VRC-HIVDNA016-00-VPOther Names: VRC DNA-HIV vaccine Drug Class: Therapeutic Vaccines Organization: NIAID Vaccine Research Center (VRC) Phase of Development: VRC-HIVDNA016-00-VP is in Phase II development as a therapeutic HIV vaccine. (VRC-HIVDNA016-00-VP has also been studied as a preventive HIV vaccine.)
(Compound details obtained from The Journal of Infectious Diseases article,1 PLoS One article,2 and New England Journal of Medicine article3)
Mechanism of Action: Therapeutic vaccine. VRC-HIVDNA016-00-VP (VRC DNA-HIV vaccine) is a DNA-based therapeutic HIV vaccine.1,2 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).4-7 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 to the point where it could suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.8
VRC-HIVDNA016-00-VP is composed of 6 separate DNA plasmids expressing clade B HIV-1 Gag, Pol and Nef and Env proteins derived from clade A, B, and C strains of HIV-1. It is designed for administration as part of a prime-boost vaccine regimen (VRC DNA/rAd5), in which VRC-HIVDNA016-00-VP is the priming component and a recombinant adenovirus type 5 vector vaccine known as VRC-HIVADV014-00-VP (VRC rAd5-HIV vaccine) is the boosting component. The VRC rAd5-HIV vaccine encodes for a clade B HIV-1 Gag-Pol fusion protein and Env proteins from clades A, B, and C.2,9,10 The VRC DNA/rAd5 prime-boost regimen is intended to induce CD4 and CD8 cellular responses in addition to antibody responses against HIV-1 and has been studied in clinical trials for both HIV therapy and prevention.2,3,11 In a Phase IIb HIV prevention efficacy trial (HVTN 505; NCT00865566), the VRC DNA/rAd5 vaccine regimen failed to show any benefit in protecting at-risk individuals from acquiring HIV when compared to placebo.3,12
As a therapeutic intervention for HIV, the combination of ART intensification plus vaccination with the VRC DNA/rAd5 prime-boost regimen was evaluated in a Phase II trial (EraMune 02; NCT00976404) for its potential to eradicate latent virus in virologically suppressed individuals with chronic HIV. Results from this study found that this approach was unable to significantly reduce the latent HIV reservoir in study participants.2,13
Select Clinical Trials
VRC-HIVDNA016-00-VP therapeutic vaccine
Study Identifiers: EraMune 02; NCT00976404
Sponsor: Robert L. Murphy
Status: This study has been completed.
Study Purpose: The purpose of this open-label trial was to evaluate whether ART intensification followed by immunomodulation with the VRC-HIVDNA016-00-VP prime vaccine and the VRC-HIVADV014-00-VP boost vaccine could reduce the latent HIV reservoir in individuals with long-term viral suppression.
- Participants were adults with HIV who had received ART without interruption for at least 3 years and who had been on a stable ART regimen for the past 3 months prior to screening.
- Participants had HIV RNA ≤500 copies/mL for at least 3 years prior to entry, undetectable HIV RNA during the past year prior to entry, and CD4 counts ≥350/mm3 within 60 days of entry.
- Participants had proviral DNA between 10 and 1,000 copies/106 PBMCs within 75 days of entry.
- Group A: Continue with ART intensification for 48 weeks
- Group B: Continue with ART intensification for 48 weeks + immunomodulation with VRC-HIVDNA016-00-VP priming vaccine (4 mg given at Weeks 8, 12, and 16) and VRC-HIVADV014-00-VP boost vaccine (1010 particle units given at Week 32).
The primary endpoint measuring a 0.5 log10 reduction in proviral DNA from baseline was assessed at Week 56.2,13-15
Selected Study Results:
- CROI, 2014: Impact of RAL/MVC intensification with or without HIV-rAd5 vaccination on HIV DNA: EraMune 02
- Lancet HIV article, 2015: Effect of therapeutic intensification followed by HIV DNA prime and rAd5 boost vaccination on HIV-specific immunity and HIV reservoir (EraMune 02): a multicentre randomised clinical trial
- PLoS One article, 2016: HIV-1-specific antibody response and function after DNA prime and recombinant adenovirus 5 boost HIV vaccine in HIV-infected subjects
The VRC DNA/rAd5 prime-boost regimen has also been evaluated in a Phase I study (VRC 101; NCT00270465). This trial assessed the safety and immunogenicity of VRC DNA/rAd5 vaccination in individuals who were virologically suppressed on ART.1,16
In the Phase II EraMune 02 (NCT00976404) trial, 28 participants were enrolled. After the 8-week ART intensification lead-in phase, 14 participants were randomized to ART intensification alone and 14 participants were randomized to ART intensification plus vaccination with the VRC DNA/rAd5 prime-boost regimen. Five serious adverse events (SAEs) occurred during the trial, though most spontaneously resolved or were unrelated to study treatment. There were no severe, moderate, or systemic reactions to vaccination with either VRC DNA-HIV or VRC rAd5-HIV. Mild reactions to vaccination were reported, such as injection site tenderness, redness, and swelling.13,14
VRC-HIVDNA016-00-VP drug interactions are currently unknown.
- Casazza JP, Bowman KA, Adzaku S, et al. Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. J Infect Dis. 2013 Jun 15;207(12):1829-1840. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654747/. Last accessed on February 16, 2018.
- Gach JS, Gorlani A, Dotsey EY, et al. HIV-1-specific antibody response and function after DNA prime and recombinant adenovirus 5 boost HIV vaccine in HIV-infected subjects. PLoS One. 2016 Aug 8;11(8):e0160341. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976892/. Last accessed on February 16, 2018.
- Hammer SM, Sobieszczyk ME, Janes H, et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med. 2013 Nov 28;369(22):2083-2092. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030634/. Last accessed on February 16, 2018.
- Lederman MM, Rodriguez B, Sieg S. Immunopathogenesis of HIV infection. In: Coffey S and Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. Available at: http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Last accessed on February 16, 2018. [Archived at WebCite].
- Miller E, Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Expert Opin Biol Ther. 2014 Nov;14(11):1545-1549. Available at: http://www.tandfonline.com/doi/full/10.1517/14712598.2014.950652. Last accessed on February 16, 2018.
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014 Jun 2;6:43. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Last accessed on February 16, 2018.
- Routy JP, Boulassel MR, 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 Feb;134(2):140-147. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818410/. Last accessed on February 16, 2018.
- Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015 Nov 9;18:20497. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641978/. Last accessed on February 16, 2018.
- Kibuuka H, Kimutai R, Maboko L, et al. A Phase I/II study of a multiclade HIV-1 DNA plasmid prime and recombinant adenovirus-type 5 boost vaccine in HIV uninfected East Africans (RV 172). J Infect Dis. 2010 Feb 15;201(4):600-607. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811694/. Last accessed on February 16, 2018.
- HIV Vaccine Trials Network (HVTN). HVTN 204: A Phase II clinical trial to evaluate the safety and immunogenicity of a multiclade HIV-1 DNA plasmid vaccine, VRC-HIVDNA016-00-VP, followed by a multiclade recombinant adenoviral vector HIV-1 vaccine boost, VRC-HIVADV014-00-VP, in HIV-1 uninfected adult participants. Version 1.0; May 24, 2005. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152265/bin/pone.0021225.s001.pdf. Last accessed on February 16, 2018.
- Churchyard GJ, Morgan C, Adams E, et al. A Phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204). PLoS One. 2011;6(8):e21225. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152265/. Last accessed on February 16, 2018.
- National Institute of Allergy and Infectious Diseases (NIAID) News Release, dated April 25, 2013. NIH discontinues immunizations in HIV vaccine study. Available at: https://www.niaid.nih.gov/news-events/nih-discontinues-immunizations-hiv-vaccine-study. Last accessed on February 16, 2018. [Archived at WebCite]
- Achenbach CJ, Assoumou L, Deeks SG, et al. Effect of therapeutic intensification followed by HIV DNA prime and rAd5 boost vaccination on HIV-specific immunity and HIV reservoir (EraMune 02): a multicentre randomised clinical trial. Lancet HIV. 2015 Mar;2(3):e82-91. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26424549. Last accessed on February 16, 2018.
- Achenbach C, Deeks S, Wilkin T, et al. Impact of RAL/MVC intensification with or without HIV-rAd5 vaccination on HIV DNA: EraMune 02. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Poster 422. Available at: http://www.croiconference.org/sites/default/files/posters/422.pdf. Last accessed on February 16, 2018. [Archived at WebCite]
- Robert L. Murphy. Multicenter, randomized, non-comparative, controlled study of therapeutic intensification plus immunomodulation in HIV-infected patients with long-term viral suppression. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 9, 2009. NLM Identifier: NCT00976404. Available at: https://clinicaltrials.gov/ct2/show/NCT00976404. Last accessed on February 16, 2018.
- National Institute of Allergy and Infectious Diseases (NIAID). VRC101: A Phase I clinical trial to evaluate the safety and immunogenicity of a prime-boost HIV-1 vaccination schedule of a 6-plasmid multiclade HIV-1 DNA vaccine, VRC-HIVDNA016-00-VP, followed by a recombinant multiclade adenoviral vector HIV vaccine. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 24, 2005. NLM Identifier: NCT00270465. Available at: https://clinicaltrials.gov/ct2/show/NCT00270465. Last accessed on February 16, 2018.
Last Reviewed: February 16, 2018