VRC01 / National Institute of Allergy and Infectious Diseases, Acuitas Therap - LARVOL DELTA

Dynamic PET imaging predicts broadly neutralizing antibody distribution and HIV prevention efficacy. (PubMed, medRxiv) - "Based on our PBPK model, we determined a >51-fold anorectal tissue VRC01 level:inhibitory concentration (IC 80 ) target would achieve 90% prevention efficacy compared to >200 based on plasma levels in the primary trial analysis. Thus, these PET-PBPK approaches are promising for noninvasive determination of bNAb penetration more closely linked with concentrations needed to prevent virus acquisition, and may be leveraged to improve efficient development of bNAbs."

Journal • Human Immunodeficiency Virus • Infectious Disease

Effects and mechanisms of monoclonal and polyclonal human antibodies in protection of humanized mice from HIV-1 challenge. (PubMed, bioRxiv) - "Using these adaptations, we observed that both neutralization and Fc-mediated effector functions contribute to the in vivo antiviral activity of broadly-neutralizing antibody VRC01, that confounding of results due to differences in mAb PK can be overcome, and most promisingly, that polyclonal human serum IgG that exhibits potent neutralizing and Fc-effector function can protect from infection. Collectively, this work demonstrates insights into antibody-mediated protection and methods that hold promise in supporting testing the protection from HIV-1 afforded by human pAb responses induced by vaccination."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials. (PubMed, bioRxiv) - "Escape mutations, primarily located in the Loop-D and β23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs, while more potent CD4bs bnAbs like N6 and 1-18 largely retained their activity. Our findings demonstrate that prophylactic VRC01 can select for viral escape after infection, underscoring the need for next-generation bnAbs with improved breadth and potency to enhance durability and efficacy of antibody-based HIV prevention."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Optimized Expression of CD4-Inducible (CD4i) Epitopes in HIV-1 Vaccine Prototypes Based on Virus-Like Particles (VLPs) (EACS 2025) - "d) Antigenicity was evaluated by VLP ELISA using CD4i antibodies and bNAbs [2F5 (MPER), VRC01 (CD4bs), PG16 (V2)]...However, for bNAbs, CD4 incorporation generally reduced binding per spike by 1.3- to 4.2-folds. Conclusions : Despite some loss in bNAb epitope accessibility, CD4 incorporation into HIV-1 VLPs represents a promising strategy to enhance ADCC activation while retaining some capacity to elicit neutralizing responses."

Human Immunodeficiency Virus • Infectious Disease • CD4

Losing Less in Translation: Relating the Preclinical Evidence Base for Active and Passive Immunity to Prevention of HIV-1 Infection in Humans. (PubMed, J Med Primatol) - "Similarly, the recent Antibody-Mediated Prevention (AMP) trials (HVTN 703, 704), which tested the ability of passive immunization with the broadly neutralizing antibody VRC01, also failed to meet predetermined overall efficacy criteria...We conclude that results from the AMP trials provide a key benchmark that has high value in gauging the clinical prospects of humoral immune responses induced by vaccines or provided by passive antibody prophylaxis. The promise of new knowledge gained through carefully designed testing of new interventions and therapeutics motivates continued exploration of means to model humoral immunity to HIV-1 in preclinical models."

Journal • Preclinical • Review • Human Immunodeficiency Virus • Infectious Disease

Differential contributions of human oligosaccharyltransferase complexes OST-A and OST-B to HIV-1 envelope glycoprotein glycosylation. (PubMed, bioRxiv) - "STT3A/3B knockout (KO) affected the neutralization sensitivity to broadly neutralizing antibodies (bNAbs) in a strain-specific manner with STT3A-KO increasing susceptibility to VRC01 bNAb for the tested HIV-1 strains...In contrast, STT3B-KO appeared to have a more pronounced effect on gp41 glycosylation, suggesting that PNGS located near the C-terminus are more dependent on STT3B. Defining the roles of the OST-A and OST-B complexes in HIV-1 Env glycosylation may bring critical information for the development of methods to control PNGS glycan occupancy of recombinant glycoprotein immunogens."

Journal • Human Immunodeficiency Virus • Infectious Disease • STT3A

The Study of Immunization in People Living With HIV Undergoing an ATI for Elicitation of VRC01-lineage Antibodies (clinicaltrials.gov) - P1 | N=40 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Suspended

Trial suspension • Human Immunodeficiency Virus • Infectious Disease • CD4

Dual Role of Glycosylation in Resistance to CD4-binding Site Broadly Neutralizing Antibodies. (PubMed, bioRxiv) - "In this study, we demonstrate that glycan-mediated escape from VRC01-class bNAbs is highly context-dependent-shaped by Env, bNAb, and the glycosylation patterns introduced by the producer cell. These findings emphasize the dual role of glycans in affecting antibody sensitivity and underscore the importance of viral and host factors in shaping effective bNAb-based cure strategies across diverse HIV-1 strains."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Parallel evolution of the elite neutralizer phenotype in divergent HIV-1 clades. (PubMed, J Virol) - "For the combined EN/controller data set, we observed that the median IC50 value for a CD4-binding site (CD4bs) bN-mAb (VRC01) was significantly lower for viruses lacking an N465 glycan...However, a heightening of a regional cross-reactive immune response concomitant with extraordinary glycosylation pointed to evolution of specific sequence for expanding antibody neutralization breadth. These results suggest that antigens displaying immunogenic bNAb epitopes in combination with rare glycosylation might help realize the production of an effective vaccine."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Structural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI G001 human vaccine trial. (PubMed, Proc Natl Acad Sci U S A) - "Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. The structures highlight how germline-encoded features drive bnAb-like recognition at early stages. This work provides molecular evidence supporting germline targeting in humans and provides guidance for designing booster immunogens to shepherd affinity maturation toward broad neutralization."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope. (PubMed, NPJ Vaccines) - "IgG transfer experiments demonstrated that circulating off-target antibodies provide a positive feedback mechanism that potentiates on-target B cell responses. Collectively, the results suggest that non-Env immunogens are not ideal for priming VRC01-class B cells, where sequential boosting with Env will be required to drive maturation of neutralizing breadth."

Journal • Human Immunodeficiency Virus • Infectious Disease

Env-pseudoviruses based on the HIV-1 genetic variant circulating in Siberia. (PubMed, Vavilovskii Zhurnal Genet Selektsii) - "It was shown that the Env-pseudoviruses are sensitive to neutralization by bnAbs VRC01 and 10E8; moderately sensitive to neutralization by bnAbs PG9 and PGT126; and resistant to neutralization by antibodies 2G12 and 2F5. The resulting collection is an important addition to the existing panels of pseudoviruses against other HIV-1 subtypes in the world."

Journal • Human Immunodeficiency Virus • Infectious Disease

Vaginal microbiome dysbiosis and sexually transmitted infections correlate with concentrations of immunoglobulin isotypes in human cervicovaginal mucus: insights into HIV-1 transmission. (PubMed, Front Immunol) - "IgG3 concentrations negatively correlated with CAP045 HIV-1 mobility and IgG1 concentrations negatively correlated with the mobility of the 92TH023 recombinant HIV-1 strain upon VRC01 depletion...Importantly, our study builds on previous work, providing a potential mechanism by which BV and STIs may modulate immunoglobulin isotype and subclass content in the CVM. These results highlight the need for proper treatment of BV and other STIs, as this could impact the effectiveness of HIV-1 vaccines targeted at enhancing specific immunoglobulin responses in the cervicovaginal mucosa."

Journal • Human Immunodeficiency Virus • Infectious Disease • Vaginitis

HIV-1 broadly neutralizing antibodies in treatment naïve and long-term virologic failure populations from Tanzania where multiple subtypes co-circulate (IAS-HIV 2025) - "Maintaining high antigenic stimulation has potential to elicit potent bNAbs with moderate durability after antigen suppression. Env immunogens targeting to elicit multiple bNAb lineages could result in highly potent bNAbs."

Clinical • Human Immunodeficiency Virus • Infectious Disease • CD4 • IL21

B-cell repertoire diversity in individuals living with HIV in a Southern African cohort: implications for vaccine design (IAS-HIV 2025) - "Overall, this study informs strategies for individuals without HIV and those living with HIV, advancing understanding of antibody diversity and vaccine development."

Clinical • Human Immunodeficiency Virus • Infectious Disease • IGH

Complementary bnAbs: CD4 binding site and Interface bnAbs demonstrate bidirectional phenotypic antagonism (IAS-HIV 2025) - "Leveraging authentic HIV-1 Envs sampled from participants in bnAb clinical trials, we identified highly statistically significant inverse bnAb susceptibility patterns between interface bnAb 8ANC195 and two CD4bs bnAbs: N49.P9.6FR and VRC01.23, putatively related to epitope overlap. Ongoing mechanistic and in vivo studies aim to determine if combination use 8ANC195 and N49/VRC01.23 will complementarily prevent emergent resistance."

Human Immunodeficiency Virus • Infectious Disease • CD4

Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials. (PubMed, bioRxiv) - "Viral recombination among post-acquisition variants was common under antibody selection and appeared to favor resistant sequences in the treatment group. These data suggest as with single antiviral therapy, passive and active immunization of bNAbs should be directed at multiple antigen targets of HIV-1."

Journal • Human Immunodeficiency Virus • Infectious Disease

Dose finding in early-phase human immunodeficiency virus type 1 prevention monoclonal antibody clinical trials. (PubMed, Clin Trials) - "Within this framework, the antibody-mediated prevention efficacy trials of VRC01, an human immunodeficiency virus type 1 monoclonal antibody, and a meta-analysis of 16 different monoclonal antibodies in non-human primates provided consistent evidence that neutralization titer is a potential pharmacodynamics biomarker of monoclonal antibody prevention efficacy...In this article, we highlight dose-finding efforts particularly for combination monoclonal antibodies regimens, including the selection of optimal dosing ratio and total dose amount in the context of human immunodeficiency virus type 1 prevention. Looking ahead, future directions in monoclonal antibody-based human immunodeficiency virus type 1 prevention include efforts to enhance dose-associated cost-effectiveness, and the identification and validation of robust pharmacokinetic and pharmacodynamic markers that are predictive of the prevention efficacy of combination monoclonal antibodies."

Journal • Human Immunodeficiency Virus • Infectious Disease

A novel FITC.Chimeric antigen receptor-T cell targeting HIV-1-infected cells with FITC-conjugated antibodies for enhanced cytotoxicity. (PubMed, Int J Biol Macromol) - "In a humanized BLT mouse model, this strategy led to an approximate 90 % reduction in HIV-1 loads after ART interruption. By coupling the specificity of bNAbs with the cytolytic power of CAR-T cells, this strategy offers a flexible and effective platform for achieving a functional HIV-1 cure."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

HIV-1 envelopes from virions that persist in plasma on antiretroviral therapy show reduced susceptibility to autologous immunoglobulins and variable sensitivity to broadly neutralizing monoclonal antibodies. (PubMed, bioRxiv) - "Two Env protein variants from one donor, R-09_A8 and R-09_C2, were less sensitive to VRC01 likely due to an additional N-glycan site at a VRC01 contact site and longer V5 regions...The CD4 binding site mAb 3BNC117 and the Gp41-specific mAb 10E8 neutralized pseudoviruses from all donors, indicating the potential for clearance of persistent viremia in these individuals studied...The results revealed that these pseudovirus were not neutralized by their autologous Igs and exhibited complex pseudovirus-specific susceptibility profiles for the monoclonal antibodies they were tested against. Collectively, our findings suggest that despite resistance to autologous Ig, likely combinations of monoclonal antibodies will be needed to clear this persistent viremia."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Structural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI G001 human vaccine trial. (PubMed, bioRxiv) - "Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. The structures highlight how germline-encoded features drive bnAb-like recognition at early stages. This work provides molecular evidence supporting germline-targeting in humans and provides guidance for designing booster immunogens to shepherd affinity maturation toward broad neutralization."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

A potent and broad CD4 binding site neutralizing antibody with strong ADCC activity from a Chinese HIV-1 elite neutralizer. (PubMed, Cell Discov) - "FD22 exhibited potent and broad neutralizing activity, comparable to that of the well-known bNAb VRC01...Our findings provide valuable insights into the mechanisms of FD22 in viral neutralization and ADCC. The dual functionality of FD22 enhances its potential as a promising therapeutic antibody and offers new avenues for designing CD4bs-targeting vaccines with enhanced ADCC capabilities."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4 • IFNG

Pharmacokinetics Analysis of Serum and Rectal Tissue Concentrations of a Pair of Anti-HIV Monoclonal Antibodies, VRC01 and VRC01LS, in Adults without HIV. (PubMed, J Clin Pharmacol) - "Median elimination half-life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

PET Imaging of Radiolabeled Anti-HIV-1 Envelope Monoclonal Antibody (VRC01) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: University of California, San Francisco | Trial completion date: Jan 2025 ➔ Dec 2026 | Trial primary completion date: Oct 2024 ➔ Oct 2026

Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease

Analytical treatment interruption among women with HIV in southern Africa who received VRC01 or placebo in the Antibody Mediated Prevention Study: ATI stakeholder engagement, implementation and early clinical data. (PubMed, J Int AIDS Soc) - P=N/A | "In a safe, well-tolerated ATI, 18% of 11 African women exhibited post-intervention control. Design and implementation lessons inform future ATIs in Africa. Analyses of peri-acquisition and post-ATI host and viral characteristics can inform the development of interventions for HIV cure, prevention and treatment."

Clinical • Clinical data • Journal • Human Immunodeficiency Virus • Infectious Disease • CD4