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

Trial Summary

What is the purpose of this trial?

Background: Researchers want see if three new HIV (human immunodeficiency virus) vaccines are safe. Two vaccines are carried by live adenoviruses, which are natural and typically cause cold symptoms or an eye infection. Researchers want to see if all the vaccines help fight HIV and if the adenoviruses are contagious. Objectives: To test the safety and effects of three new HIV vaccines. Eligibility: Healthy adults 18 49 years old (vaccinees) Their household and intimate contacts 18 65 years old Design: Vaccinees will be screened with: Physical exam Medical history Blood and urine tests Questions about HIV risk Vaccinees will learn how to prevent spreading the viruses and about required contraception during the study. Vaccinees will get consent forms for their household and intimate contacts. All contacts must be age 18 65. All intimate contacts must sign a consent form. Contacts will have 4 visits over 8 months for blood tests and a physical exam. All applicable participants will have a pregnancy test at every visit. Vaccinees will have about 9 visits over 12 months. They will repeat screening tests and get: 1 of the 2 adenovirus vaccines sprayed in the nose at 2 visits The booster vaccine by needle in an arm at 1 visit Nasal swabs taken at some visits Vaccinees will note their temperature and symptoms for at least 1 4 weeks after each vaccine. Vaccinees may choose to have: Leukapheresis. Blood will be removed by needle in a vein in one arm. A machine will remove white blood cells. The rest of the blood will be returned into the other arm. Small pieces of the tonsil removed Sponsoring Institute: National Institute of Allergy and Infectious Diseases ...

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.

What data supports the effectiveness of the HIV vaccine treatment Ad4-Env145NFL, Ad4-Env150KN, and VRC-HIVRGP096-00-VP?

The RV144 trial in Thailand showed that a similar HIV vaccine regimen using an HIV envelope protein with alum provided modest protection against HIV infection. This suggests that envelope-based vaccines, like the ones in this trial, could potentially offer some level of immune protection. ^{1 2 3 4 5}

Is the HIV vaccine generally safe for healthy volunteers?

The HIV vaccines, including those using adenovirus vectors and envelope proteins, have been tested in healthy volunteers and are generally safe. Some participants experienced mild local or systemic reactions, but no serious adverse events were linked to the vaccines. ^{6 7 8 9 10}

How is the HIV vaccine treatment Ad4-Env145NFL, Ad4-Env150KN, VRC-HIVRGP096-00-VP with alum different from other HIV treatments?

This treatment is unique because it uses adenovirus vectors (a type of virus used to deliver genetic material) to stimulate an immune response against HIV, which is different from traditional vaccines that often use proteins or inactivated viruses. The use of adenovirus vectors aims to enhance the body's immune response by delivering the HIV envelope protein directly into cells, potentially offering a new way to prevent HIV infection. ^{6 7 8 9 11}

Research Team

Mark Connors, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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.

- White blood cell count and lymphocyte count within 25% of both the lower limit and upper limit of normal for the NIH CC (ranges: 2.985-12.55 K/uL for white blood cells and 0.885 - 4.675 K/uL for lymphocytes).

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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 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]

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]

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 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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

A novel HIV vaccine adjuvanted by IC31 induces robust and persistent humoral and cellular immunity. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa. [2023]

3. Netherlands 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. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

HIV vaccines: progress to date. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Human immunodeficiency virus (HIV) immunopathogenesis and vaccine development: a review. [2011]

6. United States 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

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

8. United States 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. [2007]

9. United States pubmed.ncbi.nlm.nih.gov

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

10. United States 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. [2019]

11. United States 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). [2021]