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

HIV Vaccine Trials Network38 enrolled

Overview

This study evaluated the safety and immune response in healthy HIV-exposed and uninfected infants to the protein vaccine, CH505TF gp120, adjuvanted with GLA-SE.

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

Conditions

HIV Infections

Interventions

CH505TF gp120BIOLOGICAL

HIV-1 CH505 transmitted/founder virus Env gp120 immunogen

GLA-SE adjuvantBIOLOGICAL

An oil-in-water stable emulsion (SE) containing the immunological adjuvant Glucopyranosyl Lipid A (GLA)

PlaceboBIOLOGICAL

Sodium Chloride for Injection, 0.9% USP

Eligibility

Sex: ALLMin age: 0 DaysMax age: 5 DaysHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

Perinatal HIV Research Unit (PHRU), Soweto CRS

Johannesburg, Gauteng, South Africa

Outcomes

Primary Outcomes

WHO Anthropometric Measure of Weight-for-Age Z-Score

At each study visit, the infant's weight was measured. Using weight and age, a WHO weight-for-age z-score will be calculated using the World Health Organization (WHO) anthropometric calculator tool. Weight-for-age reflects body weight relative to the child's age on a given day. A Z-score of 0 represents the population mean, a Z-score less than -2 indicates an infant who is underweight, -2 to 2 indicates an infant who is normal weight, and above 2 indicates the infant may have a growth problem, but this is better assessed from weight-for-length. This Outcome Measure was not collected for Mothers.

Time frame: Measured at each study visit.

Number (Percentage) of Participants by WHO Anthropometric Measure of Weight-for-Age Z-Score Categories

At each study visit, the infant's weight was measured. Using weight and age, a WHO weight-for-age z-score was calculated using the World Health Organization (WHO) anthropometric calculator tool. Weight-for-age reflects body weight relative to the child's age on a given day. Z-scores less than -2 indicates an infant who is underweight, -2 to 2 indicates an infant who is normal weight, and above 2 indicates the infant may have a growth problem, but this is better assessed from weight-for-length.

Time frame: Measured at each study visit.

WHO Anthropometric Measure of Weight-for-Length Z-Score

At each study visit, the infant's length and weight was measured. Using these measurements, a WHO weight-for-length z-score was calculated using the World Health Organization (WHO) anthropometric calculator tool. Weight-for-length reflects body weight in proportion to attained growth in length. A Z-score of 0 represents the population mean, a Z-score less than -2 indicates an infant who is wasted, -2 to 2 indicates an infant who is normal weight, and above 2 indicates the infant is overweight. This Outcome Measure was not collected for Mothers.

Time frame: Measured at each study visit.

Number (Percentage) of Participants by WHO Anthropometric Measure of Weight-for-Length Z-Score Categories

At each study visit, the infant's length and weight was measured. Using these measurements, a WHO weight-for-length z-score was calculated using the World Health Organization (WHO) anthropometric calculator tool. Weight-for-length reflects body weight in proportion to attained growth in length. Z-scores less than -2 indicates an infant who is wasted, -2 to 2 indicates an infant who is normal weight, and above 2 indicates the infant is overweight.

Data from ClinicalTrials.gov

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Time frame: Measured at each study visit.

Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness

Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented. This Outcome Measure was not collected for Mothers.

Time frame: Measured through 7 days after each vaccine dose (Weeks 0, 8, 16, 32, 54).

Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration

Time frame: Measured through 7 days after each vaccine dose (Weeks 0, 8, 16, 32, 54).

Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms

Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The following symptoms are considered as systemic reactogenicity if the onset date was within the periods of assessment specified in the protocol: fever, sleepiness/lethargy, rash, vomiting, anorexia, seizure. The item Max. Systemic Symptoms is the maximum of the individual systemic reactogenicities for a participant. This Outcome Measure was not collected for Mothers.

Time frame: Measured through 7 days after each vaccine dose (Weeks 0, 8, 16, 32, 54).

Number (Percentage) of Participants With Local Laboratory Values Recorded as Meeting Grade 1 AE Criteria or Above as Specified in the Division of AIDS Table.

The number (percentage) of participants with local laboratory values recorded as meeting Grade 1 AE criteria or above as specified in the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events for alanine aminotransferase (ALT), creatinine, hemoglobin, lymphocyte count, neutrophil count, platelets, white blood cells (WBC) was summarized by treatment arm for each post vaccination time point. This Outcome Measure was not collected for Mothers.

Time frame: ALT, creatinine, hemoglobin, platelets, and WBC measured at Screening (Day 0) and Days 14, 70, 126, 238, 393, 743; Lymphocytes and Neutrophils measured at Days 14, 70, 126, 238, 393, 743.

Number of Participants Reporting AEs, by Highest Severity Grade Per Participant.

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). This Outcome Measure was not collected for Mothers.

Time frame: Comprises the entire study period for each infant participant (from the infant's study enrollment until his or her study completion or discontinuation), up to 25 months.

Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product

Time frame: Comprises the entire study period for each infant participant (from the infant's study enrollment until his or her study completion or discontinuation), up to 25 months.

Number of Participants Reporting Serious Adverse Events (SAEs)

Time frame: Comprises the entire study period for each infant participant (from the infant's study enrollment until his or her study completion or discontinuation), up to 25 months.

Magnitude of HIV-1 Env gp120, CD4 Binding Site and V1V2-specific Serum IgG Binding Antibodies, as Assessed by BAMA Two Weeks After the 5th Vaccination

Serum HIV-1-specific IgG responses were measured on a BioPlex instrument (BioRad) using a standardized custom HIV-1 Luminex assay. The readout was background-subtracted mean fluorescence intensity (MFI), where background referred to a plate level control. Net MFI less than 1 is set to 1, and net MFI \> 22,000 is set to 22,000. The area under the curve (AUC) was calculated for each participant and antigen using the trapezoidal rule, where the x-axis is log10 dilution and the y-axis is the Net MFI with negative values set to 0. AUC is considered the primary measure of response magnitude.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Quantification and Phenotypic Characterization of Peripheral B Cells Capable of Binding HIV-1 Env gp120 and the CD4 Binding Site, as Assessed by Flow Cytometry Two Weeks After the 3rd Vaccination

HIV-1 Env-specific B cells induced by vaccination were identified and characterized using fluorescently labeled recombinant Env proteins in the context of a flow cytometry panel to identify and characterize those B cell. Total B cells are identified using doublet exclusion, lymphocyte scatter profile, a viability dye to exclude dead cells, and are negative for lineage markers: CD3, CD56 and CD14; and positive for CD19 and CD20. B cells are further gated as IgD-, then IgG+, and IgA+.

Time frame: Measured at month 4.5 (2 weeks post the 3rd vaccination).

Quantification and Phenotypic Characterization of Peripheral B Cells Capable of Binding HIV-1 Env gp120 and the CD4 Binding Site, as Assessed by Flow Cytometry Two Weeks After the 5th Vaccinations

Time frame: Measured at month 13 (2 weeks after the 5th vaccination).

Secondary Outcomes

EPI Vaccine-specific Antibody Responses, as Assessed by Pediatric Vaccine Multiplex Assay (PVMA) 2 Weeks After the 5th Vaccination (Diptheria, HepB, Pertussis, Rubella, and Tetanus)

PVMA uses the same Luminex instrument and techniques as HVTN's standard Binding Antibody Multiplex Assay (BAMA) to assess serum samples for antibodies against diphtheria, tetanus, pertussis, and rubella. The assay is a reliable, high-throughput technique that requires minimal sample volume and measures multiple antibody concentrations. A Hepatitis B antigen was tested as part of the PVMA panel, but did not pass lab-internal QC. The lab opted to test this antigen via ELISA and reported those calculated concentration data for analysis in lieu of the HepB PVMA data. A HepB standard was used in each assay for quality control.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

EPI Vaccine-specific Antibody Responses, as Assessed by Pediatric Vaccine Multiplex Assay (PVMA) 2 Weeks After the 5th Vaccination (HiB and RSV)

PVMA uses the same Luminex instrument and techniques as HVTN's standard Binding Antibody Multiplex Assay (BAMA) to assess serum samples for antibodies against Haemophilus influenzae type B (HiB) and respiratory syncytial virus (RSV). The assay is a reliable, high-throughput technique that requires minimal sample volume and measures multiple antibody concentrations.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Magnitude and Breadth of Serum Neutralization of Vaccine-matched Viral Isolates, and Viruses Engineered to Detect Precursors of CD4 Binding Site and V1V2 Antibodies 2 Weeks After the 5th Vaccination.

Neutralizing antibodies against tier 1 and tier 2 strains of HIV-1 were measured as a function of reductions in Tat-regulated luciferase (Luc) reporter gene expression in TZM-bl cells. All serum samples were assayed against Tier 1 and Tier 2 strains of virus by starting with a 1:10 dilution of serum to obtain a neutralizing antibody titer. ID50 (ID80) titers are defined as the serum dilution that reduces RLUs by 50% (or 80%) relative to the RLUs in virus control wells after subtraction of background.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Response Rate of Vaccine-elicited Serum Binding Antibodies to FcR Proteins, as Assessed by BAMA 2 Weeks After the 5th Vaccination

Serum HIV-1-specific FcR responses (1:50 dilution) were measured using the standardized custom HIV-1 Luminex assay on a Luminex FLEXMAP 3D system. Readouts were background-subtracted mean fluorescence intensity (MFI), with background defined by plate-level controls. Net MFI was calculated as experimental minus reference antigen MFI, and values \<1 were set to 1. Post-enrollment samples were considered positive if they met all three criteria: (1) Net MFI ≥ antigen-specific cutoff (95th percentile of HVTN 115 Part A baseline at Day 0) and ≥ 100 above blank; (2) Net MFI \> 3 times the median baseline Net MFI; and (3) MFI \> 3 times the median baseline MFI. Response calls were based on the 1:50 dilution. Data were excluded if the blood draw was outside the allowable window, the participant was HIV positive, reference antigen MFI \> 5,000, or baseline net MFI \> 6,500.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Magnitude of Vaccine-elicited Serum Binding Antibodies to FcR Proteins, as Assessed by BAMA 2 Weeks After the 5th Vaccination

Serum HIV-1-specific FcR (dilution 1:50) responses were measured on a Luminex FLEXMAP 3D Instrument System using a standardized custom HIV-1 Luminex assay. The readout was background-subtracted mean fluorescence intensity (MFI), where background referred to a plate level control. For each sample, response magnitude is net MFI, defined as experimental antigen MFI minus reference antigen MFI. Net MFI less than 1 is set to 1. Data are excluded if blood draw date was outside the allowable window, a participant was HIV-infected, reference antigen \> 5,000 MFI, or baseline net MFI \> 6,500.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Response Rate of Serum Antibody-dependent Cellular Cytotoxicity (ADCC) to CH505TF D7gp120.Avi/293F, as Assessed by Flow Cytometry Assay 2 Weeks After the 5th Vaccination

The qualified GranToxiLux Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC-GTL) assay was performed to measure ADCC-mediated antibody responses. ADCC is quantified as net percent granzyme B activity, which is the percent of target cells positive for GTL (an indicator of granzyme B uptake) minus the percent of target cells positive for GTL when incubated with effector cells in the absence of a source of antibodies. Flow cytometry is used to quantify the frequency of granzyme B positive cells. There is no baseline subtraction applied to the responses, and a fixed positivity threshold is applied to %GzB activity. A positive response is defined as ≥ 8% GzB activity.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Magnitude of Serum Antibody-dependent Cellular Cytotoxicity (ADCC) to CH505TF D7gp120.Avi/293F, as Assessed by Flow Cytometry Assay 2 Weeks After the 5th Vaccination

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Response Rate of Serum Antibody-dependent Cellular Cytotoxicity (ADCC) to HIV CH0505s.LucR.T2A.Ecto/293T/17, as Assessed by Luciferase Assay 2 Weeks After the 5th Vaccination

ADCC-mediated antibody responses were measured by luciferase ADCC assay using HIV CH0505s.LucR.T2A.ecto/293T/17 Infectious Molecular Clone (IMC)-infected target cells. Luminescence intensity reflects the number of intact target cells remaining after incubation with effector cells in the presence or absence of ADCC-mediating serum antibodies. Lower luminescence corresponds to fewer intact target cells. The outcome measure was calculated as the percent specific change in luciferase activity, defined as: percent specific change in luciferase activity = 100 \* (RLU of target and effector well- RLU of test well)/(RLU of target and effector well). There is no baseline subtraction applied to the responses, and a fixed positivity threshold is applied to percent killing or loss of luciferase activity. A positive response is defined as percent specific killing ≥ 15%.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Magnitude of Serum Antibody-dependent Cellular Cytotoxicity (ADCC) to HIV CH0505s.LucR.T2A.Ecto/293T/17, as Assessed by Luciferase Assay 2 Weeks After the 5th Vaccination

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Response Rate of Serum Antibody-dependent Cellular Phagocytosis (ADCP) to CH505TF D7gp120.Avi/293F, as Assessed by Flow Cytometry 2 Weeks After the 5th Vaccination

ADCP assay is a qualified assay employing flow cytrometric-based technology that measures the ability of antibodies to mediate phagocytosis. A phagocytic score is determined based on the ratio of experimental sample to PBS control. Mean phagocytosis score is defined as: (% bead positive for participant x MFI bead positive for participant) / (% bead positive for PBS only control x MFI bead positive for PBS only control). Higher phagocytosis score values indicate a greater level of antibody-mediated phagocytic activity relative to the PBS control, while values closer to 1 indicate minimal activity above background. Positivity calls were based on two criteria: 1) Average ADCP score ≥ antigen specific cutoff values (max(95th percentile of HVTN 115 baseline ADCP score, 1)) and 2) Average ADCP score \> 3x antigen specific median HVTN 115 baseline average ADCP score.

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.

Magnitude of Serum Antibody-dependent Cellular Phagocytosis (ADCP) to CH505TF D7gp120.Avi/293F, as Assessed by Flow Cytometry 2 Weeks After the 5th Vaccination

Time frame: Measured at month 13, 2 weeks after the 5th vaccination.