Vaccines R&D & Vaccination

Richard T Wyatt, PhD has received his Doctorate in Immunology from Tufts University School of Medicine at the Sackler School of Graduate Biomedical Sciences in Boston, MA. Currently he is a Professor in Immunology in the Department of Immunology and Microbiology at the Scripps Research Institute. He served on the Editorial Board of the Journal of Virology, Frontiers in Immunology and Vaccines. He is a Member of the Scripps CHAVI-ID, the Bill and Melinda Gates Foundation CAVD, the UCSD CFAR Grant Review Committee, is a Member of the AmfAR American Foundation for AIDS Research Cure Working Group and the American Association for the Advancement of Science. He has co-authored over 160 peer-reviewed articles, predominantly focused on the HIV-1 envelope glycoproteins (Env) as antigens and immunogens. He was formerly a Senior Investigator and Chief of the Structural Immunology Section at the Vaccine Research Center at the NIH in Bethesda, MD and is a Charter Member of IAVI’s Neutralizing Antibody Consortium and has been listed on the Thomson-Reuters World’s Most Influential Scientific Minds and Highly Cited Researchers. His research focuses on the structure, function and especially the immunogenicity of the HIV-1 Env, the only virally encoded proteins on the surface of the virus. Because many viral vaccines protect against disease Richard T Wyatt, PhD has received his Doctorate in Immunology from Tufts University School of Medicine at the Sackler School of Graduate Biomedical Sciences in Boston, MA. Currently he is a Professor in Immunology in the Department of Immunology and Microbiology at the Scripps Research Institute. He served on the Editorial Board of the Journal of Virology, Frontiers in Immunology and Vaccines. He is a Member of the Scripps CHAVI-ID, the Bill and Melinda Gates Foundation CAVD, the UCSD CFAR Grant Review Committee, is a Member of the AmfAR American Foundation for AIDS Research Cure Working Group and the American Association for the Advancement of Science. He has co-authored over 160 peer-reviewed articles, predominantly focused on the HIV-1 envelope glycoproteins (Env) as antigens and immunogens. He was formerly a Senior Investigator and Chief of the Structural Immunology Section at the Vaccine Research Center at the NIH in Bethesda, MD and is a Charter Member of IAVI’s Neutralizing Antibody Consortium and has been listed on the Thomson-Reuters World’s Most Influential Scientific Minds and Highly Cited Researchers. His research focuses on the structure, function and especially the immunogenicity of the HIV-1 Env, the only virally encoded proteins on the surface of the virus. Because many viral vaccines protect against disease 

The elicitation of Abs directed toward conserved broadly neutralizing determinants on the HIV envelope glycoprotein (Env) remains a major challenge for an effective vaccine. Most cross-conserved sites are occluded by self N-glycans, limiting naïve B cell recognition of the underlying protein surface. Exceptions are the primary receptor CD4 binding site (CD4bs) and the furin cleavage site. Accordingly, we exposed the CD4bs by eliminating proximal N-glycans by site-directed mutagenesis while maintaining the highly homogeneous, native-like state of the cleavage-independent (NFL) trimers. We arrayed these well-ordered trimers at high-density on liposomal particles to enhance B cell activation and elicitation of neutralizing Abs. Following N-glycan-deleted trimer priming in rabbits, heterologous boosting promotes B cell recognition at cross-conserved sites, coupled with gradual N-glycan restoration to preferentially drive B cells directed to the CD4bs. We demonstrate that this strategy successfully elicited cross-neutralizing Abs detectable in the serum IgG of vaccinated animals. By single B cell FACS-based sorting from the memory compartment of selected rabbits, we isolated two tier 2 cross-neutralizing mAbs. E70 is a CD4bs-directed, N-glycan-dependent cross-mAb with a structure resolved at 3.6 Å by cryoEM. 1C2 is a broadly neutralizing Ab directed to the gp41-gp120 interface region, neutralizing 85% of clinical isolates. Trimer priming followed by heterologous boosting is a successful strategy to elicit bNAbs, validating an epitope-based approach independent of germline targeting. The rabbit immune system can generate HIV-1 bNAbs using completely different VDJ building blocks from the human repertoire. The implications of these results are important as we assess data from other animal models and move forward to clinical testing of relevant candidates toward a real-world vaccine.