Timothy R Fouts
Founders and Principle Scientists at Profectus Biosciences
Title: Development of the full length single chain gp120-CD4 (FLSC), a novel vaccine for HIV prevention
Biography
Biography: Timothy R Fouts
Abstract
Obtaining a practical, efficacious vaccine against HIV has been a public health priority for over 30 years. We have developed the Full-length Single Chain (FLSC) in order to induce broader immunity, including against new conserved epitopes, compared to conventional gp120 or trimeric gp140s. The FLSC vaccine is fusion protein consisting of a modified full length gp120 protein, derived from HIVBaL and the first two domains (D1D2) of human CD4, genetically fused via a 20 amino acid linker. Immunization with FLSC was able to protect rhesus macaques against rectal challenge of heterologous neutralization resistant SHIV(162P3) and SIVmac251. Efficacy tracked with Fc-mediated effector function of the antibody provided that the concurrent anti-vaccine T cell response is minimal. Protection is lost over time as requisite antibody titers declined consistent with the evanescent quality of antienvelope humoral responses. To advance the FLSC into clinical trials, a master cell bank expressing human FLSC was prepared from G293H, a derivative of HEK-293 cell that grows in suspension, using the GPEx® retrovector transduction system. Bioreactor production rates were consistent from the 2L to the 200L scale, yielding approximately 1 gms/liter after downstream purification. Drug substance was predominately monomeric and expressed the expected CD4 induced structure. Potency studies with the Alum formulated drug product demonstrated a significant relationship between the dose of the FLSC/Alum (IHV01) and the induction of the desired CD4i directed immune response. Immunogenicity studies performed in rhesus macaques showed that the FLSC/Alum formulation induced antibodies directed to CD4i epitopes and mediated ADCC activity while T-cell responses were modest. Toxicity studies performed in rabbits and cynomolgus macaques demonstrated that the vaccine was safe and did not induce any deleterious autoimmune effects directed to CD4. A dose escalation phase 1 clinical trial with IHV01 has started at the Institute for Human Virology in Baltimore, MD.