RESUMO
The Vaccine Research Center has developed vaccine candidates for different diseases/infectious agents (including HIV-1, Ebola, and Marburg viruses) built on an adenovirus vector platform, based on adenovirus type 5 or 35. To support clinical development of each vaccine candidate, pre-clinical studies were performed in rabbits to determine where in the body they biodistribute and how rapidly they clear, and to screen for potential toxicities (intrinsic and immunotoxicities). The vaccines biodistribute only to spleen, liver (Ad5 only), and/or iliac lymph node (Ad35 only) and otherwise remain in the site of injection muscle and overlying subcutis. Though approximately 10(11) viral particles were inoculated, already by Day 9, all but 10(3) to 10(5) genome copies per mu g of DNA had cleared from the injection site muscle. By three months, the adenovector was cleared with, at most, a few animals retaining a small number of copies in the injection site, spleen (Ad5), or iliac lymph node (Ad35). This pattern of limited biodistribution and extensive clearance is consistent regardless of differences in adenovector type (Ad5 or 35), manufacturer's construct and production methods, or gene-insert. Repeated dose toxicology studies identified treatment-related toxicities confined primarily to the sites of injection, in certain clinical pathology parameters, and in body temperatures (Ad5 vectors) and food consumption immediately post-inoculation. Systemic reactogenicity and reactogenicity at the sites of injection demonstrated reversibility. These data demonstrate the safety and suitability for investigational human use of Ad5 or Ad35 adenovector-based vaccine candidates at doses of up to 2 x 10(11) given intramuscularly to prevent various infectious diseases.