{"doi":"10.1002/jia2.26489","title":"Status of HIV vaccine development: progress and promise","abstract":"HIV Vaccine Awareness Day (HVAD) each year commemorates President Bill Clinton's 1997 declaration that “only a truly effective preventive HIV vaccine can limit and eventually eliminate the threat of AIDS.” Here, we review recent progress that the HIV vaccine field has made in inducing protective broadly neutralizing antibodies (bnAbs) that can prevent HIV acquisition. Several papers provide further review and discussion of the concepts discussed in this Viewpoint [1-3]. An HIV bnAb-based vaccine has been difficult to develop because of the extensive genetic variability of HIV, its heavily glycosylated and conformationally masked envelope (Env) surface protein and the need to induce durable high levels of multiple bnAb specificities to achieve protection [4]. In addition, because HIV mutates so rapidly, it will be necessary to induce multiple types of bnAbs to fully cover the broad range of variants. One solution to inducing naturally disfavoured bnAbs is to design immunogens that target naïve bnAb B cell precursors, expand them and select for improbable mutations that are roadblocks for bnAb affinity maturation [5, 6]. Following naïve B cell priming, sequential immunization with Env immunogens with increasing affinities will be needed to mature bnAb lineages along desired pathways [5, 7]. Thus, iterative vaccine design in animal models and in small Phase I clinical trials is required to assess the many steps in such a complex vaccine strategy. Such trials in the HIV Vaccine Trials Network (HVTN) are called Discovery Medicine trials [8]. Figure 1 shows the bnAb target epitopes on the HIV envelope for which a degree of success in inducing B cell lineages has been achieved by vaccination in immunoglobulin humanized mice, non-human primates or humans. What follows here are brief updates on trials that have initiated immunization with bnAb B cell lineages primarily in either non-human primates or in humans by vaccination. Gp41 membrane proximal external region (MPER) bnAbs are among the most broadly reactive HIV antibodies. An MPER peptide-liposome priming immunogen designed to mimic gp41 bnAb binding sites and bind to a prototype bnAb naïve B cell receptor was used in the HVTN 133 clinical trial. B cells were induced that bound to the proximal MPER bnAb epitope—the most potent of these antibodies neutralized 35% of heterologous clade B and 17% of global HIV isolates [9]. The HVTN 133 trial demonstrated that antibody mutations that take years to develop in people living with HIV (PLWH) can be induced by vaccination in months. Work is ongoing to expand the breadth and potency of induced bnabs by the design of boosting immunogens to target MPER sequences of contemporary global HIV strains. CD4 binding site (CD4bs) bnAbs are both potent and broad and thus represent key vaccine targets. There are two types of CD4bs bnAbs, which include those that mimic CD4 binding through a gene-restricted CDRH2 motif and others that utilize CDRH3 to bind the CD4bs [4]. CD4bs immunogens are based on HIV envelope (Env) proteins identified during natural infection or engineered to bind to either type of CD4bs bnAb precursor B cell lineages. These immunogens successfully activate and expand CD4 mimicking CD4bs naïve B cell precursors and intermediate antibodies in humanized mouse strains [10], non-human primates [11, 12] and humans [13]. CDRH3-mediated neutralizing antibody lineages have also been induced in the HVTN 300 trial using a stabilized germline-targeting Env trimer [14]. CD4bs immunogens are being tested in a number of clinical trials including IAVI 002, HVTN 301, HVTN 320, HVTN 321, ACTG 5422 and IAVI C101. V3-glycan bnAbs require long CDRH3 segments or nucleotide insertion mutations and thus are disfavoured by the immune system. However, using germline-targeting immunogens that bind to particular V3-glycan bnAb naïve B cell precursors, V3-glycan bnAb precursors have been induced in non-human primates (NHPs) [15] and in humanized mice [16]. V3-","journal":"Journal of the International AIDS Society","year":2025,"id":521208,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9631,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":230387,"name":"Kevin O. Saunders","orcid":"0000-0001-7399-7954","position":1,"is_corresponding":false},{"id":91120,"name":"Beatrice H. Hahn","orcid":"0000-0002-9400-9887","position":2,"is_corresponding":false},{"id":274230,"name":"Kevin Wiehe","orcid":"0000-0001-9933-9618","position":3,"is_corresponding":false},{"id":3841,"name":"Lindsey R. Baden","orcid":null,"position":4,"is_corresponding":false},{"id":253820,"name":"George M. Shaw","orcid":"0000-0002-2338-4532","position":5,"is_corresponding":false},{"id":96347,"name":"Barton F. Haynes","orcid":"0000-0002-7643-9023","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-19T02:49:44.558743Z","pmid":"40375607","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}