Haynes: B-Cell Lineage Envelope Design
The RV144 Thai vaccine trial had 31% estimated vaccine efficacy. The protective effect was short-lived, and anti-HIV-1 CD8+ T cell responses were not induced by the vaccine. Thus, a critical need is to improve on the RV144 trial by making an immunogen that induces higher levels and longer duration of protective anti-HIV-1 immune responses. One hypothesis for a correlate of protective immunity in the RV144 trial is that a short-lived antibody prevented HIV-1 acquisition at mucosal sites by one or more mechanisms.
Dr. Barton Haynes and colleagues at the Duke Human Vaccine Institute seek to develop HIV-1 envelope immunogens that improve on the results of the RV144 trial by using B cell lineage-based vaccine design based on two principles. First, inferring the reverted unmutated ancestor of a mutated antibody gives an approximation of the naïve B cell receptor (BCR) from which the antibody originated. Second, the optimal antigens for triggering naïve B cells bind naïve BCRs with the highest affinity. B cell lineage-based vaccine design is therefore the design of vaccine immunogens based on optimal binding to reverted unmutated ancestors (putative mimics of B cell receptors of naïve B cells) of the desired mutated antibody to be elicited. The research team will focus on evaluation of antibodies as candidates for correlates of protection in RV144.
1. Isolate candidate antibodies from RV144, RV305, and RV306 as well as other relevant trials that are candidates for correlates of protective immunity
2. Perform passive protection trials in NHP with recombinant mAbs from ALVAC gp120 E prime, B/E gp120 boost
3. Determine optimal modes of induction of protective antibodies: optimizing germinal center responses and overcoming any host tolerance/anergy controls
4. Design and test new Env immunogens in NHPs to induce durable protective antibodies at mucosal sites
The Haynes team has isolated and characterized four V2 monoclonal antibodies from RV144 vaccinees that recognize residue K169 (a site of immune pressure induced by the vaccine in the RV144 trial), neutralize tier 1 HIV-1, and mediate killing of tier 2 HIV-1-infected CD4 T cells. Crystal structures of two of the RV144 V2 antibodies demonstrate that residue K169 can exist within divergent helical and loop conformations, which contrast dramatically with the beta strand conformation previously observed with the PG9 broadly neutralizing antibody. Thus, RV144 vaccine-induced immune pressure appears to target a region that may be both sequence variable and structurally polymorphic. Variation may signal sites of HIV-1 envelope vulnerability, providing vaccine designers with new options. The team has begun immunization studies with new Envs in NHPs to design strategies for improving on RV144 vaccine efficacy.