52. Gorilla Adenovirus Vectors for Molecular Therapeutics and Vaccines

Abstract

Adenovirus vectors built from gorilla adenovirus are showing superior performance characteristics for molecular vaccines. These new adenovectors (GC Ads) are built from virus isolated from gorilla, and have been cloned and engineered to be replication-defective. GC Ads grow efficiently to high titer on cell lines GenVec has characterized, banked and filed with regulatory agencies for scalable manufacturing. They can be deleted of multiple regions (e.g., E1, E3, and E4) to provide space for multiple transgene cassettes, provide multiple blocks to eliminate replication competent virus and to ensure safer transgene delivery. These new adenovectors have been shown to not be recognized by human sera from either the United States or from Africa. A single intramuscular injection of these GC Ads can induce durable immune responses to encoded antigen. For example, intramuscular injection of GC Ads expressing RSV fusion (F0) glycoprotein induced neutralizing antibody titers that were durable > 24weeks, and protected the lung and nose against RSV challenge at even low doses of immunization in cotton rats. A single intramuscular administration of GC Ads expressing the malaria antigen CSP generated CD8 T cell and antibody responses to CSP that were greater than those generated with Ad5 in mice. In a mouse malaria challenge model the GC Ad regimen was more protective than Ad5. A single intramuscular administration of GC Ads expressing two HSV antigens, UL19 and UL47, resulted in high level cellular responses that were protective against intravaginal HSV2 challenge in mice and the CD8 T cell responses were shown to be durable, 26 weeks. Moreover, repeat administration of the same GC Ad resulted in a boost of antigen-specific immune response. Unlike other adenoviral vectors, homologous prime boost regimens with these GC Ads resulted in a boost of the CD8 T cell responses at all doses and intervals tested. These new GC Ads based on gorilla adenoviruses show generation of strong, durable T cell and neutralizing antibody responses to multiple antigens from a single administration that can be further enhanced by repeat administration. Based on these data, the platform shows great promise for development of a broad array of immunotherapeutic and molecular vaccine product candidates.