HIV BG505 SOSIP.664 trimer with 3M-052-AF/alum induces human autologous tier-2 neutralizing antibodies

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140, formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding and immunogenicity in a first-in-healthy adult (n=17), randomized, placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, B-cell and CD4+ T-cell responses emerged post-vaccination. Five vaccinees developed serum autologous tier-2 nAbs (ID50 titer, 1:28-1:8647) after 2-3 doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B-cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes. KEY TAKEAWAY/TAKE-HOME MESSAGES HIV BG505 SOSIP.664 trimer with novel 3M-052-AF/alum adjuvant in humans appears safe and induces serum neutralizing antibodies to matched clade A, tier 2 virus, that map to diverse Env epitopes with relatively high titers. The novel adjuvant may be an important mediator of vaccine response. ### Competing Interest Statement NR is a safety clinical trial consultant for ICON and EMMES, serves on the advisory boards for Sanofi, Seqirus and Moderna, and Emory receives funds for NR to conduct research from Sanofi, Lilly, Merck, Quidel and Pfizer. MT is a contract worker for 3M. Fred Hutch Cancer Center receives funds for MJM to conduct research from Janssen, Sanofi, Regeneron and Moderna. ### Clinical Trial NCT04177355 ### Funding Statement The trial was funded through National Institute of Allergy and Infectious Disease of the National Institutes of Health under Grants UM1 AI068614 [HVTN LOC], UM1 AI068635 [HVTN SDMC], and UM1 AI068618 [HVTN LC], UM1 AI069481 [Seattle CTU], and AI110657 HIVRAD [JPM]. Funding from the Gates Foundation OPP1107954 to Fred Hutchison (MJM) for the manufacture/formulation of 3M-052 AF, and nonclinical studies; OPP1147661 to IAVI for GMP manufacturing of the trimer protein supply for this study; INV-002022 [RWS] and INV-002916 to Scripps/Ward lab for early EMPEM analyses [ADW]. ### 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: Fred Hutchinson Cancer Center Institutional Review Board (FHIRB0010314) approved the study protocol and procedures. 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][1]. 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 Most data underlying the figures and tables can be found in the paper or the online supplemental material. FCS files from flow cytometry studies are available from the corresponding author upon reasonable request. The EMPEM representative maps ( Fig. S1) are available in Electron Microscopy Data Bank (). The remainder of the data underlying this study are not publicly available due to potential privacy issues. [1]: http://ClinicalTrials.gov