Vaccine Induction in Humans of Polyclonal HIV-1 Heterologous Neutralizing Antibodies

A major roadblock to the development of a safe and effective HIV-1 vaccine has been the inability to induce broadly neutralizing antibodies (bnAbs) in humans. Potent HIV-1 bnAb induction is disfavored by both host and viral factors. A Phase I clinical trial was conducted with a peptide/liposome immunogen targeting the unmutated ancestor of a HIV-1 envelope gp41 membrane proximal external region (MPER) bnAb B cell lineage ([NCT03934541][1]). Here, we report vaccine induction of a polyclonal heterologous nAb response in humans of gp41 MPER bnAb precursor and intermediate lineage B cells, the most potent of which neutralized difficult-to-neutralize tier 2 HIV-1 strains. Thus, this study demonstrates a proof-of-concept for vaccine induction of heterologous HIV-1 neutralizing B cell responses in humans and provides hope that development of a preventive Ab-inducing HIV-1 vaccine may ultimately be possible. Summary paragraph A major roadblock to the development of a safe and effective HIV-1 vaccine has been the inability to induce broadly neutralizing antibodies (bnAbs) in humans ( [1][2], [2][3] ). However, potent HIV-1 bnAb induction by vaccines is disfavored by both host immune tolerance and virus envelope (Env) structural constraints ( [3][4], [4][5] ). While bnAbs develop in HIV-1-infected individuals, they do so rarely and only after years of infection ( [5][6]–[7][7] ). To date, induction of Abs that neutralize HIV-1 heterologous, difficult-to-neutralize HIV strains has not been achieved by vaccination. Here, we show vaccine induction in humans of HIV-1 antibodies capable of neutralizing multiple difficult-to-neutralize HIV-1 strains. The immunogen used was a HIV-1 envelope peptide complexed with a liposome that targets a membrane proximal external region (MPER) bnAb gp41-epitope ( [8][8]–[10][9] ). Successful MPER-directed bnAbs bind to both gp41 polypeptide and to the adjacent virion lipid bilayer. Structural studies demonstrated multiple vaccine-induced modes of bnAb epitope recognition. BnAb B cell lineage analysis demonstrated that vaccine-induced antibodies had progressed to an intermediate stage of bnAb development, with incomplete ability to optimally bind to virion lipids, thus limiting full development of bnAb potency and breadth. Thus, this study demonstrates a proof-of-concept for vaccine induction of heterologous HIV-1 neutralizing B cell responses in humans and provides hope that development of a preventive antibody-inducing HIV-1 vaccine may ultimately be possible. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03934541 ### Funding Statement Supported by the HHS, NIH, NIAID, Division of AIDS, Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) grant AI100645, by the HHS, NIH, NIAID, Division of AIDS Consortia for HIV/AIDS Vaccine Discovery (CHAVD) grant AI144371, by the HHS, NIH, NIAID, Center for HIV Structural Biology grant U54 AI170752, and by a Collaboration for AIDS Vaccine Development (CAVD) grant, OPP1094352/INV-007688, from the Bill & Melinda Gates Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was reviewed and approved by the institutional review boards at all sites (Brigham and Women's Hospital, Fenway, Columbia University, New York Blood Center, University of Alabama Birmingham, and Fred Hutchinson Cancer Research Center) and written informed consent was obtained from each participant prior to enrollment. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available online upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03934541&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F14%2F2023.03.09.23286943.atom [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #ref-5 [7]: #ref-7 [8]: #ref-8 [9]: #ref-10