B-cell Lineage Envelope Design

The RV144 Thai vaccine trial had a marginal 31% efficacy. The protective effect was short-lived, and anti-HIV-1 CD8+ T cell responses were not induced by the vaccine. Therefore, a critical need is to improve upon the RV144 trial by making an immunogen that induces higher levels and a longer duration of protective anti-HIV-1 immune responses. A 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.

Through the "B-cell Lineage Envelope Design" grant, Dr. Barton Haynes and colleagues at the Duke Human Vaccine Institute seek to develop HIV-1 envelope immunogens that would improve upon the results of the RV144 trial by using B lineage-based vaccine design, which is 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. Therefore, B lineage-based vaccine design is the design of vaccine immunogens with optimal binding to reverted unmutated ancestors (putative mimics of B cell receptors of naïve B cells) of the desired mutated antibody that is to be elicited by the vaccine. The research team will focus on the evaluation of antibodies as candidates for correlates of protection in RV144.

The objectives of this project are to:

  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 non-human primate models with recombinant monoclonal antibodies from ALVAC gp120 E prime, B/E gp120 boost
  3. Determine the 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 non-human primate models to induce durable protective antibodies at mucosal sites

For more information on this project, please visit the Haynes: B-cell Lineage Envelope Design webpages on the CAVD website.