{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T02:00:31Z","timestamp":1780192831265,"version":"3.54.0"},"posted":{"date-parts":[[2026,5,27]]},"group-title":"HIV\/AIDS","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["UM1 AI068614"],"award-info":[{"award-number":["UM1 AI068614"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["UM1 AI068635"],"award-info":[{"award-number":["UM1 AI068635"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["UM1 AI068618"],"award-info":[{"award-number":["UM1 AI068618"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["5UM1AI069470"],"award-info":[{"award-number":["5UM1AI069470"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The isolation of many HIV broadly neutralizing antibodies (bnAbs) from people living with HIV (PLWH) and rigorous characterization of their ontogeny has promoted the goal of reverse engineering their natural development as a strategy for achieving an effective preventive HIV vaccine. We previously described the developmental process of CH103, a CD4-binding site (CD4bs)-specific monoclonal antibody, and the associated evolution of HIV Envelopes (Envs) within the person (CH505) from whom it was isolated. A series of monomeric gp120 protein subunit immunogens representing the transmitted founder (TF) and Envs that evolved during infection and optimally reacted with lineage members at each step of the CH103 clone maturation path were evaluated in this placebo controlled randomized vaccine trial to test--for the first time in humans--the concept of whether sequential immunization with gp120 monomeric proteins can recapitulate the development of CD4bs B-cell clonal lineages, including CH103.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>HIV Vaccine Trials Network 115 (HVTN 115) was a randomized placebo-controlled vaccine trial at US clinical research sites. We tested the safety and immunogenicity of CH505TF gp120 + GLA-SE (Part A), and then the ability of sequential CH505 gp120 proteins (corresponding to CH505\u2019s weeks 53 and 78 Envs) + GLA-SE immunizations to induce CD4bs-specific neutralizing antibodies (Part B). We assessed binding and neutralizing antibody responses, antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis, T-cell responses and B-cell phenotyping.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We enrolled 42 participants between October 2017 and May 2018 for Part A, and 65 participants from December 2020 to October 2022 for Part B. Immunization with the CH505 gp120 proteins adjuvanted with GLA-SE was well tolerated and induced CD4bs-specific B cells and Env-specific plasma antibodies. The plasma neutralizing antibody response was limited to primarily tier 1 autologous and heterologous HIV-1 strains. Blood-derived B-cell repertoire analyses identified CD4bs antibodies that preferentially bound to open-occluded trimeric Envs that exist in an intermediate state between prefusion-closed to CD4-bound open confirmations, consistent with tier 1 HIV neutralizing activity.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, these results suggest that the low-affinity CH505TF gp120 monomer elicited CD4bs antibodies in the sera and B-cell repertoires of humans. However, our findings also indicate that gp120 monomers are insufficient to induce detectable bnAb precursors to epitopes on native Env trimers. Nonetheless, our data provide a benchmark for comparison with ongoing clinical trials testing high-affinity CH505 Env trimers for induction of CD4bs bnAb precursors.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.26.26353896","type":"posted-content","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T02:25:16Z","timestamp":1779935116000},"source":"Crossref","is-referenced-by-count":0,"title":["A phase 1 randomized controlled trial to evaluate the safety and immunogenicity of a HIV monomeric gp120 protein B-cell lineage targeting HIV vaccine in healthy adults"],"prefix":"10.64898","author":[{"given":"James J.","family":"Kobie","sequence":"first","affiliation":[{"name":"University of Alabama at Birmingham, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilton B.","family":"Williams","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William O.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul T.","family":"Edlefsen","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret Brewinski","family":"Isaacs","sequence":"additional","affiliation":[{"name":"Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurine D.","family":"Miner","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Rachael","family":"Parks","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijun","family":"An","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Yurdadon","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Spreng","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongln","family":"Hwang","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Clark","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav","family":"Jain","sequence":"additional","affiliation":[{"name":"The Duke Molecular Physiology Institute, Duke University, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon G.","family":"Gregory","sequence":"additional","affiliation":[{"name":"The Duke Molecular Physiology Institute, Duke University, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Berry","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Wiehe","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Goepfert","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Van","family":"Tieu","sequence":"additional","affiliation":[{"name":"Laboratory of Infectious Disease Prevention, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, Columbia University Irving Medical Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Keefer","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Rochester, Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey R.","family":"Baden","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Brigham & Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyros","family":"Kalams","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Morgan","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Montefiori","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Regenold","sequence":"additional","affiliation":[{"name":"Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia D.","family":"Tomaras","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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