Notes

Outline

PHASE I STUDY OF AD4-DE3-HIVenv AND AD4-DE3-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 Higher levels Prolonged expression 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

Adenovirus Constructs

Study Design

Large Particle Aerosol Is Optimized for Delivery to the Upper Respiratory Tract

Study Design

Monitoring Summary

Rationale for Choice of Adenovirus Type 4 Low seroprevalence 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

Safety Issues 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.