VRC01Other Names: VRC-HIVMAB060-00-AB, VRC-HIVMAB080-00-AB, VRC01LS Drug Class: Therapeutic Vaccines (Broadly Neutralizing Antibodies) Registry Number: 1412901-55-3 (CAS) Organization: NIAID Vaccine Research Center (VRC) Phase of Development: VRC01 is in Phase 2 development as a therapeutic vaccine. (VRC01 is also being studied for HIV prevention.)
(Compound details obtained from ChemIDplus Advanced,1 Current Opinion in Virology article,2 Science Translational Medicine article,3 Treatment Action Group website,4 and Treatment Action Group HIV TB HCV Pipeline Report 20185)
Mechanism of Action: Therapeutic vaccine (broadly neutralizing antibody [bNAb]). VRC01 is a bNAb-based therapeutic HIV vaccine.2,4 Therapeutic vaccines are being investigated as an immunotherapeutic approach to correcting HIV-associated immune dysfunction, such as impaired dendritic cell (DC) responses to HIV and suboptimal adaptive immune responses (including HIV-specific T cell responses).6–9 A therapeutic vaccine may potentially increase the effectiveness of ART, simplify ART regimens, or allow for periodic structured treatment interruptions. A successful therapeutic vaccine would either completely eradicate the virus or improve an individual’s immune response sufficiently to suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.10
While the focus of therapeutic HIV vaccine study has been on the development of vaccines that induce cellular immune responses, researchers are also exploring humoral-based vaccine strategies.10 Since the identification of next-generation bNAbs – naturally occurring antibodies with potent neutralizing activity against a broad array of HIV strains – antibody research has been centered on the utility of bNAbs for both HIV prevention and treatment/cure. By binding to sites on HIV envelope and through Fc receptor interactions, bNAbs can potentially 1) inhibit cell-free and cell-to-cell viral entry, 2) induce cellular phagocytosis and destruction by macrophages or antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, and 3) promote the maturation and activity of dendritic cells.11–14 Because it is difficult to induce in vivo generation of these antibodies using conventional vaccination techniques, researchers generally believe that bNAbs will need to be given by passive transfer whereby a bNAb is directly administered to an individual.12,15
VRC01 is a human IgG1 bNAb that targets a conserved region of the CD4 biding site on the HIV envelope glycoprotein gp120. It has demonstrated in vitro neutralizing activity against approximately 90% of a diverse panel of HIV strains.3,16,17 As a passively administered vaccine, VRC01 is being studied for HIV prevention and as a possible component to an HIV cure.4,5 A long-acting version of VRC01, called VRC01LS, is also in clinical development.4
Half-life (T1/2): In a Phase 1 dose-escalation study (NCT01950325), short-term administration of intravenous (IV) infusions of VRC01 (doses ranging from 1 mg/kg – 40 mg/kg) and subcutaneous (SC) infusions of VRC01 (5 mg/kg) in adults with HIV yielded a terminal half-life of 12 days for IV VRC01 and 11 days for SC VRC01.3 In a Phase 1 study of VRC01LS (NCT02599896) administered to healthy adults without HIV, the elimination half-life of IV VRC01LS (5 mg/kg – 40 mg/kg dose range) was 71 ± 18 days.18
Resistance: HIV resistance to passively administered VRC01 has been described to occur in clinical trials.3,19 In two Phase 1 studies (NCT02463227 and NCT02471326), a total of 24 participants received multiple IV infusions of VRC01 (40 mg/kg) monotherapy to determine whether VRC01 could prevent or delay viral rebound after analytical treatment interruption (ATI) of ART. Results showed that the efficacy of VRC01 monotherapy was limited, partly due to the presence of preexisting baseline resistance to VRC01 in a high number of participants and the emergence/development of VRC01-resistant HIV, including virus with a high-level of resistance, following VRC01 administration and discontinuation of ART.19
Select Clinical Trials
Study Identifiers: RV 397; NCT02664415
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety of VRC01 and efficacy of VRC01 in preventing viral rebound in participants undergoing ATI.
- Participants were adults with HIV (from the RV254 study) who had initiated ART during acute HIV infection and who had been on ART for at least 24 months prior to enrollment.
- Participants had HIV RNA <50 copies/mL within the past 12 months of study entry and CD4 counts >400 cells/mm3 within 3 months of enrollment.
- Participants had undetectable integrated HIV DNA in PBMCs within 6 months of enrollment.20
- IAS, 2017: HIV-specific broadly-neutralizing monoclonal antibody, VRC01, minimally impacts time to viral rebound following treatment interruption in virologically-suppressed, HIV-infected participants who initiated antiretroviral therapy during acute HIV infection
- Lancet HIV article, 2019: Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a Phase 2, randomised, double-blind, placebo-controlled trial
Study Identifiers: ACTG A5357; NCT03739996
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Status: See the ClinicalTrials.gov record for this study’s status.
Study Purpose: The purpose of this open-label study is to evaluate the safety and pharmacokinetics of long-acting cabotegravir (CAB LA) plus VRC01LS and assess whether this combination can maintain viral suppression in adults with HIV.
- Participants are adults with HIV who are receiving a three-drug ART regimen consisting of two NRTIs plus a boosted PI, an NNRTI, or an INI.
- Participants have never switched their ART regimen due to virologic failure.
- Participants have had HIV RNA <50 copies/mL within the past 2 years prior to study entry and have HIV RNA <40 copies/mL at screening. Participants have CD4 counts ≥350 cells/mm3 at screening.21
Additional early-phase studies investigating HIV treatment with VRC-01 or VRC01LS are being conducted. Some of these studies include:
- NCT02591420: A Phase 1 study that will evaluate the safety and antiviral effects of VRC01 when given alone and when given with ART in adults with early acute HIV infection. This study is currently recruiting participants.22
- ACTG A5378 (NCT02840474): A Phase 1 trial that is evaluating the safety and antiviral effects of VRC01LS and another long-acting bNAb called VRC07-523LS in adults with HIV who have never received ART. This study is ongoing, but not recruiting participants.23
- NCT03831945: A Phase 1 trial that is evaluating whether the combination of VRC01 plus the bNAb 10-1074 can control viral load levels in virologically suppressed adults undergoing treatment interruptions of ART. This study is currently recruiting participants.24
- IMPAACT 2008 (NCT03208231): A Phase 1/2 trial looking at the safety of VRC01 and its effect on the latent HIV reservoir in infants with HIV who are initiating ART. This study is currently recruiting participants.25
- Tatelo Study (NCT03707977): A Phase 1/2 trial looking at the impact of VRC01LS plus 10-1074 on the maintenance of HIV suppression in early ART-treated children in Botswana. See the ClinicalTrials.gov record for this study’s status.26
RV 397 (NCT02664415):
In this Phase 2 study, 14 participants received VRC01 monotherapy and five participants received placebo. A serious adverse event (SAE) – generalized urticaria – occurred in one participant during their first infusion with VRC01 and led to study withdrawal. Infusion-related adverse events (AEs) that were reported during the trial included fatigue, nausea, pain at the infusion site, headache, and bruising at the infusion site. The majority of these AEs were mild, with just one case of moderate infusion-site bruising. No anti-VRC01 antibodies were detected among participants.20,27
Drug-drug interactions associated with VRC01 are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced: VRC01. https://chem.nlm.nih.gov/chemidplus/rn/1412901-55-3. Accessed July 25, 2019
- Gray GE, Laher F, Lazarus E, Ensoli B, Corey L. Approaches to preventative and therapeutic HIV vaccines. Curr Opin Virol. 2016;17:104-109.
- Lynch RM, Boritz E, Coates EE, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Science Translational Medicine. 2015;7(319):319ra206-319ra206. doi:10.1126/scitranslmed.aad5752
- Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed July 25, 2019
- Jefferys R. The HIV vaccines, passive immunization, and antibody gene transfer pipeline. Treatment Action Group HIV TB HCV Pipeline Report 2018. http://www.pipelinereport.org/2018/hiv-vaccines-pipeline. Accessed July 25, 2019
- Lederman M, Rodriguez B, Sieg S. Immunopathogenesis of HIV Infection. In: Coffey S, Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Accessed July 25, 2019
- Miller E, Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Expert Opin Biol Ther. 2014;14(11):1545-1549. doi:10.1517/14712598.2014.950652
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6. doi:10.12703/P6-43
- Routy J-P, Boulassel M-R, Yassine-Diab B, et al. Immunologic activity and safety of autologous HIV RNA–electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol. 2010;134(2):140-147. doi:10.1016/j.clim.2009.09.009
- Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015;18(1). doi:10.7448/IAS.18.1.20497
- Jefferys R and Jacobson J. Therapeutic vaccines and immune-based therapies. CUREiculum: HIV/AIDS and cure basics – Module 12. PowerPoint presentation available on the AIDS Vaccine Advocacy Coalition (AVAC) website: http://www.avac.org/sites/default/files/u16/Theraeutic_Vaccine_Module_June.pptx. Accessed July 25, 2019
- Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: Potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423. doi:10.1172/JCI80561
- Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7:10844.
- Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37.
- Caskey M, Klein F, Lorenzi JCC, et al. 3BNC117 a Broadly Neutralizing Antibody Suppresses Viremia in HIV-1-Infected Humans. Nature. 2015;522(7557):487-491. doi:10.1038/nature14411
- Li Y, O’Dell S, Walker LM, et al. Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01. J Virol. 2011;85(17):8954-8967. doi:10.1128/JVI.00754-11
- Wu X, Yang Z-Y, Li Y, et al. Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1. Science. 2010;329(5993):856-861. doi:10.1126/science.1187659
- Gaudinski MR, Coates EE, Houser KV, et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018;15(1). doi:10.1371/journal.pmed.1002493
- Bar KJ, Sneller MC, Harrison LJ, et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N Engl J Med. 2016;375(21):2037-2050. doi:10.1056/NEJMoa1608243
- National Institute of Allergy and Infectious Diseases (NIAID). Safety and therapeutic efficacy of the broadly neutralizing HIV-1 specific monoclonal antibody VRC01 during analytic treatment interruption in patients who initiated antiretroviral therapy during early acute HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2016. NLM Identifier: NCT02664415. https://clinicaltrials.gov/ct2/show/NCT02664415. Accessed July 25, 2019
- National Institute of Allergy and Infectious Diseases (NIAID). A study of long-acting cabotegravir plus VRC01LS to maintain viral suppression in adults living with HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 9, 2018. NLM Identifier: NCT03739996. https://clinicaltrials.gov/ct2/show/NCT03739996. Accessed July 25, 2019
- National Institute of Allergy and Infectious Diseases (NIAID). Safety and virologic effect of a human monoclonal antibody, VRC-HIVMAB060-00-AB (VRC01), with broad HIV-1 neutralizing activity, administered intravenously to adults during early acute HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 28, 2015. NLM Identifier: NCT02591420. https://clinicaltrials.gov/ct2/show/NCT02591420. Accessed July 25, 2019
- National Institute of Allergy and Infectious Diseases (NIAID). VRC 607-ACTG A5378: A Phase 1, single dose study of the safety and virologic effect of an HIV-1 specific broadly neutralizing human monoclonal antibody, VRC-HIVMAB080-00-AB (VRC01LS) or VRC-HIVMAB075-00-AB (VRC07-523LS), administered intravenously to HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered July 19, 2016. NLM Identifier: NCT02840474. https://clinicaltrials.gov/ct2/show/NCT02840474. Accessed July 25, 2019
- National Institute of Allergy and Infectious Diseases (NIAID). An exploratory study of combination therapy with 3BNC117 and 10-1074 in HIV-infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 22, 2018. NLM Identifier: NCT03571204. https://clinicaltrials.gov/ct2/show/NCT03571204. Accessed July 25, 2019
- National Institute of Allergy and Infectious Diseases (NIAID). Phase I/II multisite, randomized, controlled study of monoclonal antibody VRC01 with combination antiretroviral therapy to promote clearance of HIV-1-infected cells in infants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered June 30, 2017. NLM Identifier: NCT03208231. https://clinicaltrials.gov/ct2/show/NCT03208231. Accessed July 25, 2019
- National Institute of Allergy and Infectious Diseases (NIAID). A clinical trial to evaluate the impact of broadly neutralizing antibodies VRC01LS and 10-1074 on maintenance of HIV suppression in a cohort of early-treated children in Botswana (dual bNAb treatment in children). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). October 12, 2018. NLM Identifier: NCT03707977. https://clinicaltrials.gov/ct2/show/NCT03707977. Accessed July 25, 2019
- Crowell TA, Colby DJ, Pinyakorn S, et al. HIV-specific broadly-neutralizing monoclonal antibody, VRC01, minimally impacts time to viral rebound following treatment interruption in virologically-suppressed, HIV-infected participants who initiated antiretroviral therapy during acute HIV infection. Slides presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. http://programme.ias2017.org/PAGMaterial/PPT/2901_1662/RV%20397%20IAS%20Presentation%202017-07-24.pptx. Accessed July 25, 2019
Last Reviewed: July 25, 2019