Gallo: FLSC Phase I & II Clinical Trials
Partial efficacy observed in a recently completed Thai Phase IIb trial (RV144) helped to guide the short-term development of HIV preventive vaccines and to underscore the need for increased potency and durability of immune responses. Protection in RV144 was most likely afforded by cross-reactive antibodies recognizing the viral envelope protein. Accordingly, improved Env-based immunogens should be tested for their capacity to improve protective immunity when used in prime/boost regimens similar to RV144. The Gallo research team postulates that the monomeric gp120 protein used in RV144 was likely the "weakest" component of the vaccine. Env monomers typically elicited only type-specific antibody responses and did not protect against HIV infection in earlier trials. By substituting a different envelope construct capable of raising cross-reactive antibodies and protecting against heterologous virus challenge in nonhuman primates, the overall protection after a prime/boost regimen may be improved.
The researchers propose that a conformationally constrained and stabilized gp120, embodied by a full-length single chain gp120-CD4 complex (FLSC), has properties that will focus immune responses and better protect against HIV. Four macaque studies supported this concept. In their initial study, a single chain complex containing rhesus CD4 (rhFLSC, engineered specifically for macaque studies) elicited antibody responses against highly conserved gp120 epitopes and afforded non-sterilizing control of both plasma and tissue viremia following a single high-dose heterologous mucosal challenge with SHIV162P3. A second study showed that protection depended on vaccine dose. A third study, using multiple low dose virus challenges, showed rhFLSC immunization provided an interval of sterilizing protection against the same SHIV strain. A fourth study confirmed the third study and also showed that non-selective T-cell activation diminished the efficacy of FLSC. Overall, these experiments correlated protection with responses to highly conserved gp120 epitopes presented on a gp120-CD4 complex, including but not limited to ones termed CD4-induced (CD4i), and other functional assays showed some correlation with ADCC.
The research team seeks to develop the FLSC as a new immunogen that can be used alone or in combination with vCP1521, to improve upon the efficacy observed in RV144. This program includes production of the FLSC clinical trial materials, performance of the required detailed studies on epitope availability and immunogenicity for Env in vCP1521 and FLSC expressed in a new ALVAC recombinant, preclinical safety studies, evaluation of safety and immunogenicity for FLSC in a Phase 1 clinical trial, and supportive studies in Rhesus macaques to define the potential efficacy provided by FLSC when combined with vCP1521 as well as an exploration of different adjuvants. Proposed Phase II clinical studies will be performed in collaboration with investigators at Sanofi-Pasteur and the Military HIV Research Program, to define an optimal immunization strategy that will increase the longevity of humoral responses and extend the interval of protection. Based on these studies, follow-on Phase 2B and/or 3 clinical trials will be designed to evaluate the efficacy of vCP1521/FLSC prime/boost or FLSC alone.
1. Preclinical development and Phase I clinical testing of FLSC to identify a safe and immunogenic dose of FLSC/Alum that will be carried into Phase II studies
2. Evaluate FLSC in Phase IIa clinical trials in combination with vCP1521
3. Develop the concept of ALVAC prime/protein boost vaccines based on constrained gp120 structures. Determine whether the envelope encoded by ALVAC vCP1521 already encodes a constrained gp120 immunogen by virtue of the envelope construction like our FLSC. Develop versions of vCP1521 that express either soluble or membrane-anchored FLSC.
4. Non-Human Primate studies –
a. Compare the protection afforded by an ALVAC-gp120 (vCP1521) prime, FLSC boost (rhFLSC/EM005) to empty ALVAC prime, EM005 boost, using nonhuman primates and heterologous, repetitive low dose SHIV challenge.
b. Evaluate the immunogenic potential of FLSC formulated in four different adjuvants using nonhuman primates.