NIH Program Project Grant # P01 AI100151

Results of the RV144 HIV Vaccine Trial in Thai Adults demonstrated modest and transient protection against HIV-1 infection in healthy individuals. To improve the efficacy and duration of the antibody (Ab) response, better immunogens are required. We postulate that Abs induced by novel vaccine constructs will have higher specific activity, with stronger Ab titers and, within the total Ab response, a greater proportion of the Abs needed for protection. Such novel constructs, which could present viral epitopes in a context other than that of the whole envelope (Env), may also obviate the problems of the transient Ab response associated with whole Env. We and others have demonstrated that by focusing the Ab response on V3, cross-clade neutralizing Abs are elicited that remain detectable more than 1 year after immunization.

Therefore, we are extending the platform we previously developed for designing and developing V3-scaffold immunogens in order to create and test new epitope-scaffold protein immunogens that will focus the Ab response on 2 additional sites of vulnerability in the Env: the V2 loop and the cluster of quaternary neutralizing epitopes (QNEs) composed of portions of V2 and V3.

This HIV Research and Design (HIVRAD) Program Project Grant will be composed of:

• Project 1: Vaccines to Induce Functional Abs Targeting the V2 Loop
• Project 2: Rational Design of Immunogens Targeting the HIV-1 V2/V3 Quaternary Neutralizing Epitopes
  • Core A: Administrative Core
  • Core B: Protein Production Core
  • Core C: Animal Studies Core

The epitope-scaffold immunogens to be developed can be used individually or in combination; they will constitute powerful new tools for inducing broad and potent protective Abs. Many of the participants have worked together for >20 years to develop and characterize >100 human mAbs to HIV and other pathogens. Recently, the team has worked collaboratively and synergistically in preparing and analyzing >25 crystals of monoclonal Abs (mAbs) and mAb/epitope complexes, developing DNA Env primes and epitope-scaffold immunogens, and performing immunization experiments. Our experience places us in a strong position to extend our studies to epitopes that only recently have been recognized as important for protection from HIV infection.

By the completion of the proposed program, we plan to have identified epitope-targeting immunogens and immunization protocols that will generate Abs with protective antiviral functions directed specifically toward the conserved regions of the V2 loop and the V2/V3 quaternary neutralizing epitopes of HIV-1 gp120.