A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of Priming Regimens of 426c.Mod.Core-C4b and Optional Boost Regimen With HIV Trimer BG505 SOSIP.GT1.1 gp140, Both Adjuvanted With 3M-052-AF + Alum in Healthy, Adult Participants Without HIV
Overview
- Phase
- Phase 1
- Intervention
- 426c.Mod.Core-C4b 100 mcg
- Conditions
- HIV-1-infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 52
- Locations
- 6
- Primary Endpoint
- Frequency of CD4-bs-specific B cells
- Status
- Active, Not Recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
The clinical study is designed to evaluate the ability of two priming vaccine regimens to activate and induce the maturation of cross-reactive CD4 binding site (CD4-bs) antibodies, including VRC01-class antibodies. VRC01- class antibodies are highly desirable to elicit via vaccination because they have broad cover all clades of HIV and passive administration of VRC01 monoclonal antibodies has been demonstrated to prevent acquisition of susceptible HIV strains in clinical trials. The study will assess whether B cells expressing VRC01-like B cell receptors proliferate following immunization with a 'germline-targeting' recombinant Env immunogen. The study will also test whether an immunization strategy based upon fractionated dose delivery of the immunogen may improve the maturation of VRC01-class B cells when compared to traditional bolus dosing. In addition, the study will test whether alterations in the dose of the subsequent boost immunizations affects VRC01-class B cell activation and the rate of antibody affinity maturation.
The primary hypothesis of the optional boost regimen is that BG505 SOSIP.GT1.1 gp140 adjuvated with 3M-052-AF + Alum is safe and well-tolerated and will further mature B-cell lineages elicited by 426c.Mod.Core-C4b priming regimens.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Able and willing to complete the informed consent process, including an Assessment of Understanding: volunteer demonstrates understanding of this study; completes a questionnaire prior to first vaccination with verbal demonstration of understanding of any questionnaire items answered incorrectly.
- •18-55 years old, inclusive, on day of enrollment.
- •Available for clinic follow-up through the last clinic visit, willing to under go lymph node fine needle aspiration, and willing to be contacted 12 months after the last vaccine administration.
- •Agrees not to enroll in another study of an investigational agent during participation in the trial.
- •In good general health according to the clinical judgement 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.
- •Assessed as low risk for HIV acquisition per low risk guidelines, agrees to discuss HIV infection risks, agrees to risk reduction counseling, and agrees to avoid behavior associated with high risk of HIV exposure through the final study visit. Low risk may include persons stably taking pre-exposure prophylaxis (PrEP) as prescribed for 6 months or longer.
- •Hemoglobin:
- •≥ 11.0 g/dL for volunteers who were assigned female sex at birth
- •≥ 13.0 g/dL for volunteers who were assigned male sex at birth and transgender males who have been on hormone therapy for more than 6 consecutive months
Exclusion Criteria
- •Volunteer who is breast-feeding or pregnant.
- •Morbid Obesity. Enrollment of individuals with body mass index (BMI) ≥40, who the site investigator assesses are in good health, may be considered by PSRT on a case-by-case basis.
- •Diabetes mellitus (DM). Type 2 DM, controlled with diet alone, 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, provided the HgbA1c is ≤8% within the last 6 months (sites may draw these at screening).
- •International normalized ratio (INR) \>1.
- •Previous or current recipient of an investigational HIV vaccine (previous placebo recipients are not excluded).
- •Receipt of non-HIV experimental vaccine(s) received within the last 1 year. Exceptions may be made by the PSRT for vaccines that have subsequently undergone licensure or Emergency Use Authorization by the FDA or, if outside the United States, by the national regulatory authority or World Health Organization. For volunteers who have received control/placebo in an experimental vaccine trial, the PSRT will determine eligibility on a case-by-case basis.
- •Systemic glucocorticoid use equal to or greater than prednisone 10 mg/day within 3 months prior to enrollment, other systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator, or congenital or acquired immunodeficiency.
- •Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires PSRT approval.
- •Previous receipt of VRC01 monoclonal antibody.
- •Receipt of any live replicating vaccine within 4 weeks prior to enrollment. For receipt of ACAM2000 vaccine \>28 days prior with a vaccination scab still present.
Arms & Interventions
Fractionated Delivery, Group 2: First injection - Medium dose, Final injection - Higher dose
The first dose for the Fractionated Delivery Arm Group 2 will be divided into 6 smaller amounts (2 visits per week for 3 weeks). The second dose will be given about 3 months later and will be given all at once. At each injection visit for the first dose, the patient will get one amount divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 100 mcg
Bolus Delivery, Group 1: First injection - Medium dose, Final injection - Lower dose
The Bolus Delivery Arm Group 1 will receive injections at 2 visits scheduled 3 months apart. At each injection visit the patient will get one dose divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 30 mcg
Bolus Delivery, Group 1: First injection - Medium dose, Final injection - Lower dose
The Bolus Delivery Arm Group 1 will receive injections at 2 visits scheduled 3 months apart. At each injection visit the patient will get one dose divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 100 mcg
Bolus Delivery, Group 2: First injection - Medium dose, Final injection - Higher dose
The Bolus Delivery Arm Group 2 will receive injections at 2 visits scheduled 3 months apart. At each injection visit the patient will get one dose divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 100 mcg
Bolus Delivery, Group 2: First injection - Medium dose, Final injection - Higher dose
The Bolus Delivery Arm Group 2 will receive injections at 2 visits scheduled 3 months apart. At each injection visit the patient will get one dose divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 300 mcg
Bolus Delivery, Group 3: First injection - Placebo, Final injection - Placebo
The Bolus Delivery Arm Group 2 will receive injections at 2 visits scheduled 3 months apart. At each injection visit the patient will get one dose divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: Placebo
Fractionated Delivery, Group 1: First injection - Medium dose, Final injection - Lower dose
The first dose for the Fractionated Delivery Arm Group 1 will be divided into 6 smaller amounts (2 visits per week for 3 weeks). The second dose will be given about 3 months later and will be given all at once. At each injection visit for the first dose, the patient will get one amount divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 30 mcg
Fractionated Delivery, Group 1: First injection - Medium dose, Final injection - Lower dose
The first dose for the Fractionated Delivery Arm Group 1 will be divided into 6 smaller amounts (2 visits per week for 3 weeks). The second dose will be given about 3 months later and will be given all at once. At each injection visit for the first dose, the patient will get one amount divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 100 mcg
Fractionated Delivery, Group 2: First injection - Medium dose, Final injection - Higher dose
The first dose for the Fractionated Delivery Arm Group 2 will be divided into 6 smaller amounts (2 visits per week for 3 weeks). The second dose will be given about 3 months later and will be given all at once. At each injection visit for the first dose, the patient will get one amount divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: 426c.Mod.Core-C4b 300 mcg
Fractionated Delivery, Group 3: First injection - Placebo, Final injection - Placebo
The first dose for the Fractionated Delivery Arm Group 2 will be divided into 6 smaller amounts (2 visits per week for 3 weeks). The second dose will be given about 3 months later and will be given all at once. At each injection visit for the first dose, the patient will get one amount divided into 2 injections - one in the deltoid muscle of each arm.
Intervention: Placebo
Optional Boost Regimen with BG505
SOSIP.GT1.1 gp140
Intervention: BG505
Outcomes
Primary Outcomes
Frequency of CD4-bs-specific B cells
Time Frame: Through week 27
Measured by flow cytometry analysis
Frequency of VRC01-like BCR sequences
Time Frame: Through week 27
Determined by variable heavy chain domain (VH)/variable light chain domain (VL) sequencing of sorted B cells
Number of participants showing local vaccination reactogenicity signs and symptoms
Time Frame: 14 days following each vaccination
Assessed by clinic staff. For a given sign or symptom, each subject's reactogenicity will be counted once under the maximum severity for each injection/ vaccination.
Number of participants showing systemic vaccination reactogenicity signs and symptoms
Time Frame: 14 days following each vaccination
Assessed by clinic staff. For a given sign or symptom, each subject's reactogenicity will be counted once under the maximum severity for each injection/ vaccination.
Number of serious adverse events (SAEs)
Time Frame: Through week 64
Adverse events (AEs) will be graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (exceptions apply).
Number of medically attended adverse events (MAAEs)
Time Frame: Through week 64
Adverse events (AEs) will be graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (exceptions apply).
Number of adverse events of special interest (AESIs)
Time Frame: Through week 64
Adverse events (AEs) will be graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (exceptions apply).
Number of AEs leading to early participant withdrawal or permanent discontinuation
Time Frame: Through week 64
Adverse events (AEs) will be graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (exceptions apply).
Secondary Outcomes
- Response rate of Env-specific serum IgG binding antibodies.(Through week 27)
- Magnitude of Env-specific serum IgG binding antibodies.(Through week 27)
- Epitope-specificity of Env-specific serum IgG binding antibodies.(Through week 27)
- Avidity of Env-specific serum IgG binding antibodies.(Through week 27)
- Frequency of CD4-bs B cells and BCR sequences of isolated CD4-bs and VRC01-class memory B cells induced post-immunization with the traditional bolus dosing versus the fractionated dose delivery approach.(Through week 27)
- Frequency of CD4-bs B cells and BCR sequences of isolated CD4-bs and VRC01-class memory B cells induced post-immunization induced following a "low" or "high" dose second dose.(14 days following second vaccination)
- Frequency of VRC01-class memory B cells induced post-immunization with the traditional bolus dosing versus the fractionated dose delivery approach.(Through week 27)
- Frequency of VRC01-class memory B cells induced following a "low" or "high" dose second dose.(14 days following second vaccination)
- Response rate of serum antibody neutralization of the vaccine strain(14 days following each vaccination)
- Response rate of serum antibody neutralization of a panel of CD4-bs bnAb precursor-sensitive viruses.(14 days following each vaccination)
- Magnitude of serum antibody neutralization of the vaccine strain(14 days following each vaccination)
- Magnitude of serum antibody neutralization of a panel of CD4-bs bnAb precursor-sensitive viruses.(14 days following each vaccination)
- Comparison of CD4-bs-specific B cell frequencies in fractionated dosing versus traditional bolus dosing.(Through week 27)
- Comparison of BCR sequences frequencies in fractionated dosing versus traditional bolus dosing.(Through week 27)
- Response rate of VH/VL-pair sequence analysis of BCRs isolated from CD-4-bs-specific B cells(!4 days following each vaccination)
- Response rate of BG505 SOSIP.GT1.1 gp140 on the neutralizing activities of vaccine-induced antibodies in participants primed with 426c(Through week 27)
- Response rate of BG505 SOSIP.GT1.1 gp140 on the quality and quantity of Env-specific binding antibodies elicited after the GT1.1 immunization in participants primed with 426c(Through week 27)
- . Magnitude of BG505 SOSIP.GT1.1 gp140 on the quality and quantity of Env-specific binding antibodies elicited after the GT1.1 immunization in participants primed with 426c(Through week 27)
- Epitope specificity of BG505 SOSIP.GT1.1 gp140 on the quality and quantity of Env-specific binding antibodies elicited after the GT1.1 immunization in participants primed with 426c(Through week 27)
- Comparison of CD4-bs antibodies isolated after the GT.1 immunization, as compared to those elicited by the 426c(Through week 27)
- Response rate of BG505 SOSIP.GT1.1 gp140 on the CD4+ T cell response in participants primed with 426c(Through week 27)
- Magnitude of BG505 SOSIP.GT1.1 gp140 on the CD4+ T cell response in participants primed with 426c(Through week 27)