A First-in-human Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of Stabilized CH505 TF chTrimer in Healthy, HIV-uninfected Adult Participants.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 6
- 主要终点
- Frequency of v2 apex and V3 glycan- specific IgG+ B cells
研究概览
简要总结
This is an open-label Phase 1 study to examine the safety and immunogenicity of the CH505 TF chTrimer vaccine with 3M-052-AF +/- Alum adjuvant in healthy adults. The primary hypothesis is that the CH505 TF chTrimer will expand CH103-like B-cell precursors.
HVTN 300 Part A examined the safety and immunogenicity of the CH505TF chTrimer with 5 mcg 3M-052-AF + 500 mcg Alum.
HVTN 300 Part B was added to this protocol with a goal of assessing the optimal dosing and combination of 3M-052-AF and Alum adjuvant, that can potentially lead to improved neutralizing antibody activity and decreased reactogenicity, compared to Part A. Three groups were added to Part B (Group 2: 3 mcg 3M-052-AF without Alum, Group 3: 3 mcg 3M-052 with Alum, and Group 4: 5 mcg 3M-052-AF without Alum).
HVTN 300 Part B is being added to this protocol with a goal of assessing the optimal dosing and combination of 3M-052-AF and Alum adjuvant, that can potentially lead to improved neutralizing antibody activity and decreased reactogenicity, compared to Part A. Three groups have been added to Part B (Group 2: 3 mcg 3M-052-AF without Alum, Group 3: 3 mcg 3M-052 with Alum, and Group 4: 5 mcg 3M-052-AF without Alum).
详细描述
The primary hypothesis is that the CH505 TF chTrimer vaccine will expand B cell precursor lineages capable of ultimately producing autologous and heterologous Tier 2 broadly neutralizing antibodies (bnAbs). Participants receive CH505 TF chTrimer plus 3M-052-AF (at either a 3 mcg dose or a 5 mcg dose), with or without Alum, via two intramuscular injections administered five times throughout the study. Participants are evaluated for safety and immune responses through blood collection at specified timepoints throughout the study. Each participant has up to 18 months of scheduled clinic visits and a follow-up safety assessment 12 months after their final vaccination.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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 all 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 undergo lymph node fine needle aspiration and leukapheresis, 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 (see protocol for more information), 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 PrEP (pre- exposure prophylaxis) as prescribed for 6 months or longer.
- •Hemoglobin >12.5 mg/dL to 18 mg/dL
- •White blood cell (WBC) count > 3,500/mm³
- •Platelets ≥125,000 /mm³
- •Alanine aminotransferase (ALT) < 2.5 x ULN based on the institutional normal range
- •Serum creatinine ≤1.1 x ULN based on the institutional normal range
- •Blood pressure in the range of 90 to < 160 mmHg systolic and 50 to < 100 mmHg diastolic.
- •Negative results for HIV infection by an FDA-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA).
- •Negative for anti-Hepatitis C antibodies (anti-HCV) or negative HCV nucleic acid test (NAT) if anti-HCV antibodies are detected.
- •Negative for Hepatitis B surface antigen.
- •For a volunteer capable of becoming pregnant:
- •Volunteers who were assigned female sex at birth and are of reproductive potential must agree to use effective means of birth control from at least 21 days prior to enrollment through 8 weeks after their fifth vaccination timepoint (see Appendix E).
- •Has negative β-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment.
排除标准
- •Volunteer who is breast-feeding or pregnant.
- •Previous or current recipient of an investigational HIV vaccine (previous placebo recipients are not excluded).
- •Systemic glucocorticoid use equal to or greater than prednisone10 mg/day within 3 months prior to enrollment, congenital or acquired immunodeficiency or other systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator.
- •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 live attenuated vaccine within 4 weeks prior to enrollment.
- •Receipt of any vaccines that are not live attenuated within 14 days prior to enrollment; replication incompetent vaccines such as the Jynneos vaccine for the prevention of monkeypox disease are not considered to be live vaccines.
- •ACAM2000 vaccine for Monkeypox received within 30 days prior to enrollment or receipt of study product, or if ACAM2000 received greater than 30 days prior to enrollment or receipt of study product, vaccination scab still present; or planned administration within 30 days after enrollment or receipt of study product.
- •Initiation of antigen-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiated immunotherapy within the previous year requires PSRT approval.
- •Receipt of investigational research agents with a half-life of 7 or fewer days within 4 weeks prior to enrollment. If a potential participant has received investigational agents with a half-life greater than 7 days (or unknown half- life) within the past year, PSRT approval is required for enrollment.
- •Serious reactions to vaccines that preclude receipt of study injections as determined by the principal investigator or designee. History of serious reaction (eg. hypersensitivity, anaphylaxis) to any vaccine or any component of the study vaccine, including imidazoquinolone (eg, imiquimod).
- •Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.
- •Idiopathic urticaria within the past year.
- •Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions).
- •Seizure disorder; febrile seizures as a child or seizures secondary to alcohol withdrawal more than 5 years ago are not exclusionary.
- •Asplenia or functional asplenia.
- •Active duty and reserve US military personnel.
- •Any other chronic or clinically significant condition that in the clinical judgement of the investigator would jeopardize the safety or rights of the study participant, including, but not limited to: clinically significant forms of drug or alcohol abuse, serious psychiatric disorders, or cancer that, in the clinical judgement of the site investigator, has a potential for recurrence (excluding basal cell carcinoma).
- •Asthma is excluded if the participant has ANY of the following:
- •Required either oral or parenteral corticosteroids for an exacerbation two or more times within the past year; OR
- •Needed emergency care, urgent care, hospitalization, or intubation for an acute asthma exacerbation within the past year (eg, would NOT exclude individuals with asthma who meet all other criteria but sought urgent/emergent care solely for asthma medication refills or co-existing conditions unrelated to asthma); OR
- •Uses a short-acting rescue inhaler more than 2 days/week for acute asthma symptoms (ie, not for preventive treatment prior to athletic activity); OR
- •Uses medium-to-high-dose inhaled corticosteroids (greater than 250 mcg fluticasone or therapeutic equivalent per day), whether in single-therapy or dual-therapy inhalers (ie, with a long-acting beta agonist [LABA]);
- •Uses more than one medication for maintenance therapy daily. Inclusion of anyone on a stable dose of more than one medication for maintenance therapy daily for greater than two years requires PSRT approval.
- •A participant with a history of an immune-mediated disease, either active or remote. Specific examples are listed in Appendix F (AESI index). Not exclusionary:
- •remote history of Bell's palsy (>2 years ago) not associated with other neurologic symptoms,
- •mild psoriasis that does not require ongoing systemic treatment
- •History of allergy to local anesthetic (Novocaine, Lidocaine).
- •Investigator concern for difficulty with venous access based upon clinical history and physical examination. For example, history of IV drug abuse or substantial difficulty with previous blood draws.
研究组 & 干预措施
Group 2: Treatment
CH505 TF chTrimer 300 mcg admixed with (3 mcg) 3M-052-AF administered at months 0, 2, 4, 8 and 12.
干预措施: CH505 TF chTrimer (Biological)
Group 1: Treatment
CH505 TF chTrimer 300 mcg admixed with (5 mcg) 3M-052-AF + (500 mcg) Aluminum Hydroxide suspension, administered at months 0, 2, 4, 8 and 12.
干预措施: CH505 TF chTrimer (Biological)
Group 1: Treatment
CH505 TF chTrimer 300 mcg admixed with (5 mcg) 3M-052-AF + (500 mcg) Aluminum Hydroxide suspension, administered at months 0, 2, 4, 8 and 12.
干预措施: 3M-05-AF (Biological)
Group 3: Treatment
CH505 cTrimer, 300 mcg admixed with (3 mcg) 3M-052-AF + (500 mcg) Aluminum Hydroxide suspension (Alum) administered at months 0, 2, 4, 8 and 12.*
*On October 13, 2023, errors were identified in the study injection preparation for this Group. The instructions below state that the doses for injections in Group 3 should be 300 mcg of the study vaccine + 3 mcg of 3M-052-AF adjuvant + 500 mcg of Alum adjuvant. However, the step-by-step instructions below for preparing the injection result in 2.2 mcg of 3M-052-AF (instead of 3 mcg) and 556 mcg of Alum (instead of 500 mcg). Thus, Group 3 participants got less 3M-052-AF than intended and more Alum than intended.
干预措施: CH505 TF chTrimer (Biological)
Group 2: Treatment
CH505 TF chTrimer 300 mcg admixed with (3 mcg) 3M-052-AF administered at months 0, 2, 4, 8 and 12.
干预措施: 3M-05-AF (Biological)
Group 3: Treatment
CH505 cTrimer, 300 mcg admixed with (3 mcg) 3M-052-AF + (500 mcg) Aluminum Hydroxide suspension (Alum) administered at months 0, 2, 4, 8 and 12.*
*On October 13, 2023, errors were identified in the study injection preparation for this Group. The instructions below state that the doses for injections in Group 3 should be 300 mcg of the study vaccine + 3 mcg of 3M-052-AF adjuvant + 500 mcg of Alum adjuvant. However, the step-by-step instructions below for preparing the injection result in 2.2 mcg of 3M-052-AF (instead of 3 mcg) and 556 mcg of Alum (instead of 500 mcg). Thus, Group 3 participants got less 3M-052-AF than intended and more Alum than intended.
干预措施: 3M-05-AF (Biological)
Group 4: Treatment
CH505 chTrimer 300 mcg admixed with (5 mcg) 3M-052-AF administered at months 0, 2, 4, 8 and 12.
干预措施: CH505 TF chTrimer (Biological)
Group 4: Treatment
CH505 chTrimer 300 mcg admixed with (5 mcg) 3M-052-AF administered at months 0, 2, 4, 8 and 12.
干预措施: 3M-05-AF (Biological)
Group 1: Treatment
CH505 TF chTrimer 300 mcg admixed with (5 mcg) 3M-052-AF + (500 mcg) Aluminum Hydroxide suspension, administered at months 0, 2, 4, 8 and 12.
干预措施: Aluminum hydroxide suspension (Biological)
Group 3: Treatment
CH505 cTrimer, 300 mcg admixed with (3 mcg) 3M-052-AF + (500 mcg) Aluminum Hydroxide suspension (Alum) administered at months 0, 2, 4, 8 and 12.*
*On October 13, 2023, errors were identified in the study injection preparation for this Group. The instructions below state that the doses for injections in Group 3 should be 300 mcg of the study vaccine + 3 mcg of 3M-052-AF adjuvant + 500 mcg of Alum adjuvant. However, the step-by-step instructions below for preparing the injection result in 2.2 mcg of 3M-052-AF (instead of 3 mcg) and 556 mcg of Alum (instead of 500 mcg). Thus, Group 3 participants got less 3M-052-AF than intended and more Alum than intended.
干预措施: Aluminum hydroxide suspension (Biological)
结局指标
主要结局
Frequency of v2 apex and V3 glycan- specific IgG+ B cells
时间窗: Thru week 80
Measured by flow cytometry analysis
Magnitude of serum antibody neutralization of vaccine-matched tier 2 HIV-1 strains
时间窗: Thru week 80
Measured by TZM-b1 assay
Frequency of CH505TF-specific IgG+ B cells
时间窗: Thru week 80
Measured by flow cytometry analysis
Frequency of CD4 binding-site-specific IgG+ B cells
时间窗: Thru week 80
Measured by flow cytometry analysis
Response rate of serum antibody neutralization of vaccine-matched tier 2 HIV-1 strains
时间窗: Thru week 80
Measured by TZM-b1 assay
Number of participants showing local vaccination reactogenicity signs and symptoms
时间窗: 7 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
时间窗: 7 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 unsolicited adverse events (AEs)
时间窗: 30 days following each vaccination
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) for each injection/ vaccination.
Number of medically attended adverse events (MAAEs)
时间窗: Thru week 104
Description: 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)
时间窗: Thru week 104
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
时间窗: Thru week 104
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 serious adverse events (SAEs)
时间窗: Thru week 104
Description: 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 Participants Reporting Local Reactogenicity Events Signs and Symptoms: Erythema and/or Induration
时间窗: Measured through 7 days after each study product administration at Study Day 0 (Month 0), Day 56 (Month 2), Day 112 (Month 4), Day 224 (Month 8), and Day 364 (Month 12)
The number and percentage of subjects experiencing each type of reactogenicity sign or symptom was tabulated by severity. For a given symptom, reactogenicity per subject was counted once based on the maximum severity across all assessments. Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]
Number of Participants Reporting Local Reactogenicity Events Signs and Symptoms: Pain and/or Tenderness
时间窗: Measured through 7 days after each study product administration at Study Day 0 (Month 0), Day 56 (Month 2), Day 112 (Month 4), Day 224 (Month 8), and Day 364 (Month 12)
The number and percentage of subjects experiencing each type of reactogenicity sign or symptom was tabulated by severity. For a given symptom, reactogenicity per subject was counted once based on the maximum severity across all assessments. Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]
Number of Participants Showing Systemic Vaccination Reactogenicity Signs and Symptoms
时间窗: Measured through 7 days after each study product administration at Study Day 0 (Month 0), Day 56 (Month 2), Day 112 (Month 4), Day 224 (Month 8), and Day 364 (Month 12)
The number and percentage of subjects experiencing each type of systemic reactogenicity sign or symptom was tabulated by severity. For a given symptom, reactogenicity per subject was counted once based on the maximum severity across all assessments. Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]
Number of Participants Reporting Unsolicited Adverse Events (AEs) Tabulated by Maximum Severity Grade
时间窗: All unsolicited adverse events were collected for 30 days after any receipt of study vaccination. Some adverse events (noted in description) were collected for 12 months following any receipt of study product (up to 104 weeks)
The number and percentage of subjects reporting adverse events was tabulated by severity. For a given participant with multiple adverse events reported, maximum severity was taken. Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply). All unsolicited adverse events were collected for 30 days after any receipt of study vaccination. Serious adverse events (SAEs), medically attended adverse events (MAAEs), adverse events of special interest (AESIs) and AEs leading to early participant withdrawal or permanent discontinuation which were collected throughout the study and for twelve months following any receipt of study product
Number of Participants Reporting Serious Adverse Events (SAEs)
时间窗: Serious adverse events (SAEs) were collected throughout the study and for 12 months following any receipt of study product (up to 104 weeks)
The number and percentage of subjects reporting servious adverse events (SAEs). Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]
Number of Participants Reporting One or More Medically Attended Adverse Events (MAAEs)
时间窗: Medically attended adverse events (MAAEs) were collected throughout the study and for 12 months following any receipt of study product (up to 104 weeks)
The number and percentage of subjects reporting medically attended adverse events (MAAEs). Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]
Number of Participants Reporting Adverse Events of Special Interest (AESIs)
时间窗: Adverse events of special interest (AESIs)were collected throughout the study and for 12 months following any receipt of study product (up to 104 weeks)
The number and percentage of subjects reporting adverse events of special interest (AESIs). Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]
Number of Participants With Study Product Discontinuation Associated With an Unsolicited AE or Reactogenicity
时间窗: Measured through 12 months following any receipt of study product (up to 104 weeks
From the vaccination and adverse event case report forms, counts are tabulated by treatment arm
Frequency of the CD4 Binding-site, V2 Apex and V3 Glycan (bnAb Region at the Base of the V3 Loop), and/or CH505TF-specific IgG+ B Cells
时间窗: Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination
Measured by flow cytometry analysis
Response Rate of Serum Antibody Neutralization of Vaccine-matched Tier 2 HIV-1 Strains
时间窗: Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination
Neutralizing antibodies against HIV-1 were measured as a function of reductions in Tat-regulated luciferase (Luc) reporter gene expression in TZM-bl cells. Response to an isolate was considered positive if the neutralization titer was above a pre-specified cutoff. The pre-specified positivity call was an ID50 (or ID80) value ≥ 10,
Magnitude of Serum Antibody Neutralization of Vaccine-matched Tier 2 HIV-1 Strains
时间窗: Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination
Neutralizing antibodies against HIV-1 were measured as a function of reductions in Tat-regulated luciferase (Luc) reporter gene expression in TZM-bl cells.
次要结局
- Response rate of serum IgG binding antibodies(Thru week 80)
- Magnitude of serum IgG binding antibodies(Thru week 80)
- Response rate of serum antibody neutralization of heterologous HIV-1 strains(Thru week 80)
- Magnitude of serum antibody neutralization of heterologous HIV-1 strains(Thru week 80)
- Response Rate of Serum IgG Binding Antibodies(Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination)
- Magnitude of Serum IgG Binding Antibodies(Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination)
- Response Rate of Serum Antibody Neutralization of Heterologous HIV-1 Strains(Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination)
- Magnitude of Serum Antibody Neutralization of Heterologous HIV-1 Strains(Measured at baseline, 2 weeks post 3rd vaccination, 2 weeks post 4th vaccination and 2 weeks post 5th vaccination)