Antigen Dose and Persistence Contribute to Induction of a Durable HIV-1-Specific Neutralizing Antibody Response

Antigen Dose and Persistence Contribute to Induction of a Durable HIV-1-Specific Neutralizing Antibody Response | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Antigen Dose and Persistence Contribute to Induction of a Durable HIV-1-Specific Neutralizing Antibody Response Mark Connors, Kenta Matsuda, Mitra Harrison, Eleanor Wettstein, and 40 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5589251/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The immunogenicity of HIV-1 Env glycoprotein (Env) is limited in part by its structural instability and extensive glycan shielding and is likely the greatest obstacle to an HIV-1 vaccine. Stabilized Env trimers can elicit serum neutralizing antibodies but often require many immunizations and the response is short-lived. To understand the parameters that confer a durable neutralizing antibody response, we used a Newcastle Disease Virus-like particle (NDV-VLP) platform to present stabilized versions of HIV-1 Env at high valency and varied the conformational stability, adjuvants, dose, and antigen persistence. Influenza virus hemagglutinin (HA), or SARS-CoV2 Spike (S)-bearing VLPs were used as controls. HA or S bearing VLPs rapidly induced neutralizing antibodies, whereas they were not induced by those bearing Env. A replicating adenovirus type 4 expressing Env rapidly induced autologous neutralizing antibodies, suggesting glycan shielding or the naïve B cell repertoire were not barriers. We then tested the parameters that might approximate a replicating virus infection. Only when multiple features of a virus infection were combined did we observe durable neutralizing antibodies, with the largest impact attributable to dose and escalating dose. Our results suggest that numerous features of a replicating virus infection, including stabilization, spike density, TLR stimulation, total dose, and persistence of antigen, can be combined to improve the immunogenicity of HIV-1 Env. Biological sciences/Immunology/Vaccines/Protein vaccines Biological sciences/Immunology/Adaptive immunity/Humoral immunity/Antibodies Biological sciences/Immunology/Infectious diseases/HIV infections Biological sciences/Immunology/Infectious diseases/Viral infection Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5589251","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":392526415,"identity":"fba7f4c4-a22f-42a4-a2d4-3ef5b3d8ecce","order_by":0,"name":"Mark 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