Vacc-4xDrug Class: Therapeutic Vaccines Organization: Bionor Holding AS Phase of Development: Vacc-4x is in Phase II development as a therapeutic HIV vaccine.
(Compound details obtained from Treatment Action Group website,1 Bionor Holding AS website,2 and EU Clinical Trials Register3)
Mechanism of Action: Therapeutic vaccine. Vacc-4x is a peptide-based therapeutic HIV vaccine. 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 sufficiently to suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.8
Vacc-4x is designed primarily to induce and sustain cellular immune responses against HIV.9,10 It is composed of the following four synthetic HIV peptides which contain multiple CD4 and CD8 cell epitopes and which correspond to conserved regions on the HIV-1 Gag p24 capsid protein: Vac-10 (amino acids 186-204), Vac–11 (amino acids 273-293), Vac-12 (amino acids 288-308), and Vac–13 (amino acids 359-378). The peptide sequences are modified to improve human leukocyte antigen (HLA) binding and presentation.10–13
In individuals with HIV, Vacc-4x plus adjuvant has demonstrated immunogenicity and an ability to reduce viral load set point following ART treatment interruption.14–16 In a Phase Ib/IIa combination trial (NCT02092116), intradermal Vacc-4x and adjuvant were studied with the latency-reversing agent romidepsin to assess whether this combination could reduce the latent HIV reservoir. Results from this trial suggest that the combination of agents is capable of decreasing the size of the latent HIV reservoir, but it does not extend the time to viral rebound following treatment interruption. Researchers noted that this shock and kill strategy would need to be optimized before any clinical benefits would be evident in patients.17
Resistance: In a Phase II trial involving 38 participants with HIV, researchers evaluated whether Vacc-4x might induce HIV escape mutations. Plasma samples were analyzed pre-ART and postimmunization with Vacc-4x. HIV sequence changes within the p24 regions corresponding to the Vacc-4x peptides were rare.13
In a Phase Ib/IIa trial (NCT02092116), investigators analyzed data from a subset of seven participants and concluded that the administration of Vacc-4x and romidepsin did not lead to selective immune pressure, as determined by changes in HIV-1 genetic diversity throughout the study and the occurrence of mutations in the Vacc-4x targeted regions of the virus.18
Select Clinical Trials
Study Identifiers: REDUC; NCT02092116
Sponsor: Bionor Immuno AS
Status: This study has been completed.
Study Purpose: The REDUC trial was a two-part open-label study. The purpose of Part A was to verify a safe and effective dose of romidepsin for latency reversal prior to use in the second part of the study. The purpose of Part B was to evaluate the effect of Vacc-4x plus adjuvant combined with romidepsin on the latent HIV reservoir and on viral load control during an analytical treatment interruption of ART.
- Participants were adults with HIV who were on ART at the time of enrollment and who had been on ART for at least 1 year.
- Participants had HIV RNA <50 copies/mL for at least 1 year and had CD4 counts ≥500 cells/mm3. Participants’ nadir CD4 counts in the past 2 years were ≥200 cells/mm3.17,19,20
- PLoS Pathog article, 2015: The depsipeptide romidepsin reverses HIV-1 latency in vivo
- Lancet HIV article, 2016: Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial
- J Infect article, 2017: Sequential Vacc-4x and romidepsin during combination antiretroviral therapy (cART): Immune responses to Vacc-4x regions on p24 and changes in HIV reservoirs
Study Identifiers: CT-BI Vacc-4x 2007/1; NCT00659789
Sponsor: Bionor Immuno AS
Status: This study has been completed.
Study Purpose: The purpose of this study was to assess the safety and immunogenicity of Vacc-4x plus adjuvant and to evaluate the impact of Vacc-4x plus adjuvant on an analytical treatment interruption of ART.
- Participants were adults who have had HIV for at least 1 year.
- Participants had HIV RNA <50 copies/mL for the past 6 months and had pre-study CD4 counts ≥400 cells/mm3. Participants’ nadir CD4 counts were ≥200 cells/mm3.14,21
- Lancet Infect Dis article, 2014: Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial
- CROI, 2015: Use of preART-adjusted endpoints in the analysis of an HIV therapeutic vaccine trial
- EBioMedicine article, 2017: Cell-mediated immune predictors of vaccine effect on viral load and CD4 count in a Phase 2 therapeutic HIV-1 vaccine clinical trial
- AIDS Res Hum Retroviruses article, 2018: Post-vaccination C-reactive protein (CRP) and C5/gp41732-744 antibody level fold-changes over baseline are independent predictors of therapeutic HIV vaccine effect in a Phase 2 clinical study of Vacc-4x
Study Identifiers: CT-BI Vacc-4x 2012/1; NCT01712256
Sponsor: Bionor Immuno AS
Status: This study has been completed.
Study Purpose: The purpose of this reboosting study was to evaluate the impact of two additional Vacc-4x booster injections with adjuvant on immune responses and viral load levels of participants who had previously received Vacc-4x.
- Participants from the CT-BI Vacc-4x 2007/1 trial could enroll in the study if they had completed all immunizations of Vacc-4x and had interrupted ART for up to 26 weeks.
- Participants had pre-study HIV RNA <300,000 copies/mL and CD4 counts ≥400 cells/mm3.22,23
- IAS Towards an HIV Cure Symposium, 2015: Reduction in total HIV-1 proviral DNA following re-boost immunizations using the peptide-based therapeutic vaccine candidate, Vacc-4x, during ART
- PLoS One article, 2019: Re-boost immunizations with the peptide-based therapeutic HIV vaccine, Vacc-4x, restores geometric mean viral load set-point during treatment interruption
Study Identifiers: BIOSKILL; EudraCT 2015-003186-28
Sponsor: Bionor Pharma ASA
Status: This study is ongoing.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of Vacc-4x plus adjuvant when given prior to romidepsin. Effects on viral load, latent HIV reservoir size, and immune responses will be measured.
- Participants are adults with HIV who have been receiving uninterrupted ART for at least the past 3 years.
- Participants have a sustained HIV RNA <20 copies/mL and have CD4 counts ≥500 cells/mm3 at screening.
- Participants have had nadir CD4 counts ≥250 cells/mm3.3,24
Several other studies have evaluated the effects of Vacc-4x in individuals with HIV. These include:
- A Phase II safety and immunogenicity study of two different doses of intradermal Vacc-4x plus adjuvant where long-term follow-up of vaccine-induced immune responses was done 7 years postinjection.12,25,26
- A Phase I/II study (NCT01704781) of intradermal Vacc-4x in combination with the immune modulator lenalidomide for improving CD4 counts.27,28
- A Phase I/II study (NCT01473810) that investigated the safety and immunogenicity of three different doses of intranasal Vacc-4x with a mucosal adjuvant.29,30
In this Phase Ib/IIa study, the combination of intradermal Vacc-4x plus rhuGM-CSF adjuvant with romidepsin was evaluated in 20 participants. Among three participants who discontinued the study during the immunization phase, only one dropped out due to adverse events (AEs) that were potentially related to Vacc-4x. One hundred forty-one total AEs were reported. Of the drug-related AEs, 42 (31%) were Grade 1 AEs related to Vacc-4x and adjuvant, one was a Grade 2 AE related to Vacc-4x and adjuvant, and 57 (40%) were Grade 1 AEs related to romidepsin. The most common AEs associated with Vacc-4x and adjuvant were transient redness and itching at the injection site. Fatigue and nausea were the most frequently reported AEs associated with romidepsin. During the treatment interruption, six Grade 1 AEs and three Grade 2-3 AEs were reported. Four of the Grade 1 events were considered related to the treatment interruption. No drug-related serious adverse events (SAEs) occurred during the study.17,20
CT-BI Vacc-4x 2007/1 (NCT00659789):
In this Phase II trial, a safety analysis was conducted on 93 participants who received intradermal Vacc-4x plus rhuGM-CSF adjuvant and 42 participants who received placebo. Results showed that 81 out of 93 (87%) Vacc-4x-treated participants and 24 out of 42 (57%) placebo participants had an AE that was considered at least probably related to treatment. This difference was primarily due to a higher frequency of injection-site reactions (such as erythema, induration, and pruritus) in the Vacc-4x group. Otherwise, AEs were similar in both the Vacc-4x and placebo groups. Of nine SAEs that occurred during the study, five occurred in the Vacc-4x group and only one (exacerbation of multiple sclerosis) was categorized as being possibly related to Vacc-4x. One participant in the placebo group died (myocardial infarction) during treatment interruption. The researchers could not establish that this event was not related to ART interruption.14,21
CT-BI Vacc-4x 2012/1 (NCT01712256):
This Phase II study assessed whether the effects of Vacc-4x could be maintained by reboosting eligible participants from the CT-BI Vacc-4x 2007/1 trial. Thirty-three participants enrolled and received at least one intradermal rebooster injection. No participants discontinued treatment because of an AE or withdrew from the study because of an AE. Except for injection site reactions, treatment-related AEs associated with Vacc-4x and adjuvant were uncommon. Pruritus accounted for the majority of the treatment-related injection site reactions, and most cases were either mild or moderate in intensity.22,23
This was a Phase I/II study that evaluated low, medium, and high doses of intranasal Vacc-4x plus adjuvant versus adjuvant given alone. Twenty-three participants completed the study. No Vacc-4x-related SAEs were reported. Participants in all groups frequently experienced mild and transient soreness at the application site.29,30
Drug-drug interactions associated with Vacc-4x are currently unknown.
- Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed February 21, 2019.
- Bionor Holding AS website. About us. https://bionorholding.com/about-us/. Accessed February 21, 2019.
- EU Clinical Trials Register. EudraCT Number: 2015-003186-28; BIOSKILL: studying Vacc-4x, an HIV therapeutic vaccine, an assessment of immune-mediated anti-viral effects, when administered with adjuvant GM-CSF prior to HIV latent reservoir activation by the HDAC inhibitor, romidepsin. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003186-28/DK. Accessed February 21, 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 February 21, 2019.
- Miller E and Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Opin Biol Ther. 2014;14(11):1545-1549.
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6:43. 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):20497.
- Ellefsen-Lavoie K, Rockstroh J, Pollard R, et al. Quality of T-cell responses versus reduction in viral load: results from an exploratory Phase II clinical study of Vacc-4x, a therapeutic HIV vaccine. Abstract presented at: AIDS Vaccine; September 9-12, 2012; Boston, MA. Abstract OA11.05 LB. http://vaccineenterprise.org/conference/2012/sites/default/files/AV12%20Abstract_WebFinal.pdf. Accessed February 21, 2019.
- Åsjö B, Stavang H, Sørensen B, Baksaas I, Nyhus J, Langeland N. Phase I trial of a therapeutic HIV type 1 vaccine, Vacc-4x, in HIV type 1-infected individuals with or without antiretroviral therapy. AIDS Res Hum Retroviruses. 2002;18(18):1357-1365.
- Nyhus J, Kran A-M, Sommerfelt MA, Baksaas I, Sørensen B, Kvale D. Multiple antigen concentrations in delayed-type hypersensitivity (DTH) and response diversity during and after immunization with a peptide-based HIV-1 immunotherapy candidate (Vacc-4x). Vaccine. 2006;24(10):1543-1550.
- Kran A-M, Sørensen B, Nyhus J, et al. HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc-4x). AIDS. 2004;18(14):1875-1883.
- Kran A-M, Jonassen TO, Sommerfelt MA, Løvgården G, Sørensen B, Kvale D. Low frequency of amino acid alterations following therapeutic immunization with HIV-1 Gag p24-like peptides. AIDS. 2010;24(17):2609-2618.
- Pollard RB, Rockstroh JK, Pantaleo G, et al. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: A phase 2 randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2014;14(4):291-300.
- Rockstroh JK, Asmuth D, Pantaleo G, et al. Reduction in total HIV-1 proviral DNA following re-boost immunizations using the peptide-based therapeutic vaccine candidate, Vacc-4x, during ART. Abstract presented at: International AIDS Society (IAS) Towards an HIV Cure Symposium; July 18-19, 2015; Vancouver, Canada. Abstract PE64. https://www.iasociety.org/Web/WebContent/File/HIV_Cure_Symposium_2015/Posters/PE64.pdf. Accessed February 21, 2019.
- Kran A-M, Sørensen B, Sommerfelt MA, Nyhus J, Baksaas I, Kvale D. Long-term HIV-specific responses and delayed resumption of antiretroviral therapy after peptide immunization targeting dendritic cells. AIDS. 2006;20(4):627-630.
- Leth S, Schleimann MH, Nissen SK, et al. Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial. Lancet HIV. 2016;3(10):e463-72.
- Winckelmann A, Morcilla V, Shao W, et al. Genetic characterization of the HIV-1 reservoir after Vacc-4x and romidepsin therapy in HIV-1-infected individuals. AIDS Lond Engl. 2018;32(13):1793-1802. doi:10.1097/QAD.0000000000001861
- Søgaard OS, Graversen ME, Leth S, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015;11(9). doi:10.1371/journal.ppat.1005142
- Bionor Immuno AS. An open Phase I/IIa study to evaluate the safety and effect of therapeutic HIV-1 immunization using Vacc-4x + rhuGM-CSF, and HIV-1 reactivation using romidepsin, on the viral reservoir in virologically suppressed HIV-1 infected adults on cART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2014. NLM Identifier: NCT02092116. https://clinicaltrials.gov/ct2/show/NCT02092116. Accessed February 21, 2019.
- Bionor Immuno AS. A Phase II, randomized, double-blind, multicenter, immunogenicity study of Vacc-4x versus placebo in patients infected with HIV-1 who have maintained an adequate response to ART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 14, 2008. NLM Identifier: NCT00659789. https://clinicaltrials.gov/ct2/show/NCT00659789. Accessed February 21, 2019.
- Bionor Immuno AS. Re-boosting of subjects previously included in the CT BI-Vacc-4x 2007/1 study. An open, multicenter, immunogenicity, follow-up re-boosting study with Vacc-4x in subjects infected with HIV-1 who have maintained an adequate response to ART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 16, 2012. NLM Identifier: NCT01712256. https://clinicaltrials.gov/ct2/show/NCT01712256. Accessed February 21, 2019.
- Rockstroh JK, Asmuth D, Pantaleo G, et al. Re-boost immunizations with the peptide-based therapeutic HIV vaccine, Vacc-4x, restores geometric mean viral load set-point during treatment interruption. PLoS ONE. 2019;14(1). doi:10.1371/journal.pone.0210965
- Bionor Pharma. Press Release, dated December 21, 2015. Bionor announces that the HIV ‘Shock & Kill’ trial REDUC with Vacc-4x and romidepsin meets its primary endpoint by significantly reducing latent HIV reservoir and demonstrates control of viral load. https://globenewswire.com/news-release/2015/12/21/797102/10158683/en/Bionor-announces-that-the-HIV-Shock-Kill-trial-REDUC-with-Vacc-4x-and-romidepsin-meets-its-primary-endpoint-by-significantly-reducing-latent-HIV-reservoir-and-demonstrates-control-.html. Accessed February 21, 2019.
- Kvale D, Kran A-M, Sommerfelt MA, et al. Divergent in vitro and in vivo correlates of HIV-specific T-cell responses during onset of HIV viraemia. AIDS. 2005;19(6):563–7.
- Lind A, Sommerfelt M, Holmberg JO, Baksaas I, Sørensen B, Kvale D. Intradermal vaccination of HIV-infected patients with short HIV Gag p24-like peptides induces CD4 + and CD8 + T cell responses lasting more than seven years. Scand J Infect Dis. 2012;44(8):566-572. doi:10.3109/00365548.2011.653581
- Bionor Immuno AS. A double-blind placebo controlled immunogenicity study of Vacc-4x + lenalidomide versus Vacc-4x with an initial open-label dose escalation assessment of lenalidomide in HIV-1-infected subjects on antiretroviral therapy (ART). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 11, 2012. NLM Identifier: NCT01704781. https://clinicaltrials.gov/ct2/show/NCT01704781. Accessed February 21, 2019.
- van Lunzen J, Pantaleo G, Arastéh K, et al. Vacc-4x/lenalidomide increases naïve CD4 T-cells in well controlled patients on ART with low preART CD4 counts and poor immune reconstitution. Abstract presented at: International AIDS Society (IAS) Towards an HIV Cure Symposium; July 18-19, 2015; Vancouver, Canada. Abstract PE61. https://www.iasociety.org/Web/WebContent/File/HIV_Cure_Symposium_2015/Posters/PE61.pdf. Accessed February 21, 2019.
- Oslo University Hospital. Immunotherapy of HIV-infected patients: a single-blinded, randomized, immunogenicity, pilot study of intranasal administration of Vacc-4x with Endocine as adjuvant. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 1, 2011. NLM Identifier: NCT01473810. https://clinicaltrials.gov/ct2/show/NCT01473810. Accessed February 21, 2019.
- Brekke K, Lind A, Holm-Hansen C, et al. Intranasal administration of a therapeutic HIV vaccine (Vacc-4x) induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial. PLoS One. 2014;9(11). doi:10.1371/journal.pone.0112556
Last Reviewed: February 21, 2019