HIV Vaccines Safety and Response in Healthy Volunteers

Overseen By Mark Connors, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Glucocorticoids, Immunosuppressives, Antivirals, others

Disqualifiers: Immunodeficiency, Uncontrolled diabetes, Asthma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 10

Duration: 6 months

300 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of three new HIV vaccines and evaluate their effectiveness in helping the body fight HIV. Two of these vaccines, Ad4-Env145NFL and Ad4-Env150KN, use live adenoviruses, which are common viruses that typically cause mild cold or eye symptoms. The study will also assess whether these viruses can spread to others. Healthy adults at low risk of HIV infection and willing to follow safety guidelines can participate. Participants will visit the clinic multiple times over a year to receive the vaccines and undergo health checks. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive these new vaccines.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking glucocorticoids or other immunosuppressive medications, or if you have taken antiviral medications within 30 days prior to vaccination.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have tested the vaccines Ad4-Env150KN and Ad4-Env145NFL, which use live adenoviruses, for safety. These vaccines did not transmit HIV and were expected to be safe for humans. However, the adenoviruses might cause mild symptoms like a cold or an eye infection, which are common for these types of viruses.

Research has shown that the VRC-HIVRGP096-00-VP (Trimer 4571) with alum was safe and well-tolerated in other studies. No serious side effects were found, and it helped the immune system respond to HIV.

These vaccines are in an early phase of testing, which focuses on safety and usually involves a small number of people. Although safety data is limited at this stage, no major concerns have been reported so far. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these HIV vaccine treatments because they use innovative viral vector technology and unique protein constructs to stimulate the immune system. Unlike traditional methods that focus on antiretroviral drugs to manage the virus, these vaccines, like Ad4-Env150KN and Ad4-Env145NFL, introduce specific HIV proteins to encourage the body to build immunity. The VRC-HIVRGP096-00-VP (Trimer 4571) component further enhances this response by presenting a trimeric form of the HIV envelope protein, which is designed to mimic the virus's structure more closely and potentially elicit a stronger immune defense. This approach aims to provide long-lasting protection, offering a proactive solution rather than managing the condition post-infection.

What evidence suggests that this trial's HIV vaccines could be effective?

Research has shown that the Ad4-Env150KN and Ad4-Env145NFL vaccines, which participants in this trial may receive, are designed to help the body fight HIV. These vaccines use adenoviruses, typically causing mild cold-like symptoms, to deliver parts of the HIV virus into the body. Early studies indicate they are safe and can trigger immune responses. Another treatment option in this trial, the VRC-HIVRGP096-00-VP (Trimer 4571) with alum, has also been proven safe and can activate the immune system in humans. These vaccines aim to teach the body's immune system to recognize and combat HIV effectively. ^{1 2 4 6 7}

Who Is on the Research Team?

Mark Connors, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

Healthy adults aged 18-49 (vaccinees) and their close contacts aged 18-65 can join this trial. Participants must test negative for HIV, not be pregnant or breastfeeding, agree to use contraception, and have no history of immune or lung function issues. They should also commit to the full duration of the study.

Inclusion Criteria

You cannot receive any other experimental or HIV vaccines during the study.

I am using birth control pills, Norplant, or Depo-Provera without any interfering medications.

- The female vaccinee and her male intimate contact(s) agree to be heterosexually inactive or consistently practice contraception at least 21 days prior to each vaccination through 28 days following each vaccination. Acceptable methods of contraception include any of the following:

Exclusion Criteria

I am not taking steroids or other immune-suppressing drugs.

- Indeterminate HIV Western blot test.

The following exclusion criteria apply only to vaccinees and not to household or intimate contacts:

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive the Ad4-Env150KN or Ad4-Env145NFL vaccine intranasally at months 0 and 2, followed by a booster vaccine at month 6

6 months

9 visits (in-person)

Follow-up

Participants are monitored for safety and immunogenicity, with assessments at specified time points through month 12

6 months

Ongoing assessments

Extension

Participants may opt into additional monitoring or exploratory analysis if previously vaccinated

Ongoing

What Are the Treatments Tested in This Trial?

Interventions

• Ad4-Env145NFL
• Ad4-Env150KN
• VRC-HIVRGP096-00-VP (Trimer 4571) with alum

Trial Overview The trial is testing three new HIV vaccines: two are adenovirus-based nasal sprays and one is a booster shot with alum given by needle. The goal is to assess safety, immune response, and whether the live viruses used in vaccines spread.

How Is the Trial Designed?

Group I: B2 (exploratory) Experimental Treatment 2 Interventions

Previously vaccinated; Ad4-Env145NFL at Day 0 and 2 months followed VRC-HIVRGP096-00-VP at 6 months.

Group II: B1 (exploratory) Experimental Treatment 2 Interventions

Previously vaccinated; Ad4-Env150KN at Day 0 and 2 months followed VRC-HIVRGP096-00-VP at 6 months.

Group III: A2 Experimental Treatment 2 Interventions

Ad4-Env145NFL at Day 0 and 2 months followed VRC-HIVRGP096-00-VP at 6 months.

Group IV: A1 Experimental Treatment 2 Interventions

Ad4-Env150KN at Day 0 and 2 months followed VRC-HIVRGP096-00-VP at 6 months.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

The Ad26-EnvA HIV vaccine was found to be generally safe and well-tolerated in a phase 1 study involving 60 healthy participants, with no serious adverse events related to the vaccine reported.

All participants who received the vaccine developed strong immune responses, including neutralizing antibodies and specific T-cell responses, indicating that the vaccine is immunogenic and may be a promising candidate for further HIV prevention efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env vaccine (IPCAVD 001). Baden, LR., Walsh, SR., Seaman, MS., et al.[2021]

In a study involving 1398 healthy HIV-negative volunteers across 26 clinical trials, candidate HIV-1 vaccines were generally well tolerated, with only mild to moderate local and systemic reactions linked to certain adjuvants.

No serious adverse effects or significant immunosuppressive events were reported, indicating that the envelope-based recombinant or synthetic HIV-1 vaccines are safe and pave the way for more complex vaccine testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of phase I and II preventive HIV type 1 envelope vaccination: experience of the NIAID AIDS Vaccine Evaluation Group. Keefer, MC., Wolff, M., Gorse, GJ., et al.[2007]

A new HIV vaccine strategy using a clade C CN54gp140 envelope protein with the TLR9 agonist IC31® showed improved immune responses in mice, leading to better antibody production compared to traditional alum adjuvants.

The combination of gp140 priming with IC31® and boosting with the NYVAC-CN54 vector resulted in strong T cell responses and the formation of long-lasting memory immune cells, suggesting this approach could enhance protection against HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel HIV vaccine adjuvanted by IC31 induces robust and persistent humoral and cellular immunity. Pattacini, L., Mize, GJ., Graham, JB., et al.[2021]

Over 1500 healthy individuals have participated in studies of HIV-1 vaccines, which have shown good safety profiles with no serious toxicity reported, indicating that these vaccines are well tolerated.

Candidate vaccines, particularly those using gp120 and vaccinia vectors, successfully induce immune responses, including neutralizing antibodies and cytotoxic T cell activity, although they currently only neutralize laboratory-adapted HIV-1 strains, not primary isolates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human studies in the development of human immunodeficiency virus vaccines. Dolin, R.[2019]

The RV306 trial, involving 367 healthy HIV-uninfected participants, found that additional vaccine boosts at longer intervals after the initial RV144 regimen significantly improved immune responses, particularly in antibody levels against HIV antigens.

No serious vaccine-related adverse events were reported, indicating that the additional boosts were safe and well-tolerated, which is crucial for the potential efficacy of the vaccine in preventing HIV acquisition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial. Pitisuttithum, P., Nitayaphan, S., Chariyalertsak, S., et al.[2021]

The HVTN 120 trial, involving 160 healthy HIV-uninfected adults, demonstrated that the ALVAC-HIV vaccine was generally safe and well tolerated, with no significant safety concerns reported.

Among the different vaccine regimens tested, the 40 μg gp120 protein adjuvanted with AS01B produced the strongest immune responses, showing higher CD4+ T-cell responses and binding antibody levels compared to other formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protein dose-sparing effect of AS01B adjuvant in a randomized preventive HIV vaccine trial of ALVAC-HIV (vCP2438) and adjuvanted bivalent subtype C gp120. Chirenje, ZM., Laher, F., Dintwe, O., et al.[2023]

The ALVAC-HIV vCP1521 vector has shown over 31% protective efficacy in the RV144 phase III HIV vaccine study, indicating its potential as an effective vaccine delivery system.

Two robust immunoplaque methods confirmed that the ALVAC-HIV vCP1521 lots expressed the gp120 and gag proteins in over 99% of infectious plaques, demonstrating the stability and potency of this vaccine construct.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short communication: evaluating the level of expressed HIV type 1 gp120 and gag proteins in the vCP1521 vector by two immunoplaque methods. Azizi, A., Edamura, KN., Leung, G., et al.[2019]

The HVTN 097 trial in South Africa showed that the RV144 HIV vaccine elicited significantly stronger cellular and humoral immune responses compared to the original RV144 trial in Thailand, indicating enhanced immunogenicity in a different population.

Cross-clade immune responses in the HVTN 097 trial were better than anticipated, suggesting that the vaccine regimen may have broader applicability against diverse HIV strains, particularly clade C, which is prevalent in South Africa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa. Gray, GE., Huang, Y., Grunenberg, N., et al.[2023]

The RV144 Thai trial showed that a vaccine regimen using envelope-based immunogens provided modest protection against HIV-1 infection in a low-risk population, despite not inducing neutralizing antibodies, suggesting alternative mechanisms like antibody-dependent cell-mediated cytotoxicity may play a role in protection.

The study highlights the need for a new approach to HIV-1 vaccine design that balances the induction of both humoral and cell-mediated immunity, as traditional methods have not yet achieved the desired efficacy, particularly in light of previous trials that raised safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HIV vaccines: progress to date. Munier, CM., Andersen, CR., Kelleher, AD.[2021]

The RV144 Phase III trial in Thailand is the only human study to show a statistically significant level of protection against HIV-1 infection, highlighting the potential for developing an effective vaccine.

Despite the modest success of the RV144 trial, further research is crucial to understand the immune mechanisms that provided protection, which could accelerate the development of a more effective HIV vaccine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human immunodeficiency virus (HIV) immunopathogenesis and vaccine development: a review. Girard, MP., Osmanov, S., Assossou, OM., et al.[2011]

The recombinant adenovirus serotype 26 HIV-1 Env vaccine was found to be generally safe in a study of 60 healthy volunteers, with no serious vaccine-related adverse events reported.

The vaccine successfully induced immune responses, including neutralizing antibodies and cellular responses against the HIV envelope protein, which persisted for at least one year, suggesting potential for further efficacy trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress in the development of an adenovirus 26 vector platform for HIV vaccines. Esparza, J.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03878121

Safety and Immunogenicity of Ad4-HIV Envelope Vaccine ... The overall goal will be to compare the safety and immunogenicity of the Ad-HIV vaccine regimens. Participants who have previously received another HIV vaccine ...

2. reporter.nih.gov reporter.nih.gov/project-details/8487365

RePORT RePORTER - National Institutes of Health (NIH) | The development of a safe and protective vaccine against the Human Immunodeficiency Virus (HIV) that causes AIDS has been very difficult. The proposed research ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03878121?term=AREA%5BConditionSearch%5D(%22Alzheimer%20Disease%20Type%203%22)&rank=2

Safety and Immunogenicity of Ad4-HIV Envelope Vaccine ... Each study vaccinee will receive 5x10^8 viral particles of either Ad4-Env150KN or Ad4-Env145NFL, administered as an intranasal spray at months 0 and 2. An ...

4. withpower.com withpower.com/trial/phase-1-3-2019-0148a

HIV Vaccines Safety and Response in Healthy Volunteers What data supports the effectiveness of the HIV vaccine treatment Ad4-Env145NFL ... The ALVAC-HIV vCP1521 vector has shown over 31% protective efficacy in ...

5. avac.org avac.org/trial/19-i-0069/

19-I-0069 - AVAC Objective:Safety and Immunogenicity of Ad4-HIV Envelope Vaccine Vectors in Healthy VolunteersResearchers want see if three new HIV (human immunodeficiency ...

6. niaid.nih.gov niaid.nih.gov/clinical-trials/wings-healthy-volunteer-study

WINGS Healthy Volunteer Study | NIAID The purpose of the study is to test HIV vaccines to see if they are safe. It is not possible to get HIV through participating in the study.

7. clinicalstudies.info.nih.gov clinicalstudies.info.nih.gov/protocoldetails.aspx?id=19-I-0069&&query=Adult

19-I-0069 Phase I Open-Label Study of Safety and Immunogenicity of AD4-HIV Envelope Vaccine Vectors in Healthy Volunteers. This study is currently recruiting ...