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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 1
- 主要终点
- WHO Anthropometric Measure of Weight-for-Age Z-Score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 0 Days 至 5 Days（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Infant Inclusion Criteria:
- •Born via Caesarean section to an HIV-1-infected woman who meets all maternal inclusion/
排除标准
- •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.
研究组 & 干预措施
Part A, Group 1: CH505TF gp120 + GLA-SE
Participants received 20 mcg Stable CH505TF gp120 admixed with 2.5 mcg GLA-SE, administered as a 0.25 mL intramuscular (IM) injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: CH505TF gp120 (Biological)
Part A, Group 1: CH505TF gp120 + GLA-SE
Participants received 20 mcg Stable CH505TF gp120 admixed with 2.5 mcg GLA-SE, administered as a 0.25 mL intramuscular (IM) injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: GLA-SE adjuvant (Biological)
Part A, Group 2: Placebo
Participants received Placebo administered as a 0.25 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: Placebo (Biological)
Part B, Group 3: CH505TF gp120 + GLA-SE
Participants received 20 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: CH505TF gp120 (Biological)
Part B, Group 3: CH505TF gp120 + GLA-SE
Participants received 20 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: GLA-SE adjuvant (Biological)
Part B, Group 4: Placebo
Participants received Placebo administered as a 0.5 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: Placebo (Biological)
Part C, Group 5: CH505TF gp120 + GLA-SE
Participants received 20 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: CH505TF gp120 (Biological)
Part C, Group 5: CH505TF gp120 + GLA-SE
Participants received 20 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: GLA-SE adjuvant (Biological)
Part C, Group 6: Placebo
Participants received Placebo administered as a 0.5 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: Placebo (Biological)
Part C, Group 7: CH505TF gp120 + GLA-SE
Participants received 5 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: CH505TF gp120 (Biological)
Part C, Group 7: CH505TF gp120 + GLA-SE
Participants received 5 mcg Stable CH505TF gp120 admixed with 5 mcg GLA-SE, administered as a 0.5 mL IM injection into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: GLA-SE adjuvant (Biological)
Part C, Group 8: Placebo
Participants received Placebo administered as a 0.5 mL IM injection, into either thigh at Weeks 0, 8, 16, 32, and 54.
干预措施: Placebo (Biological)
结局指标
主要结局
WHO Anthropometric Measure of Weight-for-Age Z-Score
时间窗: Measured at each study visit.
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.
Number (Percentage) of Participants by WHO Anthropometric Measure of Weight-for-Age Z-Score Categories
时间窗: Measured at each study visit.
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.
WHO Anthropometric Measure of Weight-for-Length Z-Score
时间窗: Measured at each study visit.
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.
Number (Percentage) of Participants by WHO Anthropometric Measure of Weight-for-Length Z-Score Categories
时间窗: Measured at each study visit.
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.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness
时间窗: Measured through 7 days after each vaccine dose (Weeks 0, 8, 16, 32, 54).
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.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration
时间窗: Measured through 7 days after each vaccine dose (Weeks 0, 8, 16, 32, 54).
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.
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms
时间窗: Measured through 7 days after each vaccine dose (Weeks 0, 8, 16, 32, 54).
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.
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.
时间窗: 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.
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.
Number of Participants Reporting AEs, by Highest Severity Grade Per Participant.
时间窗: 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.
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.
Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product
时间窗: 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.
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.
Number of Participants Reporting Serious Adverse Events (SAEs)
时间窗: 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.
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.
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
时间窗: Measured at month 13, 2 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.
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
时间窗: Measured at month 4.5 (2 weeks post 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+.
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
时间窗: Measured at month 13 (2 weeks after the 5th 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+.
次要结局
- 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)(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)(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.(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(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(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(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(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(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(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(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(Measured at month 13, 2 weeks after the 5th vaccination.)