The positive outcome of the RV144 Phase III vaccine trial (the """"""""Thai trial"""""""") that tested an ALVAC-HIV/AIDSVAX B/E prime/boost protocol has prompted the field to refocus on humoral immunity as a means of achieving sterilizing immunity. This has also renewed interest in positioned other envelope-based subunit immunogens that may provide a better booster to achieve protection. One such immunogen is the Full Length Single Chain (FLSC) a gp120 human CD4 fusion that replicates the conserved envelope-CD4 complex, a key transition state that all HIV isolates must realize during infection. In 2 rhesus macaque studies, rhFLSC, a surrogate version of FLSC that contains CD4 derived from rhesus macaques, provided statistically significant protection (rapid clearance of post-acute plasma viremia, as well as potent and sustained suppression of tissue viremia) against rectal challenge with R5 tropic, and heterologus SHIV162P3. This observation indicates that FLSC could provide similar effects in humans and may provide the foundation for an effective vaccine against HIV. The goal of this project, therefore, is to initiate the preclinical development of FLSC in preparation for its evaluation in Phase I clinical trial as the next step in discerning whether FLSC can be an effective HIV vaccine. To reach this goal, this Fast Track Phase 1 &2 project has the following aims. Phase 1 Segment Aim 1. Develop pedigreed HEK293 cell lines suitable for the production of FLSC.
Aim 2. Identify and optimize release assays. Phase 2 Segment Aim 3. Manufacture lots of material suitable for potency studies (Aim 4) and preclinical toxicology (Aim 5).
Aim 4. Confirm that FLSC/adjuvant formulation induces CD4i responses in rabbits.
Aim 5. Evaluate FLSC in preclinical safety studies. Overall, the single chain complex has emerged as one of the rare envelope-based subunit immunogen that by itself affords protection against mucosal infection with a completely heterologous SHIV. These findings suggest that single chain complexes should be considered as viable candidates for a vaccine against HIV-1.
The positive outcome of the RV144 Phase III vaccine trial has prompted the field to refocus on defining immunogens that can generate humoral immunity as a means of achieving sterilizing immunity. One such immunogen is the Full Length Single Chain (FLSC) a gp120 human CD4 fusion that replicates the conserved envelope-CD4 complex, a key transition state that all HIV isolates must realize during infection. The goal of this project, therefore, is to initiate the preclinical development of FLSC in preparation for its evaluation in Phase I clinical trial as the next step in discerning whether FLSC can be an effective HIV vaccine.
| Schwartz, Jennifer A; Prado, Ilia; Misamore, Johnathan et al. (2016) An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques. Clin Vaccine Immunol 23:618-27 |
| Gallo, Robert C (2015) Developing a Successful HIV Vaccine. J Infect Dis 212 Suppl 1:S40-1 |
| Fouts, Timothy R; Bagley, Kenneth; Prado, Ilia J et al. (2015) Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection. Proc Natl Acad Sci U S A 112:E992-9 |
