Drugs

ChAdV63.HIVconsv

Other Names: HIVconsv vaccine vectored by ChAdV63 Drug Class: Therapeutic Vaccines Organization: University of Oxford Phase of Development: ChAdV63.HIVconsv is in Phase 2 development as a therapeutic vaccine. (ChAdV63.HIVconsv has also been studied for HIV prevention.)

(Compound details obtained from Treatment Action Group website1 and ClinicalTrials.gov2)

Pharmacology


Mechanism of Action: Therapeutic vaccine. ChAdV63.HIVconsv is a therapeutic HIV vaccine based on an adenovirus vector.3 Therapeutic vaccines are being investigated as an immunotherapeutic approach to correcting HIV-associated immune dysfunction, such as impaired dendritic cell 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 sufficiently to suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.8

The ChAdV63.HIVconsv vaccine is composed of a recombinant chimpanzee adenovirus serotype 63 (ChAdV63) vector, which is modified to ensure it is incapable of replication and nonpathogenic.3 The ChAdV63 vector carries a transgene (HIVconsv) encoding 14 HIV-1 Gag, Pol, Vif, and Env protein fragments, representing some of the most conserved segments of the HIV-1 genome across subtypes A, B, C, and D. ChAdV63.HIVconsv is designed to induce HIV-specific CD8 cell responses against the covered vaccine antigens.3,9,10 As a therapeutic vaccine, ChAdV63.HIVconsv has been studied as part of a prime-boost vaccine regimen, in which ChAdV63.HIVconsv functions as the priming component and an MVA.HIVconsv vaccine functions as the boosting component.11–13 ChAdV63.HIVconsv has also been evaluated in HIV prevention trials.2,14,15

In a recent Phase 2 eradication study (RIVER; NCT02336074), researchers investigated a kick and kill approach consisting of ART, the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccines, and the latency-reversing agent vorinostat in individuals with primary HIV infection who were virologically suppressed. Although this vaccine regimen demonstrated significant HIV-specific cellular immunogenicity, this approach to treatment was no more effective than ART alone at reducing the size of latent HIV reservoirs.13,16


Select Clinical Trials


Study Identifiers: (1) BCN01; NCT01712425 and (2) BCN02-Romi; NCT02616874
Sponsor: IrsiCaixa
Phase: 1
Status: BCN01 and BCN02-Romi have both been completed.
Study Purpose:
  • BCN01 was an open-label trial that evaluated the safety and immunogenicity of the ChAdV63.HIVconsv and MVA.HIVconsv vaccines in individuals with recent HIV infection who had suppressed viral load levels on ART.
  • BCN02-Romi was an open-label rollover study that evaluated the impact of booster doses of MVA.HIVconsv plus the latency-reversing agent romidepsin on latent HIV reservoir size and on viral rebound following a treatment interruption of ART.
Study Population:
  • BCN01: Participants were adults with recently diagnosed HIV infection who had initiated ART with raltegravir + tenofovir DF/emtricitabine within 1 week of diagnosis. Participants were virologically suppressed within 6 months of initiating ART and had CD4 counts >350 cells/mm3.
  • BCN02-Romi: Participants had completed the BCN01 trial, had at least 3 years of virological suppression, and had CD4 counts ≥500 cells/mm3.11,12,17
Selected Study Results:
Study Identifiers: RIVER; NCT02336074
Sponsor: Imperial College London
Phase: 2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label, proof-of-concept study is to determine whether an approach that uses ART plus the ChAdV63.HIVconsv and MVA.HIVconsv vaccines plus vorinostat can lead to a greater reduction in the size of the latent HIV reservoir than using ART alone.
Study Population: Participants are adults who had received a diagnosis of acute HIV infection within 4 weeks of enrollment.13,18
Selected Study Results:


Adverse Events


BCN01 (NCT01712425):

In this Phase 1 study, 22 of 24 participants experienced local or systemic adverse events (AEs) after vaccination. Most of these AEs were Grade 1 or 2 in severity, and most of the AEs related to vaccination were transient and resolved within 3 days. Pain was the most commonly reported local AE following vaccination and occurred more frequently with MVA.HIVconsv than with ChAdV63.HIVconsv. The most common systemic AE after vaccination was malaise.19

RIVER (NCT02336074):

In this Phase 2 study, 29 of 30 participants (97%) who received ART, ChAdV63.HIVconsv, MVA.HIVconsv, and vorinostat experienced an AE. Seventy percent of these AEs were mild, 23% were moderate, and 3% were severe in intensity. In the ART-only arm, 22 of 30 participants (73%) experienced an AE, of which 33% were mild, 20% were moderate, and 20% were severe. No intervention-related serious adverse events were reported.13,16,18


Drug Interactions


Drug-drug interactions associated with ChAdV63.HIVconsv are currently unknown.


References


  1. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed August 5, 2019
  2. University of Oxford. A Phase I study to evaluate the safety and immunogenicity of simultaneous prime-boost immunisations with candidate HCV and HIV-1 vaccines, AdCh3NSmut1 / ChAdV63.HIVconsv and MVA-NSmut / MVA.HIVconsv, in healthy volunteers. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered November 6, 2014. NLM Identifier: NCT02362217. https://clinicaltrials.gov/ct2/show/NCT02362217. Accessed August 5, 2019
  3. The Joint Research Centre of the European Commission. GMO Register: B/ES/12/09. ChAdV63.HIVconsv – Summary notification information format for the release of genetically modified organisms other than higher plants in accordance with article 11 of directive 2001/18/ec; 02/17/2012. https://gmoinfo.jrc.ec.europa.eu/bsnifs-gmo/B-ES-12-09.pdf. Accessed August 5, 2019
  4. 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 August 5, 2019
  5. 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
  6. Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6:43. doi:10.12703/P6-43
  7. 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
  8. 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
  9. Borthwick N, Ahmed T, Ondondo B, et al. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther. 2014;22(2):464-475. doi:10.1038/mt.2013.248
  10. Rosario M, Bridgeman A, Quakkelaar ED, et al. Long peptides induce polyfunctional T cells against conserved regions of HIV-1 with superior breadth to single-gene vaccines in macaques. European Journal of Immunology. 2010;40(7):1973-1984. doi:10.1002/eji.201040344
  11. IrsiCaixa. Safety and immunogenicity of ChAdV63.HIVconsv and MVA.HIVconsv candidate HIV-1 vaccines in recently HIV-1 infected individuals with early viral suppression after initiation of antiretroviral therapy (HAART). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered October 4, 2012. NLM Identifier: NCT01712425. https://clinicaltrials.gov/ct2/show/NCT01712425. Accessed August 5, 2019
  12. IrsiCaixa. An open label Phase I trial to evaluate the safety and effect of HIVconsv vaccines in combination with histone deacetylase inhibitor romidepsin on the viral rebound kinetic after treatment interruption in early treated HIV-1 infected individuals (BCN02-Romi). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered November 9, 2015. NLM Identifier: NCT02616874. https://clinicaltrials.gov/ct2/show/NCT02616874. Accessed August 5, 2019
  13. Imperial College London. Research in viral eradication of HIV reservoirs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 23, 2014. NLM Identifier: NCT02336074. https://www.clinicaltrials.gov/ct2/show/NCT02336074. Accessed August 5, 2019
  14. University of Oxford. A randomized single-blind placebo-controlled study to evaluate the safety and immunogenicity of three candidate HIV-1 vaccines, pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv, administered in combination to healthy HIV 1 uninfected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered June 24, 2010. NLM Identifier: NCT01151319. https://clinicaltrials.gov/ct2/show/NCT01151319. Accessed August 5, 2019
  15. University College, London. A randomised double-blind, placebo-controlled Phase I/IIa trial to investigate the effect of depletion of serum amyloid P component (SAP) on the immune response to DNA vaccination in healthy male volunteers. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered April 29, 2013. NLM Identifier: NCT02425241. https://clinicaltrials.gov/ct2/show/NCT02425241. Accessed August 5, 2019
  16. Fidler S, Stohr W, Pace M, et al. A randomised controlled trial comparing the impact of antiretroviral therapy (ART) with a “Kick-and-Kill” approach to ART alone on HIV reservoirs in individuals with primary HIV infection (PHI); RIVER trial. Abstract presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands. Abstract TUAA0202LB. http://programme.aids2018.org/Abstract/Abstract/12977. Accessed August 5, 2019
  17. Mothe B, Manzardo C, Coll P, et al. Shaping CTL immunodominance with conserved HIV vaccines after early treatment (BCN01). Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Poster 320. http://www.croiconference.org/sites/default/files/posters-2016/320.pdf. Accessed August 5, 2019
  18. Fidler S. RIVER research in viral eradication of HIV reservoirs: A two-arm (proof of concept) randomised Phase II trial vorinostat plus a prime boost vaccine. Slides presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands. https://programme.aids2018.org/PAGMaterial/PPT/6106_3214/RIVER%20presentation%20at%20IAS%2024.7.2018%20final%20draft.pptx. Accessed August 5, 2019
  19. Mothe B, Manzardo C, Sanchez-Bernabeu A, et al. Therapeutic vaccination refocuses T-cell responses towards conserved regions of HIV-1 in early treated individuals (BCN 01 study). EClinicalMedicine. 2019;11:65-80. doi:10.1016/j.eclinm.2019.05.009


Last Reviewed: August 5, 2019