Report Summary

Biodistribution and Toxicological Safety of Adenovirus Type 5 and Type 35 Vector Vaccines Against Human Immunodeficiency Virus-1 (HIV-1), Ebola, or Marburg Are Similar Despite Differing Adenovirus Serotype Vector, Manufacturer's Construct, or Gene Inserts

Study Summary

Overall Study Design 
The Vaccine Research Center has developed vaccine candidates for different diseasesinfectious 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 andor iliac lymph node Ad35 only and otherwise remain in the site of injection 
muscle and overlying subcutis Though 1011 viral particles were inoculated already by Day 9 all but 103 to 105 genome 
copies per 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 manufacturers 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  10e11 given intramuscularly to 
prevent various infectious diseases 
Rabbits were chosen as the test model for these studies as they are a species large enough to receive a full human dose of 
vaccine This is important since the immunogenicity andor pharmaceutical effect of vaccines does not scale directly to body 
weight or body surface area as may be the case for most drugs that disseminate through the blood to other parts of the 
body Vaccines act at the local site of injection if delivered parenterally to induce an immune response that traffics 
systemically Thus delivery of a full human dose to the animal model is deemed the most suitable means of addressing 
potential human toxicities CBER 2006 Chang et al 2007 Based on current clinical experience with Ad5 vectors as 
vaccine candidates rabbits appear to be a good predictor of the reactogenicity that is being observed in the clinic 
Catanzaro et al 2006 For Ad35 there are not yet sufficient clinical data to validate the rabbit as the appropriate animal 
model However Ad35 as a vaccine vector for tuberculosis and malaria entered clinical trials in late 2006 Crucell 2006a 
2006b so these data will be forthcoming In addition the Ad35 vaccine described herein has also entered clinical trials 
GenVec 2007 While Ad5 a subgroup C Adenovirus primarily enters cells by binding to the Coxsackie and Adenovirus 
receptor CAR Ad35 a subgroup B Adenovirus utilizes CD46 membrane cofactor protein as a receptor The tissue 
distribution of CD46 expression is reported for a small number of species but has not yet been elucidated for rabbits 
Further it should be noted that this is not the appropriate animal model for HIV disease or AIDS Nor is it the appropriate 
model to assess the effect vaccination might have on subsequent acquisition of HIV or appropriate model such as SIV or 
disease as would be assessed in a challenge-protection model The studies undertaken as reported herein were not 
intended to model HIV acquisition or disease progression in vaccinated animals only to assess acute or sub-acute intrinsic 
toxicities and immunotoxicities as recommended by regulatory authorities specifically the United States Food and Drug 
Administration FDA which has regulatory jurisdiction over the clinical trials we have proposed or performed with these 
investigational vaccines 
In order to provide preclinical data to support the safety and suitability of the candidate vaccines to proceed into human 
clinical testing three biodistribution studies and four repeated dose toxicology studies were performed on the four 
adenovector-based vaccine products that will be described herein In addition two of the repeated dose toxicology studies 


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