mRNA Vaccines for HIV Prevention

Recruiting at 6 trial locations

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Must not be taking: Glucocorticoids, Immunoglobulin, Antiseizure, others

Disqualifiers: Pregnancy, Diabetes, Immunodeficiency, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This is a multicenter, open-label, non-randomized, dose escalation, first-in-human (FIH) trial to evaluate the safety and immunogenicity of CH505M5 N197D mRNA-gp160 and CH505 TF mRNA-gp160. Both products are mRNA encapsulated in lipid nanoparticles (LNPs) (subsequently referred to as mRNA-LNPs). The primary hypotheses are: 1. the CH505M5 N197D mRNA-gp160 will expand CH235-like B cell precursors, 2. the CH505 TF mRNA-gp160 will boost CH235-like bnAb B cell precursors to acquire more functional mutations needed for broadly neutralizing antibody (bnAb) development, and 3. these mRNA-LNPs will be safe and well tolerated among individuals living without HIV.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on medications that might impair your immune response, like certain steroids, you may need to discuss this with the trial team. It's best to consult with the trial staff about your specific medications.

What data supports the effectiveness of the treatment CH505M5 N197D mRNA-gp160, CH505M5 N197D mRNA-gp160, CH505 TF mRNA-gp160 for HIV prevention?

Research suggests that mRNA vaccines, when combined with certain immune-boosting agents, can enhance the body's immune response against HIV. This approach has shown promise in improving HIV-specific T-cell responses, which are crucial for controlling the virus. ^{1 2 3 4 5}

Is the mRNA vaccine for HIV prevention safe for humans?

The recombinant gp160 vaccine, which is related to the mRNA vaccine for HIV prevention, has been tested in several studies and found to be safe in humans, with no major adverse reactions reported. ^{1 6 7 8 9}

How is the mRNA vaccine treatment for HIV prevention different from other treatments?

The mRNA vaccine treatment for HIV prevention is unique because it uses mRNA to produce virus-like particles that stimulate the immune system to produce neutralizing antibodies, potentially reducing the risk of HIV infection. This approach is different from traditional vaccines as it involves mRNA technology, which is a newer method that instructs cells to make proteins that trigger an immune response. ^{1 10 11 12 13}

Eligibility Criteria

This trial is for adults in good health who do not have HIV. It's designed to test the safety and potential of two new mRNA-based vaccines that aim to prepare the immune system against HIV.

Inclusion Criteria

Agrees to specific requirements for HIV prevention and counseling

My blood counts, liver, kidney functions, calcium levels, and blood pressure are within required ranges.

Agrees to contraception and pregnancy testing requirements

Exclusion Criteria

Breastfeeding/chestfeeding or pregnant

I have recently received blood products or immunoglobulin.

I have recently been vaccinated.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CH505M5 N197D mRNA-gp160 at weeks 0, 8, and 16, followed by CH505 TF mRNA-gp160 at week 24

24 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• CH505M5 N197D mRNA-gp160 (Cancer Vaccine)
• CH505 TF mRNA-gp160 (Cancer Vaccine)

Trial Overview The study involves two experimental vaccines, CH505M5 N197D mRNA-gp160 and CH505 TF mRNA-gp160, which are given in stages to see if they can stimulate the body's immune cells to fight HIV more effectively.

Participant Groups

Group I: Group 4 (150 mcg) Experimental Treatment 2 Interventions

150 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16. Followed by: 150 mcg CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.

Group II: Group 3 (100 mcg) Experimental Treatment 2 Interventions

100 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16. Followed by: 100 mcg of CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.

Group III: Group 2 (50 mcg) Experimental Treatment 2 Interventions

50 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16. Followed by: 50 mcg of CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.

Group IV: Group 1 (25 mcg) Experimental Treatment 2 Interventions

25 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16. Followed by: 25 mcg of CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Department of Health and Human Services

Collaborator

Trials

240

Recruited

944,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

A novel HIV therapeutic vaccine using unmodified and modified mRNA showed promise in enhancing HIV-specific T-cell responses when combined with immunomodulators like Vesatolimod and Nivolumab, indicating a potential strategy for achieving a functional cure.

In vitro assays demonstrated that this combination therapy not only boosted T-cell responses but also increased the secretion of key mediators (IFNγ, IP10, MIP-1α, and MIP-1β) that are crucial for controlling the virus, suggesting a robust immune response against HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses. Usero, L., Leal, L., Gómez, CE., et al.[2023]

Recent advancements in HIV-1 vaccine development have led to a better understanding of the virus's structure and function, resulting in innovative vaccine strategies that show promise in eliciting immune responses.

Several vaccine candidates are currently in clinical trials, with some demonstrating the ability to reduce disease severity in nonhuman primates, indicating potential effectiveness in humans, even if they do not completely prevent infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current advances and challenges in HIV-1 vaccines. Rodriguez-Chavez, IR., Allen, M., Hill, EL., et al.[2019]

Despite the challenges faced in the past fifteen years of HIV vaccine trials, significant progress has been made in understanding how to design effective vaccines that elicit strong immune responses, particularly through the induction of CD8+ CTL responses.

Current promising HIV vaccine regimens are being evaluated in human trials, and recent successes in simian models provide hope that a safe and effective vaccine could soon be developed to help control the global HIV epidemic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HIV vaccine development: lessons from the past and promise for the future. Spearman, P.[2019]

The V-1 Immunitor HIV vaccine was well tolerated in a study of 40 patients, showing no significant adverse effects and resulting in a mean body weight gain of 2.2 kg over 27 weeks.

The vaccine led to significant increases in CD4 and CD8 cell counts, with increases of 51 (18%) and 172 (16%) cells/mm3 respectively, suggesting potential efficacy in enhancing immune response against HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of an oral HIV vaccine (V-1 Immunitor) in AIDS patients at various stages of the disease. Jirathitikal, V., Bourinbaiar, AS.[2004]

Recent studies indicate that lower doses of broad neutralizing antibodies may effectively prevent HIV-1 infection, suggesting a new approach to vaccine development.

The RV144 trial demonstrated a 31% efficacy for an HIV-1 vaccine, providing optimism for future vaccine strategies, but further research is needed to enhance immunogens and understand how to better induce protective antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is developing an HIV-1 vaccine possible? Haynes, BF., Liao, HX., Tomaras, GD.[2021]

The study evaluated the safety and immune response of the rgp160 HIV-1 vaccine in 138 HIV-negative volunteers, finding it to be safe with no major adverse reactions reported.

The vaccine induced strong antibody responses, particularly at the highest dose of 1,280 micrograms, and generated T cell responses against both the vaccine strain and some heterologous HIV strains, suggesting potential for further development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of humoral and cell-mediated anti-human immunodeficiency virus (HIV) responses in HIV sero-negative volunteers by immunization with recombinant gp160. Kovacs, JA., Vasudevachari, MB., Easter, M., et al.[2018]

The MN rgp160 vaccine was found to be safe for healthy, uninfected volunteers, with no serious adverse effects reported during the study.

The vaccine effectively induced a strong immune response, with 15 out of 20 participants developing neutralizing antibodies and significant T cell memory, particularly with the regimen that included a fourth dose of 800 micrograms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of immunologic responses to HIV-1MN recombinant gp160 vaccine by dose and schedule of administration. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. Gorse, GJ., McElrath, MJ., Matthews, TJ., et al.[2019]

An mRNA vaccine that co-expresses HIV-1 envelope and SIV Gag proteins successfully induced broad neutralizing antibodies and significantly reduced the risk of infection in rhesus macaques, demonstrating its potential as a protective vaccine against HIV.

The vaccination regimen, which included priming with a specific HIV-1 envelope followed by multiple boosters, resulted in a 79% reduction in infection risk during repeated challenges, indicating strong immunogenicity and effectiveness against prevalent HIV strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multiclade env-gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques. Zhang, P., Narayanan, E., Liu, Q., et al.[2023]

Modified Newcastle disease virus (NDV) vectors expressing the SIV envelope protein gp160 were shown to be safe and effective in eliciting strong immune responses in guinea pigs, indicating their potential as a vaccine vector for HIV.

These NDV vectors not only induced SIV-specific humoral and mucosal immune responses but also effectively generated neutralizing antibodies against different strains of SIV, suggesting their promise in HIV vaccine development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified Newcastle Disease virus as an improved vaccine vector against Simian Immunodeficiency virus. Manoharan, VK., Khattar, SK., LaBranche, CC., et al.[2019]

The new mRNA-based therapeutic vaccine, combining activation signals (TriMix) with HIV-specific antigens, effectively activated dendritic cells from HIV-infected individuals, leading to enhanced T-cell responses and cytokine production.

In mouse models, the vaccine not only increased antigen-specific cytotoxic T-lymphocyte responses but also showed that the addition of TriMix further boosted these immune responses, indicating its potential for developing effective therapeutic HIV vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix). Guardo, AC., Joe, PT., Miralles, L., et al.[2019]

Nucleoside-modified mRNA-lipid nanoparticle vaccines targeting the HIV-1 envelope showed promising immune responses, generating high levels of gp120-specific antibodies in rabbits and rhesus macaques, indicating potential for effective vaccination.

While some non-human primates developed antibodies that could neutralize a tier 2 HIV strain, the overall neutralization breadth and durability of the antibodies were limited, suggesting that further optimization of the vaccine design and protocols is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of HIV-1 Nucleoside-Modified mRNA Vaccines in Rabbits and Rhesus Macaques. Pardi, N., LaBranche, CC., Ferrari, G., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses. [2023]

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

Current advances and challenges in HIV-1 vaccines. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

HIV vaccine development: lessons from the past and promise for the future. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of an oral HIV vaccine (V-1 Immunitor) in AIDS patients at various stages of the disease. [2004]

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

Is developing an HIV-1 vaccine possible? [2021]

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

Safety and immunogenicity of a fully glycosylated recombinant gp160 human immunodeficiency virus type 1 vaccine in subjects at low risk of infection. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group Network. [2019]

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

Induction of humoral and cell-mediated anti-human immunodeficiency virus (HIV) responses in HIV sero-negative volunteers by immunization with recombinant gp160. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Modulation of immunologic responses to HIV-1MN recombinant gp160 vaccine by dose and schedule of administration. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Recombinant gp160 as a therapeutic vaccine for HIV-infection: results of a large randomized, controlled trial. European Multinational IMMUNO AIDS Vaccine Study Group. [2019]

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

A multiclade env-gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Modified Newcastle Disease virus as an improved vaccine vector against Simian Immunodeficiency virus. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix). [2019]

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

Characterization of HIV-1 Nucleoside-Modified mRNA Vaccines in Rabbits and Rhesus Macaques. [2022]