Evaluating Safety and Immune Response to the HIV-1 CH505 Transmitted/Founder gp120 Adjuvanted With GLA-SE in Healthy, HIV-exposed Uninfected Infants

Study Overview
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Brief Summary
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This study will evaluate the safety and immune response in healthy HIV-exposed and uninfected infants to the protein vaccine, CH505TF gp120, adjuvanted with GLA-SE.

Detailed Description
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This study will evaluate the safety and immune response in healthy HIV-exposed and uninfected infants to the protein vaccine, CH505TF gp120, adjuvanted with GLA-SE. This study will enroll 38 mother-infant pairs. To quantify the maternal HIV antibody response, mothers will also be enrolled in the study but will not receive study product. Infants will receive the CH505TF gp120 protein adjuvanted with GLA-SE at Weeks 0, 8, 16, 32, and 54. The first dose will be given within the first five days of life. The study will be conducted in three parts (Parts A, B, and C), and to ensure safety, enrollment will proceed in stages. Part A (Initial Safety) will enroll first. 5 infants in Part A will receive a low dose of protein with a low dose of adjuvant and 2 infants will receive placebo. After safety review post first vaccination of infants in Part A, Part B will enroll. In Part B (Safety Ramp-Up), 2 infants will receive a higher dose of protein with a higher dose of adjuvant and 2 infants will receive placebo. After safety review post first vaccination of infants in Part B, Part C will enroll. In Part C (Immunogenicity), 5 infants will receive low dose protein with higher dose of adjuvant, 16 infants will receive a higher dose of protein with higher dose of adjuvant, and 6 infants will receive placebo. There are 14 scheduled clinic visits over 24.5 months. For infants, study visits may include physical examinations, medical history, vaccine injections, HIV testing, and blood, cord blood, and stool collection. For mothers, study visits may include medical history, physical examinations, questionnaires, risk reduction counseling, and blood, breastmilk, and stool collection.

Official Title
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A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of the HIV-1 CH505 Transmitted/Founder gp120 Adjuvanted With GLA-SE in Healthy, HIV-exposed Uninfected Infants

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: CH505TF gp120
* Biological: GLA-SE adjuvant
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Infant Inclusion Criteria: Born via Caesarean section to an HIV-1-infected woman who meets all maternal inclusion/exclusion criteria listed below. Estimated gestational age at birth is at least 37 weeks. Weight at birth is at least 2.5 kg. Has initiated antiretroviral prophylaxis consistent with current site-specific standard of care. Hemoglobin >14.0 g/dL. White Blood Cell Count ≥ 7000 cells/mm3 Platelets > 100,000 cells/mm3 Alanine aminotransferase (ALT) <1.25 times upper limit of age adjusted normal. Creatinine < 1.1 times upper limit of age adjusted normal. Negative HIV-1 nucleic acid test on specimen drawn within 72 hours of birth. Written informed consent provided by mother. Age is equal to or less than five days. Infant Exclusion Criteria: Any clinically significant congenital anomaly/birth defect. Documented or suspected serious medical illness, infection, clinically significant finding from physical examination or immediate life-threatening condition, including requirement for ongoing supplemental oxygen, as judged by the examining clinician. Receipt of or anticipated need for blood products, immunoglobulin, or immunosuppressive therapy. This includes infants who require Hepatitis B Immunoglobulin (HBIG) but does not require exclusion of infants who receive Hepatitis B vaccine in the newborn period. Receipt of any other investigational product. Mother Inclusion Criteria: Mother's age is at least 18 years, and willing and able to provide written informed consent for her and her infant's participation in this study. Mother is in the second or third trimester of singleton pregnancy, as determined by a clinical exam, or sonography and reported menstrual history. Mother agrees to donate umbilical cord blood. Mother has a planned Caesarian Section at Chris Hani Baragwanath Academic Hospital, Soweto and plans to remain in the area after delivery. Mother is determined by the site investigator to be in good overall health at the time of delivery based on medical history, and physical exam. Mother has a documented CD4 count > 350 cells/microliter during her pregnancy. Mother has a documented SARS-CoV-2 negative PCR test within 2 days before delivery to 5 days after delivery Mother has access to the participating HVTN CRS and willingness to be followed for the planned duration of the study. Assessment of understanding: Mother demonstrates understanding of this study; completes a questionnaire prior to delivery with verbal demonstration of understanding of all questionnaire items answered incorrectly. Mother agrees not to enroll either herself or her infant in another research study for the duration of the trial without prior approval of the HVTN 135 PSRT. Mother has confirmed HIV-1 infection documented by medical records at any time during or prior to screening, and confirmed by the HVTN CRS by serology. Mother has been on cART for at least sixteen weeks prior to delivery and intends to continue with cART for the duration of breastfeeding.\ Mother has a viral load of less than 400 copies/mL between two weeks before and 5 days after delivery. Mother Exclusion Criteria: Any WHO Grade IV illness within one year prior to study enrollment as determined by the history and physical examination and review of the medical record (if available). These include HIV wasting syndrome, PJP Pneumonia, Cerebral Toxoplasmosis, extrapulmonary Cryptococcosis, Progressive Multifocal Leukoencephalopathy, any disseminated endemic mycosis (histoplasmosis), candidiasis of the esophagus, trachea, bronchi or lung, disseminated atypical mycobacteria, non-typhoid Salmonella septicemia, extrapulmonary tuberculosis, lymphoma, Kaposi's sarcoma. Prior participation in any HIV-1 vaccine or anti-HIV antibody-mediated prevention trial. Receipt of any investigational agent during this pregnancy. Receipt of blood products, immunoglobulin, or immunomodulating therapy within 45 days prior to delivery of the placenta. Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or reactogenicity, or a volunteer's ability to give informed consent. Any condition that places the newborn at higher risk of early-onset sepsis, such as concern for active maternal infection at delivery as determined by local site investigators (eg, fever). Detectable Hepatitis B surface antigen.

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 5 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Group 1: CH505TF gp120 + GLA-SE<br>Participants will receive 20 mcg Stable CH505TF gp120 admixed with 2.5 mcg GLA-SE, to be administered as a 0.25 mL intramuscular (IM) injection into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: CH505TF gp120<br>* HIV-1 CH505 transmitted/founder virus Env gp120 immunogen<br>Biological: GLA-SE adjuvant<br>* An oil-in-water stable emulsion (SE) containing the immunological adjuvant Glucopyranosyl Lipid A (GLA)<br>|
| Placebo Comparator: Part A, Group 2: Placebo<br>Participants will receive Placebo to be administered as a 0.25 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: Placebo<br>* Sodium Chloride for Injection, 0.9% USP<br>|
| Experimental: Part B, Group 3: CH505TF gp120 + GLA-SE<br>Participants will receive 20 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, to be administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: CH505TF gp120<br>* HIV-1 CH505 transmitted/founder virus Env gp120 immunogen<br>Biological: GLA-SE adjuvant<br>* An oil-in-water stable emulsion (SE) containing the immunological adjuvant Glucopyranosyl Lipid A (GLA)<br>|
| Placebo Comparator: Part B, Group 4: Placebo<br>Participants will receive Placebo to be administered as a 0.5 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: Placebo<br>* Sodium Chloride for Injection, 0.9% USP<br>|
| Experimental: Part C, Group 5: CH505TF gp120 + GLA-SE<br>Participants will receive 20 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, to be administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: CH505TF gp120<br>* HIV-1 CH505 transmitted/founder virus Env gp120 immunogen<br>Biological: GLA-SE adjuvant<br>* An oil-in-water stable emulsion (SE) containing the immunological adjuvant Glucopyranosyl Lipid A (GLA)<br>|
| Placebo Comparator: Part C, Group 6: Placebo<br>Participants will receive Placebo to be administered as a 0.5 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: Placebo<br>* Sodium Chloride for Injection, 0.9% USP<br>|
| Experimental: Part C, Group 7: CH505TF gp120 + GLA-SE<br>Participants will receive 5 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, to be administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: CH505TF gp120<br>* HIV-1 CH505 transmitted/founder virus Env gp120 immunogen<br>Biological: GLA-SE adjuvant<br>* An oil-in-water stable emulsion (SE) containing the immunological adjuvant Glucopyranosyl Lipid A (GLA)<br>|
| Placebo Comparator: Part C, Group 8: Placebo<br>Participants will receive Placebo to be administered as a 0.5 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54. | Biological: Placebo<br>* Sodium Chloride for Injection, 0.9% USP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local reactogenicity signs and symptoms | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 | Measured through week 55 | 
| Systemic reactogenicity signs and symptoms | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 | Measured through week 55 | 
| Frequency of adverse events (AEs) | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 | Measured through week 106 | 
| Frequency of serious adverse events (SAEs) | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 | Measured through week 106 | 
| Magnitude of HIV-1 specific serum IgG binding antibodies | Measured by Binding antibody multiplex assay (BAMA) | Measured at week 56 | 
| Quantification of peripheral B cells capable of binding HIV-1 Env gp120, the CD4 binding site (including differential binding to the IΔ371 mutant) and the V1V2 binding site | Measured by flow cytometry | Measured at week 18 | 
| Quantification of peripheral B cells capable of binding HIV-1 Env gp120, the CD4 binding site (including differential binding to the IΔ371 mutant) and the V1V2 binding site | Measured by flow cytometry | Measured at week 56 | 
| Phenotypic characterization of peripheral B cells capable of binding HIV-1 Env gp120, the CD4 binding site (including differential binding to the IΔ371 mutant) and the V1V2 binding site | Measured by flow cytometry | Measured at week 18 | 
| Phenotypic characterization of peripheral B cells capable of binding HIV-1 Env gp120, the CD4 binding site (including differential binding to the IΔ371 mutant) and the V1V2 binding site | Measured by flow cytometry | Measured at week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EPI vaccine-specific antibody responses | Measured by Pediatric Vaccine Multiplex Assay (PVMA) | Measured at week 56 | 
| Magnitude of serum neutralization of vaccine-matched viral isolates, and viruses engineered to detect precursors of CD4 binding site and V1V2 antibodies | Measured by TZM-bl assay | Measured at week 56 | 
| Serum neutralization of vaccine-matched viral isolates, and viruses engineered to detect precursors of CD4 binding site and V1V2 antibodies | Measured by TZM-bl assay | Measured at week 56 | 
| Response rate of vaccine-elicited serum binding antibodies to FcR proteins | Measured by BAMA | Measured at week 56 | 
| Magnitude of vaccine-elicited serum binding antibodies to FcR proteins | Measured by BAMA | Measured at week 56 | 
| Response rate of serum Antibody-dependent cellular cytotoxicity (ADCC) | Measured by flow cytometry and/or luciferase assays | Measured at week 56 | 
| Magnitude of serum Antibody-dependent cellular cytotoxicity (ADCC) | Measured by flow cytometry and/or luciferase assays | Measured at week 56 | 
| Response rate of serum Antibody-dependent cellular phagocytosis (ADCP) | Measured by flow cytometry | Measured at week 56 | 
| Magnitude of serum Antibody-dependent cellular phagocytosis (ADCP) | Measured by flow cytometry | Measured at week 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Vaccine, Infant