PHASE I STUDY OF AD4-
E3-HIVenv AND AD4-
E3-HIVgag-pro RECOMBINANT VACCINES IN HIV-NEGATIVE VOLUNTEERS
Approaches to HIV Vaccination in Pre-Clinical or Clinical Trials
Replication Incompetent Ad-HIV Recombinants are Immunogenic and Lower Plasma Viral RNA Levels of Rhesus Macaques
Theoretical Reasons for Increased Immunogenicity of Live Adenovirus Vaccines
Potential for greater total antigen dose
Expression persists until terminated by an effective immune response
Potential for inducing cellular and humoral mucosal immune responses
Induces proinflammatory cytokines and costimulatory molecules
May more readily overcome subtype-specific immunity
Summary of Non-Human Primate Studies with Ad-HIV Recombinants
Large Particle Aerosol Is Optimized for Delivery to the Upper Respiratory Tract
Rationale for Choice of Adenovirus Type 4
34% seropositive in new recruits
Extensive safety record
Now has been given enterically to >10 million people (Gaydos et al, Military Med, 1995)
Extensively studied for shedding, safety, and transmissibility
E3 deletion previously shown to enhance pulmonary pathology
E3 insert abrogates this effect (Patterson et al, 2002).
May be shed up to 2 years
Prolonged shedding is infrequent and at very low levels.
Not typically associated with Ad4
Some Adenoviruses are oncogenic in rodents.
Not associated with Ad 4
Oncogenesis not observed in humans
Safety, Shedding, and Transmission of Experimental Adenovirus Infections
Summary of Safety, Shedding, and Transmissibility
Selective infection of the GI tract does not typically result in upper respiratory or other attributable disease.
Seropositive subjects are infectable.
Disease (sore throat, rhinorrhea, occ. fever) can result from IN administration to seronegatives.
Ad4 is not commonly transmitted in a community or household setting.
<0.2% of 1,792 isolates in children (Brandt et al, 1969)
Intimate contact is required for transmission during enteric shedding.