A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of CH505M5 N197D mRNA-gp160 Followed by CH505 TF mRNA-gp160 in Adults in Overall Good Health Without HIV
Overview
- Phase
- Phase 1
- Intervention
- CH505M5 N197D mRNA-gp160
- Conditions
- HIV Infections
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 53
- Locations
- 14
- Primary Endpoint
- Number of serious adverse events (SAEs) leading to early participant withdrawal or permanent discontinuation
- Status
- Active, not recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
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:
- the CH505M5 N197D mRNA-gp160 will expand CH235-like B cell precursors,
- 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
- these mRNA-LNPs will be safe and well tolerated among individuals living without HIV.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Demonstrates an understanding of the study and is able and willing to complete the informed consent process.
- •18 to 55 years old, inclusive, on day of enrollment.
- •Available for clinic follow-up through the last clinic visit and willing to undergo FNA of an axillary lymph node and undergo leukapheresis.
- •Agrees not to enroll in another study of an investigational agent during participation in the trial. If a potential participant is already enrolled in another clinical trial, approvals from the other trial sponsor and the HVTN 312 Protocol Safety Review Team (PSRT) are required prior to enrollment into HVTN
- •In good general health according to the clinical judgment of the site investigator.
- •Physical examination and laboratory results without clinically significant findings that would interfere with assessment of safety or reactogenicity in the clinical judgement of the site investigator.
- •For US sites: Agrees to discuss their potential for HIV acquisition and agrees to prevention counseling.
- •For non-US sites: Assessed by clinical staff as having a low likelihood of acquiring HIV per guidelines, agrees to discuss their potential for HIV acquisition, agrees to prevention counseling, and agrees to avoid behaviors associated with a higher likelihood of acquiring HIV through the final study visit. "Low likelihood" may include persons stably taking pre-exposure prophylaxis (PrEP) as prescribed.
- •Hemoglobin (Hgb):
- •≥ 11.0 g/dL for AFAB volunteers
Exclusion Criteria
- •Volunteer who is breastfeeding/chestfeeding or pregnant.
- •Body mass index (BMI) ≥
- •Enrollment of individuals with BMI ≥ 40, whom the site investigator assesses are in good health, may be considered by PSRT approval.
- •Diabetes mellitus (DM). Type 2 DM controlled with diet alone (and confirmed by HgbA1c ≤ 8% within the last 6 months) or a history of isolated gestational diabetes are not exclusionary. Enrollment of individuals with Type 2 DM that is well controlled on hypoglycemic agent(s) may be considered by the PSRT on a case-by-case basis, provided that the HgbA1c is ≤ 8% within the last 6 months (sites may draw these at screening).
- •Previous or current recipient of an investigational HIV vaccine or HIV mAb (previous placebo/control recipients are not excluded).
- •Receipt of non-HIV investigational vaccine(s) received within the last 1 year. Exceptions include vaccines that have subsequently undergone licensure or Emergency Use Authorization (EUA) by the FDA or World Health Organization (WHO) Emergency Use Listing (EUL), or if outside the US, by the national Regulatory Authority (RA) authorizing this clinical trial.
- •Congenital or acquired immunodeficiency, including systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator, such as glucocorticoid use, ≥ prednisone 10 mg/day within 3 months prior to enrollment.
- •Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires PSRT approval.
- •Receipt of any of the following within 4 weeks prior to enrollment:
- •Live replicating vaccine
Arms & Interventions
Group 1 (25 mcg)
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.
Intervention: CH505M5 N197D mRNA-gp160
Group 1 (25 mcg)
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.
Intervention: CH505 TF mRNA-gp160
Group 2 (50 mcg)
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.
Intervention: CH505M5 N197D mRNA-gp160
Group 2 (50 mcg)
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.
Intervention: CH505 TF mRNA-gp160
Group 3 (100 mcg)
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.
Intervention: CH505M5 N197D mRNA-gp160
Group 3 (100 mcg)
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.
Intervention: CH505 TF mRNA-gp160
Group 4 (150 mcg)
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.
Intervention: CH505M5 N197D mRNA-gp160
Group 4 (150 mcg)
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.
Intervention: CH505 TF mRNA-gp160
Outcomes
Primary Outcomes
Number of serious adverse events (SAEs) leading to early participant withdrawal or permanent discontinuation
Time Frame: 20 months
Number of adverse events (AEs) leading to early participant withdrawal or permanent discontinuation
Time Frame: 20 months
Response rate of serum Ab neutralization of vaccine-matched tier 2 HIV-1 strains, as measured by TZM-bl assay
Time Frame: Day 127 and 183 (2 weeks after the third and fourth vaccinations)
Number of medically attended adverse events (MAAEs) leading to early participant withdrawal or permanent discontinuation
Time Frame: 20 months
Number of adverse events of special interest (AESIs) leading to early participant withdrawal or permanent discontinuation
Time Frame: 20 months
Magnitude of differential serum antibody neutralization of precursor detection virus and corresponding epitope KO virus, as measured by the TZM-bl assay
Time Frame: Day 127 and 183 (2 weeks after the third and fourth vaccinations)
Frequency of local reactogenicity signs and symptoms after receipt of any study vaccine
Time Frame: Day 15, 71, 127 and 183 (14 days following receipt of any study vaccine)
Frequency of systemic reactogenicity signs and symptoms after receipt of any study vaccine
Time Frame: Day 15, 71, 127 and 183 (14 days following receipt of any study vaccine)
Magnitude of serum Ab neutralization of vaccine-matched tier 2 HIV-1 strains, as measured by TZM-bl assay
Time Frame: Day 127 and 183 (2 weeks after the third and fourth vaccinations)
Response rate of differential serum antibody neutralization of precursor detection virus and corresponding epitope KO virus, as measured by the TZM-bl assay
Time Frame: Day 127 and 183 (2 weeks after the third and fourth vaccinations)
Response rate of CD4-bs and CH505M5-specific IgG+ B cells as assessed by flow cytometry
Time Frame: Day 127 and 183 (2 weeks after the third and fourth vaccinations)
Secondary Outcomes
- Epitope specific response rates as measured by electron microscopy-based polyclonal epitope mapping (EMPEM)(Day 183 (2 weeks after the fourth vaccination))
- Magnitude of serum IgG binding Abs to Env Trimers and neutralizing epitopes as assessed by BAMA(Day 337 (24 weeks after the fourth vaccination))
- Response rate of serum IgG binding antibodies to autologous and heterologous HIV Env stabilized trimers, as assessed by binding antibody multiplex assay (BAMA)(Day 127 and 183 (2 weeks after the third and fourth vaccinations))
- Magnitude of serum Ab neutralization of heterologous HIV-1 strains as measured by TZM-bl assay(Day 127 and 183 (2 weeks after the third and fourth vaccinations))
- Frequency of CD4-bs specific sequences, as measured by BCR single cell sequencing of CD4-bs and CH505M5-specific IgG+ B cells(20 months)
- Magnitude of serum Ab neutralization of autologous, heterologous and precursor HIV-1 strains as measured by TZM-bl assay(Day 337 (24 weeks after the fourth vaccination))
- Response rate of CD4-bs and CH505M5-specific IgG+ B cells as measured by flow cytometry(Day 337 (24 weeks after the fourth vaccination))
- Magnitude of serum IgG binding antibodies to autologous and heterologous HIV Env stabilized trimers, as assessed by BAMA(Day 127 and 183 (2 weeks after the third and fourth vaccinations))
- Response rate of serum IgG binding Abs to Env Trimers and neutralizing epitopes as assessed by BAMA(Day 337 (24 weeks after the fourth vaccination))
- Response rate of serum Ab neutralization of autologous, heterologous and precursor HIV-1 strains as measured by TZM-bl assay(Day 337 (24 weeks after the fourth vaccination))
- Response rate of serum Ab neutralization of heterologous HIV-1 strains as measured by TZM-bl assay(Day 127 and 183 (2 weeks after the third and fourth vaccinations))