Functionally inactivated dominant viral antigens of human cytomegalovirus delivered in replication incompetent adenovirus type 6 vectors as vaccine candidates

ABSTRACT

T cell immunity is critical in controlling human cytomegalovirus (HCMV) infection in transplant recipients, and T cells targeting viral immediate early proteins such as IE1, IE2 and pp65 have been speculated to be more effective against reactivation. Here we report efforts to construct replication incompetent adenovirus 6 vectors expressing these viral antigens as vaccine candidates. To reduce the potential liabilities of these viral proteins as vaccine antigens, we introduced mutations to inactivate their reported functions including their nuclear localization signals. The modifications greatly reduced their localization to the nuclei, thus limiting their interactions with cellular proteins important for cell cycle modulation and transactivation. The immunogenicity of modified pp65, IE1 and IE2 vaccines was comparable to their wild-type counterparts in mice and the immunogenicity of the modified antigens was demonstrated in non-human primates.

KEYWORDS:

• adenovirus vector
• cytomegalovirus (CMV)
• non-human primate
• T cell immunity
• vaccine

Disclosure of potential conflicts of interest

All authors were employees of Merck & Co., Inc. at the time of the study, and had no conflict of interest to disclose.

Acknowledgments

We thank all animal care staff at Merck & Co., Inc., West Point, PA, USA and New Iberia Research Center, New Iberia, LA, USA for their technical supports in animal studies. We also acknowledge the critical review by Amy S. Espeseth, and the technical assistance provided by Kiersten Anderson and Jeffrey Sadler of Merck & Co., Inc., West Point, PA, USA.