ALBERT

Description: Development of broadly neutralizing antibodies (bnAbs) against HIV-1 usually requires prolonged infection and induction of Abs with unusual features, such as long heavy-chain complementarity-determining region 3 (HCDR3) loops. Here we sought to determine whether the repertoires of HIV-1–naïve individuals contain Abs with long HCDR3 loops that could mediate HIV-1 neutralization....

Description: A challenge for HIV-1 immunogen design is the difficulty of inducing neutralizing antibodies (NAbs) against neutralization-resistant (tier 2) viruses that dominate human transmissions. We show that a soluble recombinant HIV-1 envelope glycoprotein trimer that adopts a native conformation, BG505 SOSIP.664, induced NAbs potently against the sequence-matched tier 2 virus in rabbits and similar but weaker responses in macaques. The trimer also consistently induced cross-reactive NAbs against more sensitive (tier 1) viruses. Tier 2 NAbs recognized conformational epitopes that differed between animals and in some cases overlapped with those recognized by broadly neutralizing antibodies (bNAbs), whereas tier 1 responses targeted linear V3 epitopes. A second trimer, B41 SOSIP.664, also induced a strong autologous tier 2 NAb response in rabbits. Thus, native-like trimers represent a promising starting point for the development of HIV-1 vaccines aimed at inducing bNAbs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498988/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498988/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanders, Rogier W -- van Gils, Marit J -- Derking, Ronald -- Sok, Devin -- Ketas, Thomas J -- Burger, Judith A -- Ozorowski, Gabriel -- Cupo, Albert -- Simonich, Cassandra -- Goo, Leslie -- Arendt, Heather -- Kim, Helen J -- Lee, Jeong Hyun -- Pugach, Pavel -- Williams, Melissa -- Debnath, Gargi -- Moldt, Brian -- van Breemen, Marielle J -- Isik, Gozde -- Medina-Ramirez, Max -- Back, Jaap Willem -- Koff, Wayne C -- Julien, Jean-Philippe -- Rakasz, Eva G -- Seaman, Michael S -- Guttman, Miklos -- Lee, Kelly K -- Klasse, Per Johan -- LaBranche, Celia -- Schief, William R -- Wilson, Ian A -- Overbaugh, Julie -- Burton, Dennis R -- Ward, Andrew B -- Montefiori, David C -- Dean, Hansi -- Moore, John P -- 280829/European Research Council/International -- HHSN27201100016C/PHS HHS/ -- P01 AI082362/AI/NIAID NIH HHS/ -- P51 OD011106/OD/NIH HHS/ -- P51OD011106/OD/NIH HHS/ -- R01 AI076105/AI/NIAID NIH HHS/ -- R01 AI084817/AI/NIAID NIH HHS/ -- R37 AI036082/AI/NIAID NIH HHS/ -- R56 AI084817/AI/NIAID NIH HHS/ -- T32 GM007266/GM/NIGMS NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):aac4223. doi: 10.1126/science.aac4223. Epub 2015 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA. Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, Netherlands. jpm2003@med.cornell.edu rws2002@med.cornell.edu. ; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, Netherlands. ; Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, Neutralizing Antibody Center, and Collaboration for AIDS Vaccine Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA. ; International AIDS Vaccine Initiative, Neutralizing Antibody Center, and Collaboration for AIDS Vaccine Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA. ; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. ; International AIDS Vaccine Initiative, New York, NY 10004, USA. ; Pepscan Therapeutics, 8243RC Lelystad, Netherlands. ; Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA. ; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. ; Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, Neutralizing Antibody Center, and Collaboration for AIDS Vaccine Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10004, USA. Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA. ; International AIDS Vaccine Initiative, Neutralizing Antibody Center, and Collaboration for AIDS Vaccine Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA. Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, Neutralizing Antibody Center, and Collaboration for AIDS Vaccine Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, CA 92037, USA. Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA. ; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA. jpm2003@med.cornell.edu rws2002@med.cornell.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089353" target="_blank"〉PubMed〈/a〉

Description: An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562404/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562404/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Williams, Wilton B -- Liao, Hua-Xin -- Moody, M Anthony -- Kepler, Thomas B -- Alam, S Munir -- Gao, Feng -- Wiehe, Kevin -- Trama, Ashley M -- Jones, Kathryn -- Zhang, Ruijun -- Song, Hongshuo -- Marshall, Dawn J -- Whitesides, John F -- Sawatzki, Kaitlin -- Hua, Axin -- Liu, Pinghuang -- Tay, Matthew Z -- Seaton, Kelly E -- Shen, Xiaoying -- Foulger, Andrew -- Lloyd, Krissey E -- Parks, Robert -- Pollara, Justin -- Ferrari, Guido -- Yu, Jae-Sung -- Vandergrift, Nathan -- Montefiori, David C -- Sobieszczyk, Magdalena E -- Hammer, Scott -- Karuna, Shelly -- Gilbert, Peter -- Grove, Doug -- Grunenberg, Nicole -- McElrath, M Juliana -- Mascola, John R -- Koup, Richard A -- Corey, Lawrence -- Nabel, Gary J -- Morgan, Cecilia -- Churchyard, Gavin -- Maenza, Janine -- Keefer, Michael -- Graham, Barney S -- Baden, Lindsey R -- Tomaras, Georgia D -- Haynes, Barton F -- P30 AI064518/AI/NIAID NIH HHS/ -- P30-AI-64518/AI/NIAID NIH HHS/ -- U01 AI069412/AI/NIAID NIH HHS/ -- UM1 AI068614/AI/NIAID NIH HHS/ -- UM1 AI068618/AI/NIAID NIH HHS/ -- UM1 AI068635/AI/NIAID NIH HHS/ -- UM1 AI069412/AI/NIAID NIH HHS/ -- UM1 AI069470/AI/NIAID NIH HHS/ -- UM1 AI069481/AI/NIAID NIH HHS/ -- UM1 AI069511/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- UM1AI068618/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 14;349(6249):aab1253. doi: 10.1126/science.aab1253. Epub 2015 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. barton.haynes@duke.edu wilton.williams@duke.edu. ; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. ; Department of Microbiology, Boston University School of Medicine, Boston, MA, USA. ; Department of Medicine, Columbia University Medical Center, New York, NY, USA. ; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ; The Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; The Aurum Institute, Johannesburg, South Africa. ; University of Rochester School of Medicine, Rochester, NY, USA. ; Brigham and Women's Hospital, Boston, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26229114" target="_blank"〉PubMed〈/a〉

Description: 〈p〉Characterizing the antigen-binding and innate immune-recruiting properties of the humoral response offers the chance to obtain deeper insights into mechanisms of protection than revealed by measuring only overall antibody titer. Here, a high-throughput, multiplexed Fab-Fc Array was employed to profile rhesus macaques vaccinated with a gp120-CD4 fusion protein in combination with different genetically encoded adjuvants, and subsequently subjected to multiple heterologous simian immunodeficiency virus (SIV) challenges. Systems analyses modeling protection and adjuvant differences using Fab-Fc Array measurements revealed a set of correlates yielding strong and robust predictive performance, while models based on measurements of response magnitude alone exhibited significantly inferior performance. At the same time, rendering Fab-Fc measurements mathematically independent of titer had relatively little impact on predictive performance. Similar analyses for a distinct SIV vaccine study also showed that Fab-Fc measurements performed significantly better than titer. These results suggest that predictive modeling with measurements of antibody properties can provide detailed correlates with robust predictive power, suggest directions for vaccine improvement, and potentially enable discovery of mechanistic associations.〈/p〉

Description: A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell...

Description: Most simian–human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375,...