Drug Database: ChAdV63.HIVconsv

Pharmacology

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).^4–6 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.⁷

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.^3,8,9 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.^10–12 ChAdV63.HIVconsv has also been evaluated in HIV prevention trials.^2,13,14

In a 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.^12,15

Select Clinical Trials

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.^10,11,16

Selected Study Results: Results from the BCN01 trial published in EClinicalMedicine (2019) showed that the ChAdV63.HIVconsv and MVA.HIVconsv vaccines were safe, with the majority of adverse events (AEs) being Grade 1 or 2. The vaccine regimen demonstrated strong HIV-specific immunogenicity and refocused T-cell responses towards highly conserved regions of HIV-1.¹⁷ BCN02 trial results published in Frontiers in Immunology (2020) showed that the administration of MVA.HIVconsv booster doses and romidepsin was generally safe; however, one participant experienced a serious adverse event (SAE) that was possibly related to romidepsin. The combined intervention resulted in only a modest reduction in the size of the latent HIV reservoir.¹⁸

Study Identifiers: RIVER; NCT02336074

Sponsor: Imperial College London
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label, proof-of-concept study was to determine whether an approach that used ART plus the ChAdV63.HIVconsv and MVA.HIVconsv vaccines plus vorinostat could lead to a greater reduction in the size of the latent HIV reservoir than using ART alone.
Study Population: Participants were adults who had received a diagnosis of HIV infection within 6 months of enrollment and had started ART within 1 month from the time of diagnosis.^12,19,20
Selected Study Results: Results presented at AIDS 2018 and published in Lancet (2020) showed that the kick and kill regimen of ART plus the ChAdV63.HIVconsv and MVA.HIVconsv vaccines plus vorinostat conferred no significant benefit in reducing the latent HIV reservoir as compared to ART alone.^19,20
Additional Published Material:

• Sci Rep article, 2023: Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions

Adverse Events

Adverse Events

BCN01 (NCT01712425)

In this Phase 1 study, 22 of 24 participants experienced local or systemic 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.¹⁷

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 SAEs were reported.^12,15,19

A substudy evaluated the CNS impacts of trial interventions and found no evidence of increased neuronal damage with ART, therapeutic vaccination, and vorinostat compared to ART alone.²¹

Drug Interactions

Drug Interactions

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

References

References

1. Treatment Action Group website. Research toward a cure trials. Accessed December 4, 2023
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. Accessed December 4, 2023
3. European Commission website. 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; 01/12/2012. Accessed December 4, 2023
4. 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. Accessed December 4, 2023
5. Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6:43. doi:10.12703/P6-43. Accessed December 4, 2023
6. 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. Accessed December 4, 2023
7. 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. Accessed December 4, 2023
8. 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. Accessed December 4, 2023
9. 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. Accessed December 4, 2023
10. 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. Accessed December 4, 2023
11. 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. Accessed December 4, 2023
12. 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. Accessed December 4, 2023
13. 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. Accessed December 4, 2023
14. 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. Accessed December 4, 2023
15. 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. Accessed December 4, 2023
16. 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. Accessed December 4, 2023
17. 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. Accessed December 4, 2023
18. Mothe B, Rosás-Umbert M, Coll P, et al. HIVconsv vaccines and romidepsin in early-treated HIV-1-infected individuals: safety, immunogenicity and effect on the viral reservoir (Study BCN02). Front Immunol. 2020;11:823. doi:10.3389/fimmu.2020.00823. Accessed December 4, 2023
19. 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. Accessed December 4, 2023
20. Fidler S, Stöhr W, Pace M, et al. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial. Lancet. 2020;395(10227):888-898. doi:10.1016/S0140-6736(19)32990-3. Accessed December 4, 2023
21. Alagaratnam J, Stöhr W, Toombs J, et al. No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach. J Virus Erad. 2021;7(3):100056. doi:10.1016/j.jve.2021.100056. Accessed December 4, 2023
    

Last Reviewed: December 4, 2023