What is an investigational vaccine?
An investigational vaccine is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational vaccine. These research studies are also called clinical trials. Once an investigational vaccine has been proven safe and effective in clinical trials, FDA may approve the vaccine for sale in the United States.
To learn more about investigational vaccines and investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.
What is Vacc-4x?
Vacc-4x is an investigational vaccine that is being studied as a therapeutic vaccine for HIV.1 A therapeutic HIV vaccine is a type of vaccine that’s designed to improve the body’s immune response to HIV in a person who is already infected with HIV.3
HIV researchers are developing and testing therapeutic vaccines (1) to slow down the progression of HIV infection, (2) to eliminate the need for antiretroviral therapy (ART) while still keeping undetectable levels of HIV, and (3) as part of a combination strategy that includes HIV medicines and a therapeutic vaccine to eliminate all HIV from the body. (ART is the recommended treatment for HIV infection and involves using a combination of different HIV medicines to prevent HIV from replicating.) The AIDSinfo fact sheet What is a Therapeutic HIV Vaccine? has more information on therapeutic HIV vaccines.4,5
Vacc-4x is made up of HIV peptides (pieces of HIV proteins). The HIV peptides help the body produce an immune response to fight the virus.6
How are clinical trials of investigational vaccines conducted?
Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.7
- Phase I trials: Researchers test an investigational vaccine in a small group of people (20–80) for the first time. The purpose is to evaluate its safety, identify side effects, and determine if the vaccine produces an immune response in the body.
- Phase II trials: The investigational vaccine is administered to a larger group of people (100–300). Researchers further evaluate the vaccine’s safety and ability to produce an immune response in the body. Some effectiveness data on the health benefits of the vaccine may also be collected.
- Phase III trials: The investigational vaccine is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational vaccine to be used safely.7,8
In most cases, an investigational vaccine must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some vaccines go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a vaccine is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the vaccine’s risks, benefits, and optimal use.7 (Some clinical trials are categorized as “a” or “b,” such as “Phase Ia” or “Phase IIb.” These different subphases typically mean that a study is researching certain types of information or using a certain type of participant population.)
In what phase of testing is Vacc-4x?
Vacc-4x has been studied in Phase II clinical trials.1,9-11
What are some studies on Vacc-4x?
Study Names: REDUC trial; NCT02092116
Sponsor: Bionor Immuno AS
- Participants were HIV-infected adults who were on ART at the start of the study and who had been on ART for at least 1 year.
- Participants had viral load levels (the amount of HIV in a blood sample) of less than 50 copies/mL for at least 1 year.
- Participants had CD4 counts of at least 500 cells/mm3, and their lowest ever CD4 counts in the past 2 years were no less than 200 cells/mm3. (A CD4 count is a laboratory test that measures the number of CD4 cells—a type of immune cell—in a sample of blood and is an important indicator of immune function.)
: The REDUC trial was a 2-part study. Part A was designed to find a safe and effective dose
of the investigational drug romidepsin
to use in the second part of the study. Part B was designed to evaluate (1) the safety of Vacc-4x when combined with romidepsin
, and (2) whether this drug combination could reduce the amount of hidden and inactive HIV (known as latent HIV) in the body and control viral load levels during a planned break from ART.9,12
: CT-BI Vacc-4x 2007/1; NCT00659789
: Bionor Immuno AS
: Germany, Italy, Spain, United Kingdom, United States
- Participants were adults who had been infected with HIV for at least 1 year.
- Participants had viral load levels of less than 50 copies/mL for the past 6 months.
- Before the start of the study, participants’ CD4 counts were at least 400 cells/mm3, and their CD4 counts had never been less than 200 cells/mm3.
: The purpose of this study was to evaluate the safety of Vacc-4x and its ability to produce an immune response in the body. The study also looked at what effects Vacc-4x would have while participants were on a planned break from ART.10
: CT-BI Vacc-4x 2012/1; NCT01712256
: Bionor Immuno AS
: Germany, Italy, Spain, United Kingdom, United States
- Participants had completed the CT-BI Vacc-4x 2007/1 trial described above.
- Before the start of the study, participants had viral load levels below 300,000 copies/mL and CD4 counts of at least 400 cells/mm3.
: The purpose of this study was to evaluate how 2 additional Vacc-4x injections affected the immune responses and viral loads of participants who had received Vacc-4x in a previous study.11
: BIOSKILL; EudraCT 2015-003186-28
: Bionor Pharma ASA
: Australia, Europe, United States
- Participants are HIV-infected adults who have been receiving ART continuously for at least 3 years.
- Participants have maintained viral load levels of less than 20 copies/mL and have CD4 counts of 500 cells/mm3 or more at the start of the study.
- Participants’ lowest ever CD4 counts were 250 cells/mm3 or above.
: The purpose of this study is to evaluate the safety and effectiveness of Vacc-4x when given prior to the investigational drug romidepsin
. The researchers will measure the effects of Vacc-4x on viral load, latent HIV, and the body’s immune responses.13
For more details on the studies listed above, see the Health Professional version
A number of other studies have evaluated the effects of Vacc-4x in HIV-infected participants. These include:
- A Phase II study that looked at the safety of Vacc-4x and its ability to produce an immune response in the body. Some participants from this study were followed for more than 7 years after their last injection.14,15
- A Phase I/II study (NCT01704781) that evaluated whether using Vacc-4x along with a drug called lenalidomide could improve participants’ CD4 counts.16
- A Phase I/II study (NCT01473810) that looked at an intranasal form of Vacc-4x, which is given to participants through the nose rather than through an injection. Researchers evaluated the safety of intranasal Vacc-4x and its ability to produce an immune response in the body.17
What side effects might Vacc-4x cause?
In the REDUC trial (NCT02092116) discussed under the previous question, 1 participant dropped out of the study early because of side effects that may have been related to Vacc-4x. Most of the side effects associated with Vacc-4x or the drug that was given to boost Vacc-4x’s effects, called an adjuvant, were mild in severity. The most common side effects related to Vacc-4x and its adjuvant were temporary redness and itching at the location where the injection was given. No serious side effects related to a study drug were reported. Other notable side effects that occurred during the study were related to romidepsin or to the planned break from ART.9,18
In the CT-BI Vacc-4x 2007/1 trial (NCT00659789), the majority of participants who received Vacc-4x plus an adjuvant had a side effect that the researchers thought might be related to treatment. Participants who received Vacc-4x plus an adjuvant experienced reactions at the location where the injection was given more often than participants who did not receive the vaccine. These reactions included itchiness, reddening, or hardening of the skin. Five serious side effects occurred in the Vacc-4x group but only 1 may have been caused by Vacc-4x.10,19
In the study evaluating intranasal Vacc-4x (NCT01473810), no serious side effects related to Vacc-4x were reported. Participants in all of the study groups, including the group that did not receive Vacc-4x, frequently experienced mild and temporary soreness inside their noses.17,20
Because Vacc-4x is still being studied, information on possible side effects of the vaccine is not complete. As testing of Vacc-4x continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying Vacc-4x?
More information about Vacc-4x-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.
How can I find more information about participating in a clinical trial?
Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.7
Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.
- Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on February 1, 2017.
- Bionor Pharma website. Fighting HIV infection. Available at: http://www.bionorpharma.com/en/About_us/. Last accessed on February 1, 2017.
- The History of Vaccines website. The Development of HIV Vaccines. Available at: http://www.historyofvaccines.org/content/articles/development-hiv-vaccines. Last accessed on February 1, 2017.
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014 Jun 2; 6:43. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Last accessed on February 1, 2017.
- Graziani GM and Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015; 18(1): 20497. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641978/. Last accessed on February 1, 2017.
- 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 Nov 13;24(17):2609-18. Available at: http://journals.lww.com/aidsonline/Fulltext/2010/11130/Low_frequency_of_amino_acid_alterations_following.2.aspx. Last accessed on February 1, 2017.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: https://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on February 1, 2017.
- Hudgens MG, Gilbert PB, Self SG. Endpoints in vaccine trials. Stat Methods Med Res. 2004; 13: 1-26. Available at: http://faculty.washington.edu/peterg/Vaccine2006/articles/HudgensGilbertSelfSMMR.pdf. Last accessed on February 1, 2017.
- 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. Available at: https://clinicaltrials.gov/ct2/show/NCT02092116. Last accessed on February 1, 2017.
- 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. Available at: https://clinicaltrials.gov/ct2/show/NCT00659789. Last accessed on February 1, 2017.
- 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. Available at: https://clinicaltrials.gov/ct2/show/NCT01712256. Last accessed on February 1, 2017.
- Søgaard OS, Graversen ME, Leth S, et al. The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PloS Pathog. 2015 Sep 17;11(9):e1005142. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575032/. Last accessed on February 1, 2017.
- 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. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003186-28/DK. Last accessed on February 1, 2017.
- 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 Sep 24;18(14):1875-83. Available at: http://journals.lww.com/aidsonline/Fulltext/2004/09240/HLA__and_dose_dependent_immunogenicity_of_a.3.aspx. Last accessed on February 1, 2017.
- 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 Aug;44(8):566–72. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22339485. Last accessed on February 1, 2017.
- 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. Available at: https://clinicaltrials.gov/ct2/show/NCT01704781. Last accessed on February 1, 2017.
- 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. Available at: https://clinicaltrials.gov/ct2/show/NCT01473810. Last accessed on February 1, 2017.
- 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 Oct;3(10):e463-72. Available at: http://www.natap.org/2016/HIV/PIIS23523018163005581.pdf. Last accessed on February 1, 2017.
- 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 Apr;14(4):291-300. Available at https://www.researchgate.net/publication/260195422/. Last accessed on February 1, 2017.
- 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 Nov 14;9(11): e112556. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232368/. Last accessed on February 1, 2017.
Last Reviewed: February 1, 2017