Mechanism of Action: Therapeutic vaccine. VRC-HIVADV014-00-VP (VRC rAd5-HIV vaccine) is a therapeutic HIV vaccine based on an adenovirus vector.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 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
The VRC rAd5-HIV vaccine is composed of 4 replication-defective recombinant serotype 5 adenoviral vectors. Each vector encodes 1 of the following HIV-1 antigens: clade A gp140, clade B gp140, clade C gp140, and clade B Gag-Pol fusion protein. VRC rAd5-HIV has been studied as part of a prime-boost vaccine regimen (VRC DNA/rAd5), in which the DNA vaccine VRC-HIVDNA016-00-VP (VRC DNA-HIV vaccine) is the priming component and the VRC rAd5-HIV vaccine is the boosting component. The VRC DNA-HIV vaccine expresses clade B HIV-1 Gag, Pol and Nef, as well as Env proteins derived from clade A, B, and C strains of HIV-1.2,9,10 The VRC DNA/rAd5 prime-boost regimen is intended to induce CD4 and CD8 cellular responses and antibody responses against HIV-1, and it 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 did not protect at-risk individuals from acquiring HIV any more effectively than placebo.3,12
As a therapeutic intervention for HIV, vaccination with the VRC DNA/rAd5 prime-boost regimen in combination with ART intensification was evaluated in a Phase II trial (EraMune 02; NCT00976404) for its potential to eradicate latent virus in virologically suppressed individuals with chronic HIV. This study found that this approach was unable to significantly reduce the latent HIV reservoir in study participants.2,13
Select Clinical Trials
VRC-HIVADV014-00-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 DNA-HIV prime vaccine and the VRC rAd5-HIV boost vaccine could reduce the latent HIV reservoir in individuals with long-term viral suppression.
- Participants were adults with HIV who had received uninterrupted ART for at least 3 years and who had been on a stable ART regimen for the 3 months prior to screening.
- Participants had HIV RNA ≤500 copies/mL for at least 3 years prior to study entry, undetectable HIV RNA during the year prior to entry, and CD4 counts ≥350/mm3 within 60 days of entry.
- Participants had a proviral DNA level between 10 and 1,000 copies/106 PBMCs within 75 days of entry.
: All participants received an 8-week lead-in period of ART intensification that added raltegravir (400 mg twice daily) and maraviroc (150, 300, or 600 mg twice daily) to their suppressive ART regimen. Participants were then randomized to 1 of the following groups:
- Group A: Continue with ART intensification for 48 weeks
- Group B: Continue with ART intensification for 48 weeks + immunomodulation with VRC DNA-HIV prime vaccine (4 mg given at Weeks 8, 12, and 16) and VRC rAd5-HIV boost vaccine (1010 particle units given at Week 32)
The primary endpoint was 0.5 log10 or greater reduction in proviral DNA from baseline, which was assessed at Week 56.2,13-15
Selected Study Results
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, 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 after the 8-week ART intensification lead-in phase. 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
Drug interactions associated with the VRC rAd5-HIV vaccine 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 28, 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 28, 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 28, 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 28, 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 28, 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 28, 2018.
- 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 Feb;134(2):140-147. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818410/. Last accessed on February 28, 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 28, 2018.
- Kibuuka H, Kimutai R, Maboko L. 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 28, 2018.
- HIV Vaccine Trials Network (HVTN). Protocol 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 28, 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 28, 2018.
- National Institute of Allergy and Infectious Diseases (NIAID) News Release, dated April 25, 2013. NIH discontinues immunizations in HIV vaccine study. Available at: http://wayback.archive-it.org/7761/20160909164121/http://www.niaid.nih.gov/news/newsreleases/2013/Pages/HVTN505April2013.aspx Last accessed on February 28, 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 28, 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 28, 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 28, 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 28, 2018.
Last Reviewed: February 28, 2018