Aug 2026· Current Opinion in HIV and AIDS· 0 citations· 76 references
Medicine
TL;DR
Progress toward a protective CD4bs-directed HIV-1 vaccine will require further optimization of adjuvants, delivery systems, and sequential immunogen design to balance precursor recruitment with structural constraint and to sustain affinity maturation across multidose regimens.
Abstract
Purpose
OF REVIEW
To summarize current preclinical and clinical efforts to induce CD4bs-directed broadly neutralizing antibodies (bnAbs) against HIV-1 Env using germline-targeting and lineage-based vaccination strategies, and to highlight how differences in immunogen design, particularly along gradients of precursor affinity and structural constraint, shape VRC01-class responses and inform subsequent shaping and polishing steps in vaccine regimens.
RECENT
Findings
Phase 1 trials of CD4bs-directed germline-targeting immunogens have shown that VRC01-class precursors can be reproducibly expanded in humans. Smaller gp120-based immunogens exhibit higher precursor affinity and recruit larger, more diverse VRC01-class pools, whereas native-like trimers prime fewer lineages but drive more on-track somatic hypermutation, early glycan accommodation, and neutralization of heterologous viruses. In parallel, preclinical work is centred around the selection of shaping and polishing immunogens, alternative dosing strategies, and controlled-release or mRNA-LNP platforms to extend maturation.
SUMMARY
With proof-of-concept for VRC01-class priming being achieved, the next challenge is to induce strong serum antibodies and memory B cells with breadth and potency. Progress toward a protective CD4bs-directed HIV-1 vaccine will require further optimization of adjuvants, delivery systems, and sequential immunogen design to balance precursor recruitment with structural constraint and to sustain affinity maturation across multidose regimens, ultimately driving rare lineages to durable bnAb responses in diverse populations.
PURPOSE OF REVIEW
Since our last review of progress in inducing HIV broadly neutralizing antibodies (bnAbs) in 2023, advances have been made in achieving bnAb induction in humans. The purpose of this review is to discuss this progress and to outline remaining tasks needed to complete a prototype HIV vaccine.
RECENT FINDINGS
Several published clinical trials have succeeded in inducing bnAb precursors of multiple types, including membrane proximal external region (MPER), CD4+-mimicking CD4+-binding site (bs) and HCDR3-dominant CD4bs. Trials are underway or nearing completion for inducing V2-apex and V3-glycan bnAb precursors.
SUMMARY
Progress is being made in developing vaccine immunogens that induce bnAb B cell lineages in humans. The next tasks are to design boosting immunogens that complete bnAb affinity maturation, and to do so for two to three different bnAb specificities to prevent transmitted-founder virus escape during HIV transmission. A final task is to utilize a vaccine platform that will induce high-tittered, durable serum bnAb activity capable of providing protection for multiple years.
Barton F. Haynes, Chen-Hao Yeh, L. Baden· Current Opinion in HIV and A...· 0 citations
HIV vaccine development has been exceptionally challenging, for myriad reasons. Nevertheless, protective HIV broadly neutralizing antibodies (bnAbs) exist and have been proposed as templates for vaccine development. Germline-targeting is a conceptually radical approach to vaccine design, aiming to prime rare bnAb-precursor B cells possessing pre-determined human genetic sequence motifs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous booster vaccines. While the approach has shown promise, it faces many novel immunological challenges, commonly thought to be insurmountable in aggregate. To date, germline-targeting has not succeeded in generating bnAbs in nontransgenic animals.
Here, we report a germline-targeting vaccine tested in outbred nonhuman primates that successfully generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates.
Neutralizing Ab clones were generated in ≥ 50% of animals, achieving a remarkable aggregate 62% neutralization breadth compared to the reference bnAb. 200 different bnAb-class clonal families were primed. The vaccine generated large and diverse bnAb-class clonal lineages, including multiple lineages containing > 1,000 memory cells. Furthermore, serum bnAb activity developed in 44% of animals; in the most striking instance serum bnAb breadth reached 84% that of BG18.
These results demonstrate that germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs through the priming and maturation of rare precursor B cells under endogenous conditions. Simultaneously, these results also demonstrate fundamental immunological findings, including demonstration that exceptionally rare B cells can be primed and recruited into germinal centers, competitive within germinal centers, affinity matured for extended periods, differentiated into memory B cells, boosted repeatedly with new immunogens, and differentiated into large numbers of bnAb plasma cells.
NIH NIAID CHAVD UM1 AI144462
Vaccines and Immunotherapy (VAC)
S. Crotty, Jon M. Steichen, Patrick J. Madden et al.· Journal of Immunology· 0 citations
Inducing broadly neutralizing antibodies (bnAb) is a central challenge in HIV vaccine development. The HIV envelope (Env) fusion peptide (FP) is a highly conserved bnAb epitope, yet is inefficiently targeted by antibodies elicited by experimental vaccines. Here, we test how Env trimer design and dosing strategies shape the magnitude and specificity of antibody responses by pairing FP priming with boosts using native-like Env trimers. Escalating-dose (ED) immunization regimens are a recently described approach to deliver antigens over a prolonged period, resulting in sustained increased antigen stability in the lymph node and germinal-center activity, improved immune kinetics, and enhanced recruitment and selection of targeted B-cell populations. The impact of ED regimens on boosting HIV-1 FP-specific responses has not been explored.
Here, guinea pigs (n = 5 per group) were primed with FP-rTTHC followed by boosts with prefusion trimers from clade A (BG505), clade C (ConC), or a Triple-Tandem-Trimer (three trimeric units of ConC, linked one after another: ConC-DS-14ln-TTT), delivered either as bolus injections or ED regimens.
All strategies elicited strong Env-specific responses, but the quality of these responses varied among immunogen designs. Bolus boosts using BG505 or ConC generated the most robust FP-specific recall responses, but neutralization levels ultimately converged across regimens. However, the TTT trimer expanded reactivity to non-FP epitopes, suggesting broader epitope engagement during boosting. Notably, cross-reactive BG505-binding antibodies appeared as early as week 6 after two FP primes, highlighting rapid activation of FP-targeting B cells.
These findings clarify how trimer architecture and dosing influence the trajectory of epitope targeting, strengthening the case for FP priming as a powerful method for engaging a vulnerable HIV Env epitope and demonstrating that the TTT platform may serve as an effective boost to epitopes beyond FP.
N/A
Vaccines and Immunotherapy (VAC)
Shreyanshu Ray, Cheng Cheng, K. McKee et al.· Journal of Immunology· 0 citations
Human immunodeficiency virus type 1 remains a major global health challenge, with persistent transmission despite advances in antiretroviral therapy and preventive interventions. The viral envelope glycoproteins gp120 and gp41, organized as trimeric spikes on the virion surface, mediated host cell entry and represented the principal targets of neutralizing antibodies; however, extensive glycan shielding, conformational masking, and genetic variability historically hindered vaccine development. The purpose of this review was to critically evaluate current progress in mRNA vaccine platforms encoding HIV 1 envelope glycoproteins and to examine their potential to overcome longstanding immunological barriers. A structured narrative synthesis of recent preclinical and early clinical studies, integrated with advances in structural biology and molecular engineering, was undertaken to assess emerging evidence. Accumulating data indicated that mRNA platforms permitted precise encoding of stabilized envelope trimers, germline targeting constructs, and mosaic immunogens, resulting in improved antigen expression and enhanced induction of neutralizing antibody precursors in animal models and early human trials. Nevertheless, induction of broadly neutralizing antibodies with sufficient breadth and durability remained elusive. mRNA-based approaches provided unprecedented flexibility and translational promise for HIV vaccine design, yet required iterative immunogen optimization and rigorous clinical evaluation to achieve meaningful protective efficacy.
Keywords: HIV 1, mRNA vaccine, Envelope glycoprotein, Broadly neutralizing antibodies, Structural vaccinology.
Arionget Jemima· IDOSR Journal of Scientific...· 0 citations
Induction of broadly neutralizing antibody (bnAb) responses remains a central challenge to designing efficacious HIV vaccines. Lineage design strategies, in which bnAb precursors are guided via iterative immunizations to their mature forms, depend on high levels of somatic mutation and the recall of antigen-specific B cells. Recent studies have identified spatial context as an important determinant of boosting efficacy, but the application of this to HIV vaccines and the underlying mechanisms are incompletely understood. Here, using mice harboring a V3-glycan bnAb lineage precursor knock-in combined with lineage-tracing and single-cell analyses, we show that persistent germinal centers (GCs) support continued affinity maturation of founder clones and ipsilateral boosting preferentially engages these lineages in secondary GCs. In contrast, contralateral boosting predominantly recruits naïve B cells and memory B cells not directed towards the immunizing antigen. The few memory cells recruited at this site were biased towards a plasma cell fate. Finally, we identify disfavored mutational trajectories within the V3-glycan bnAb lineage, revealing intrinsic constraints on bnAb lineage evolution.
John S. Barber, K. Tonouchi, Chen-Hao Yeh et al.· bioRxiv· 0 citations
ABSTRACT To identify strategies for augmenting vaccine immunogenicity, we compared a pox-protein prime-boost regimen comprising recombinant modified vaccinia virus Ankara and multimeric HIV-1 Env gp145, adjuvanted with Army Liposomal Formulation (ALF) either adsorbed to aluminum salt (ALFA) or formulated with the QS-21 saponin (ALFQ), in rhesus macaques. ALFQ promoted greater magnitude and more durable humoral and cellular immune responses than ALFA, which exhibits similar immunogenicity to aluminum-based adjuvants. Peak Env-specific CD4+ T cell responses assessed by intracellular cytokine staining were 10-fold greater with ALFQ, and CD8+ T cell responses were unexpectedly robust, averaging greater than 1%. ALFQ induced higher levels of several immunostimulatory cytokines in plasma, which correlated with adaptive immune responses. However, vaccination did not protect against heterologous intrarectal challenge with transmitted/founder SHIV-CH505. We provide evidence that CH505 Env may maintain a relatively closed conformation, rendering it less susceptible to targeting by Fc-mediated antibody functions. Overall, ALFQ is a promising adjuvant to improve antibody and T cell response magnitude. IMPORTANCE An effective and durable vaccine preventing HIV-1 acquisition is urgently needed to end the HIV-1 pandemic. To date, of the nine vaccine efficacy trials conducted in humans, only the RV144 vaccine trial demonstrated efficacy in reducing infections, although immune responses waned rapidly. We evaluated a modified HIV-1 vaccine regimen incorporating next-generation adjuvants to improve immune responses and vaccine efficacy in a gold standard, pre-clinical primate model. Adjuvanted protein boosting markedly increased antibody, T cell, and pro-inflammatory response magnitude. These data, combined with the adjuvant’s strong safety and immunogenicity track record in clinical trials, indicate that novel adjuvants represent a promising strategy for improving immune responses to protein immunogens. Future vaccine regimens against HIV-1 and other pathogens for which eliciting robust immunity has been difficult may benefit from incorporating these or related next-generation adjuvants. An effective and durable vaccine preventing HIV-1 acquisition is urgently needed to end the HIV-1 pandemic. To date, of the nine vaccine efficacy trials conducted in humans, only the RV144 vaccine trial demonstrated efficacy in reducing infections, although immune responses waned rapidly. We evaluated a modified HIV-1 vaccine regimen incorporating next-generation adjuvants to improve immune responses and vaccine efficacy in a gold standard, pre-clinical primate model. Adjuvanted protein boosting markedly increased antibody, T cell, and pro-inflammatory response magnitude. These data, combined with the adjuvant’s strong safety and immunogenicity track record in clinical trials, indicate that novel adjuvants represent a promising strategy for improving immune responses to protein immunogens. Future vaccine regimens against HIV-1 and other pathogens for which eliciting robust immunity has been difficult may benefit from incorporating these or related next-generation adjuvants.
Hannah A. D. King, C. Subra, Emily Tourtellott et al.· Journal of Virology· 0 citations
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