Determinants of poor immunogenicity of rare-serotype adenovirus vaccine vectors

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIAID	IMMUNO/INFLAM-25

* FARE Award Winner

Authors

• M Johnson
• C Petrovas
• J Gall
• E Haddad
• R Sekaly
• R Koup

Abstract

Several different human adenovirus serotypes are currently under development as potential HIV vaccine vectors. Human adenovirus 5 (Ad5), once considered a leading candidate for a vaccine, stimulates strong immunity, but extensive pre-existing immunity limits its usefulness as a clinical product. Viral vectors derived from rare-serotype adenoviruses, such as Ad28 and Ad35, avoid issues with pre-existing immunity but have proven to be less immunogenic than Ad5-based vectors. We sought to determine which attributes of rare serotype adenoviral vectors inhibit their immunogenicity, or conversely which features of Ad5 increase its immunogenicity. Despite the previously observed decreased immunogenicity of Ad28 and Ad35, our data demonstrate that these serotypes are far more infectious of human primary cells and stimulate greater innate immunity than Ad5. In particular, Ad28 and Ad35 induce interferon alpha (IFNα) production and stimulate many interferon-related intracellular pathways. Additionally, in mice, an increase in both the in vitro and in vivo production of IFNα by Ad28 and Ad35 is observed. We further demonstrate that interferon alpha-beta receptor knockout (IFNabrKO) mice are able to generate a significantly higher frequency T cell response to Ad28 than wildtype mice. Our results indicate that vector-induced IFNα production may negatively impact adenoviral vector immunogenicity.

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