The overall mission of this CHAVI-ID application is to define immunogens and immunization regimens that induce sustained HIV cross-protective B cell and CD4+ T cell responses in preclinical models and, thereby, guide product development strategies for a preventive human AIDS vaccine. Focus #1 will concentrate on B cell and antibody research to facilitate the development of immunogens and immunization protocols that elicit protective broadly neutralizing antibody responses. Our overall strategy in this focus can be briefly summarized in the following goals: 1) To fully define a comprehensive map of the broadly neutralizing (bn) epitopes of the HIV Env spike. Breakthroughs in generating broadly neutralizing human monoclonal antibodies (bnMAbs) in the last two years are bringing this goal within reach;2) To determine which of the HIV bnMAbs provide the most effective protection against viral challenge in the non-human primate (NHP) model. At the same time, we shall closely monitor developments in the field, including suggestions that some non-neutralizing antibodies may have protective qualifies that might be exploited in vaccine discovery;3) To determine which HIV broadly neutralizing Abs (bnAbs) are most readily elicited through natural infection and how and when they are elicited using several large cohorts to which we have unique access;4) To determine which immunogens and immunization strategies best stimulate HIV bnAb generation in the knock-in mouse and NHP models, drawing upon data collected on bnAbs in goals 1-3 and emerging from Focus #2. As we gather together information on optimal immunogens and immunization strategies, we will move forward with small-scale human trials with the advice and close involvement of our Vaccine Discovery Scientific Research Support Component.
With 33 million infected individuals worldwide, an HIV vaccine is urgently needed to slow and eventually eliminate new infections. Protection by most licensed vaccines is associated with the induction of neutralizing antibodies. This proposal seeks to discover immunogens and immunization strategies that induce broadly neutralizing antibodies able to protect against exposure to global HIV isolates.
|Sok, Devin; Doores, Katie J; Briney, Bryan et al. (2014) Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV. Sci Transl Med 6:236ra63|
|Murin, Charles D; Julien, Jean-Philippe; Sok, Devin et al. (2014) Structure of 2G12 Fab2 in complex with soluble and fully glycosylated HIV-1 Env by negative-stain single-particle electron microscopy. J Virol 88:10177-88|
|Scharf, Louise; Scheid, Johannes F; Lee, Jeong Hyun et al. (2014) Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep 7:785-95|
|Doria-Rose, Nicole A; Schramm, Chaim A; Gorman, Jason et al. (2014) Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509:55-62|
|Tong, Tommy; Crooks, Ema T; Osawa, Keiko et al. (2014) Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques. Virology 456-457:55-69|
|Li, Shuzhao; Rouphael, Nadine; Duraisingham, Sai et al. (2014) Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Nat Immunol 15:195-204|
|Gitlin, Alexander D; Shulman, Ziv; Nussenzweig, Michel C (2014) Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509:637-40|
|Pulendran, Bali (2014) Systems vaccinology: probing humanity's diverse immune systems with vaccines. Proc Natl Acad Sci U S A 111:12300-6|
|Bates, John T; Keefer, Christopher J; Slaughter, James C et al. (2014) Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein. Virology 454-455:139-44|
|Sundling, Christopher; Zhang, Zhenhai; Phad, Ganesh E et al. (2014) Single-cell and deep sequencing of IgG-switched macaque B cells reveal a diverse Ig repertoire following immunization. J Immunol 192:3637-44|
Showing the most recent 10 out of 58 publications