fiber knob. This study supports the feasibility of developing replication-incompetent HAdVs as vaccines against pathogenic HAdVs.