Evaluating the Safety and Immunogenicity of an HIV Vaccine (gp145 C.6980) in Healthy, HIV-Uninfected Adults in the United States

Phase 1

Completed

• Conditions: HIV Infections
• Interventions: Biological: gp145 C.6980 Vaccine; Biological: Placebo; Biological: Aluminum Hydroxide Adjuvant

• Registration Number: NCT03382418
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, and immunogenicity of an HIV vaccine (gp145 C.6980) with aluminum hydroxide adjuvant in healthy, HIV-1-uninfected adults in the United States.

Detailed Description

This study will evaluate the safety, tolerability, and immunogenicity of an HIV vaccine (gp145 C.6980) with aluminum hydroxide adjuvant in healthy, HIV-1-uninfected adults in the United States.

Participants will be randomly assigned to one of three groups. Participants in Group 1 will receive 300 mcg of gp145 C.6980 and aluminum hydroxide adjuvant on Day 0 and Months 2 and 6. Participants in Group 2 will receive 100 mcg of gp145 C.6980 and aluminum hydroxide adjuvant on Day 0 and Months 2 and 6. Participants in Group 3 will receive placebo on Day 0 and Months 2 and 6.

Study visits will occur at Day 0 (study entry), Weeks 1 and 2, and Months 2, 2.5, 6, 6.25, 6.5, 9, and 12. Visits may include physical examinations, blood and urine collection, HIV testing, risk reduction counseling, and questionnaires.

Study Timeline

• Study First Submitted: 2017-12-11
• Study First Submitted QC: 2017-12-18
• Study First Posted: 2017-12-22
• Study Start: 2017-12-27
• Primary Completion: 2019-09-25
• Study Completion: 2019-09-25
• Results First Submitted: 2020-12-11
• Results First Submitted QC: 2021-07-04
• Results First Posted: 2021-07-27
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-06
• Last Update Posted: 2021-10-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

General and Demographic Criteria

• Age of 18 to 50 years
• Access to a participating HIV Vaccine Trials Network (HVTN) clinical research site (CRS) and willingness to be followed for the planned duration of the study
• Ability and willingness to provide informed consent
• Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first vaccination with verbal demonstration of understanding of all questionnaire items initially answered incorrectly
• Agrees not to enroll in another study of an investigational research agent before the last scheduled protocol clinic visit
• Good general health as shown by medical history, physical exam, and screening laboratory tests

HIV-Related Criteria:

• Willingness to receive HIV test results
• Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling.
• Assessed by the clinic staff as being at "low risk" for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit. Low risk guidelines are found on the protocol web page under Study Materials on the HVTN Members' site (https://members.hvtn.org/protocols/hvtn122).

Laboratory Inclusion Values

Hemogram/Complete Blood Count (CBC)

• Hemoglobin greater than or equal to 11.0 g/dL for volunteers who were born female, greater than or equal to 13.0 g/dL for volunteers who were born male
• White blood cell count equal to 3,300 to 12,000 cells/mm^3
• Total lymphocyte count greater than or equal to 800 cells/mm^3
• Remaining differential either within institutional normal range or with site physician approval
• Platelets equal to 125,000 to 550,000/mm^3

Chemistry

• Chemistry panel: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase less than 1.25 times the institutional upper limit of normal; creatinine less than or equal to institutional upper limit of normal.

Virology

• Negative HIV-1 and -2 blood test: US volunteers must have a negative US Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA).
• Negative Hepatitis B surface antigen (HBsAg)
• Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive

Urine:

• Normal urine:

  • Negative urine glucose, and
  • Negative or trace urine protein, and
  • Negative or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a microscopic urinalysis with red blood cells levels within institutional normal range).

Reproductive Status:

• Volunteers who were born female: negative serum or urine beta human chorionic gonadotropin pregnancy test performed prior to vaccination on the day of initial vaccination. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing.

• Reproductive status: A volunteer who was born female must:

  • Agree to consistently use effective contraception (see the protocol for more information) for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment until after the last required protocol clinic visit. Effective contraception is defined as using the following methods:
  • Condoms (male or female) with or without a spermicide,
  • Diaphragm or cervical cap with spermicide,
  • Intrauterine device (IUD),
  • Hormonal contraception, or
  • Any other contraceptive method approved by the HVTN 122 Protocol Safety Review Team (PSRT),
  • Successful vasectomy in the male partner (considered successful if a volunteer reports that a male partner has [1] documentation of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy);
  • Or not be of reproductive potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy, bilateral oophorectomy, or tubal ligation;
  • Or be sexually abstinent.

• Volunteers who were born female must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit

Read More

Exclusion Criteria

General

• Blood products received within 120 days before first vaccination
• Investigational research agents received within 30 days before first vaccination
• Body mass index (BMI) greater than or equal to 40; or BMI greater than or equal to 35 with 2 or more of the following: age greater than 45, systolic blood pressure greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg, current smoker, known hyperlipidemia
• Intent to participate in another study of an investigational research agent or any other study that requires non-HVTN HIV antibody testing during the planned duration of the HVTN 122 study
• Pregnant or breastfeeding
• Active duty and reserve US military personnel

Vaccines and other Injections

• HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 122 PSRT will determine eligibility on a case-by-case basis.
• Non-HIV experimental vaccine(s) received within the last 5 years in a prior vaccine trial. Exceptions may be made by the HVTN 122 PSRT for vaccines that have subsequently undergone licensure by the FDA. For volunteers who have received control/placebo in an experimental vaccine trial, the HVTN 122 PSRT will determine eligibility on a case-by-case basis. For volunteers who have received an experimental vaccine(s) greater than 5 years ago, eligibility for enrollment will be determined by the HVTN 122 PSRT on a case-by-case basis.
• Live attenuated vaccines other than influenza vaccine received within 30 days before or scheduled and intended to be received within 14 days after the first vaccination (eg, measles, mumps, and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever)
• Influenza vaccine or any vaccines that are not live attenuated vaccines and were received within 14 days prior to first vaccination (eg, tetanus, pneumococcal, Hepatitis A or B)
• Allergy treatment with antigen injections within 30 days before first vaccination or that are scheduled and intended to be received within 14 days after first vaccination

Immune System

• Immunosuppressive medications received within 168 days before first vaccination. (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of prednisone or equivalent at doses less than 60 mg/day and length of therapy less than 11 days with completion at least 30 days prior to enrollment.)
• Serious adverse reactions to vaccines or to vaccine components, including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded from participation: a volunteer who had a nonanaphylactic adverse reaction to pertussis vaccine as a child.)
• Immunoglobulin received within 60 days before first vaccination
• Autoimmune disease
• Immunodeficiency

Clinically significant medical conditions

• Untreated or incompletely treated syphilis infection

• Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to:

  • A process that would affect the immune response,
  • A process that would require medication that affects the immune response,
  • Any contraindication to repeated injections or blood draws,
  • A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period,
  • A condition or process for which signs or symptoms could be confused with reactions to vaccine, or
  • Any condition specifically listed among the exclusion criteria below.

• 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

• Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.

• Current anti-tuberculosis (TB) prophylaxis or therapy

• Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program (NAEPP) Expert Panel report). Exclude a volunteer who:

  • Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
  • Uses moderate/high dose inhaled corticosteroids, or
  • In the past year has either of the following:
  • Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids;
  • Needed emergency care, urgent care, hospitalization, or intubation for asthma.

• Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not excluded: history of isolated gestational diabetes.)

• Thyroidectomy, or thyroid disease requiring medication during the last 12 months

• Hypertension:

  • If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined as consistently less than or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be less than or equal to 150 mm Hg systolic and less than or equal to 100 mm Hg diastolic. For these volunteers, blood pressure must be less than or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg diastolic at enrollment.
  • If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure greater than or equal to 150 mm Hg at enrollment or diastolic blood pressure greater than or equal to 100 mm Hg at enrollment.

• Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions)

• Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study)

• Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.

• Asplenia: any condition resulting in the absence of a functional spleen

• History of hereditary angioedema, acquired angioedema, or idiopathic angioedema.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1: gp145 C.6980 (high dose)	Aluminum Hydroxide Adjuvant	Participants will receive 300 mcg of the gp145 C.6980 vaccine admixed with aluminum hydroxide adjuvant at Day 0 and Months 2 and 6.
Group 2: gp145 C.6980 (low dose)	gp145 C.6980 Vaccine	Participants will receive 100 mcg of the gp145 C.6980 vaccine admixed with aluminum hydroxide adjuvant at Day 0 and Months 2 and 6.
Group 1: gp145 C.6980 (high dose)	gp145 C.6980 Vaccine	Participants will receive 300 mcg of the gp145 C.6980 vaccine admixed with aluminum hydroxide adjuvant at Day 0 and Months 2 and 6.
Group 2: gp145 C.6980 (low dose)	Aluminum Hydroxide Adjuvant	Participants will receive 100 mcg of the gp145 C.6980 vaccine admixed with aluminum hydroxide adjuvant at Day 0 and Months 2 and 6.
Group 3: Placebo	Placebo	Participants will receive placebo at Day 0 and Months 2 and 6.

Primary Outcome Measures

Name	Time	Method
Hematology Laboratory Measures: WBC, Neutrophils , Lymphocytes and Platelets	Measured at 2 weeks after first vaccination	For each chemistry laboratory measure, summary statistics were presented by analyte and treatment group for the overall population.
Chemistry and Hematology Laboratory Measures With Grade 1 or Higher, Through First Vaccination	Measured at 2 weeks after first vaccination	Laboratory results are summarized by analyte and timepoint. Analytes and timepoint combinations with grade 1 or higher results are shown.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness	Measured through 7 days after first vaccination at Month 0	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1, dated July 2017. The maximum grade observed for each symptom over the time frame is presented.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms：Erythema and/or Induration	Measured through 7 days after first vaccination at Month 0	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1, dated July 2017. The maximum grade observed for each symptom over the time frame is presented.
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms	Measured through 7 days after first vaccination at Month 0	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1, dated July 2017. The following symptoms are considered as systemic reactogenicity if the onset date was within the periods of assessment specified in the protocol: malaise and/or fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, and body temperature. The item Max. Systemic Reaction is the maximum of the individual systemic variables for a participant. It does not include temperature.
Number of Participants Reporting Adverse Events (AEs), by Severity Grade	Measured through 30 days after first vaccination at Month 0	Severity definitions are found in The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017); For participants reporting multiple AEs over the time frame, the maximum severity grade is counted.
Number of Participants Reporting Serious Adverse Events (SAEs)	Measured through 30 days after first vaccination at Month 0	Measured as outlined in Version 2.0 (January 2010) of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product	Measured through 30 days after first vaccination at Month 0	Severity definitions are found in The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017); For participants reporting multiple AEs over the time frame, the maximum severity grade is counted.
Chemistry Laboratory Measures: Hemoglobin, Creatinine	Measured at 2 weeks after first vaccination	For each chemistry laboratory measure, summary statistics were presented by analyte and treatment group for the overall population.
Chemistry Laboratory Measures: ALT	Measured at 2 weeks after first vaccination	For each chemistry laboratory measure, summary statistics were presented by analyte and treatment group for the overall population.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms	Measured through Month 6.5	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1, dated July 2017. The following symptoms are considered as systemic reactogenicity if the onset date was within the periods of assessment specified in the protocol: malaise and/or fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, and body temperature. The item Max. Systemic Reaction is the maximum of the individual systemic variables for a participant. It does not include temperature.
Frequency of Serious Adverse Events (SAEs)	Measured through Month 12	Measured as outlined in Version 2.0 (January 2010) of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
Chemistry Laboratory Measures: Hemoglobin, Creatinine, Through All Vaccinations	Measured during Screening, Month 0.5, 2.5, 6.5 and 9	For each chemistry laboratory measure, summary statistics were presented by analyte and treatment group for the overall population.
Occurrence of Neutralizing Antibody Responses Against HIV-1 Isolates	Measured at 2 weeks after the third vaccination	Assessed by multiplex assay. Response to a virus/isolate in the TZM-bl assay is considered positive if the neutralization titer is above a pre-specified cutoff (one-half the lowest dilution tested). A titer is defined as the serum dilution that reduces relative luminescence units (RLUs) by 50% relative to the RLUs in virus control wells (cells + virus only) after subtraction of background RLU (cells only). The pre-specified cutoff is 10 for TZM-bl cells.
Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product	Measured through Month 7	Severity definitions are found in The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017); For participants reporting multiple AEs over the time frame, the maximum severity grade is counted.
Number of Participants Reporting Adverse Events (AEs), by Severity Grade	Measured through Month 7	Severity definitions are found in The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017); for participants reporting multiple AEs over the time frame, the maximum severity grade is counted.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms：Erythema and/or Induration	Measured through Month 6.5	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1, dated July 2017. The maximum grade observed for each symptom over the time frame is presented.
Chemistry and Hematology Laboratory Results With Grade 1 or Higher, Through All Vaccinations	Measured during Screening, Month 0.5, 2.5, 6.5 and 9	Laboratory results are summarized by analyte and timepoint. Analytes and timepoint combinations with no grade 1 or higher results are not shown.
Hematology Laboratory Measures: WBC, Platelets, Lymphocytes, Neutrophils , Through All Vaccinations	Measured during Screening, Month 0.5, 2.5, 6.5 and 9	For each chemistry laboratory measure, summary statistics were presented by analyte and treatment group for the overall population.
Chemistry Laboratory Measures: ALT, Through All Vaccinations	Measured during Screening, Month 0.5, 2.5, 6.5 and 9	For each chemistry laboratory measure, summary statistics were presented by analyte and treatment group for the overall population.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness	Measured through Month 6.5	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1, dated July 2017. The maximum grade observed for each symptom over the time frame is presented.
Level of Vaccine-induced Binding Antibodies to HIV Proteins Measured by the Binding Antibody Multiplex Assay (BAMA)	Measured at 2 weeks after the third vaccination	Serum HIV-1-specific IgG responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay. The readout is background-subtracted mean fluorescent intensity (MFI), with background adjustment for an antigen-specific 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. Samples from post-enrollment visits have positive responses if they meet three conditions: (1) net MFI greater than or equal to an antigen-specific response threshold (defined as the maximum of 100 and the 95th percentile of pre-vaccination net MFI), (2) net MFI values are greater than 3 times pre-vaccination net MFI, and (3) experimental antigen MFI values are greater than 3 times pre-vaccination MFI. Data are excluded if the blood draw date was outside the allowable window, a participant was HIV-infected, or the reference antigen exceeds 5000 MFI.
Level of Neutralizing Antibody Responses Against HIV-1 Isolates	Measured at 2 weeks after the third vaccination	Assessed by multiplex assay. Response to a virus/isolate in the TZM-bl assay is considered positive if the neutralization titer is above a pre-specified cutoff (one-half the lowest dilution tested). A titer is defined as the serum dilution that reduces relative luminescence units (RLUs) by 50% relative to the RLUs in virus control wells (cells + virus only) after subtraction of background RLU (cells only). The pre-specified cutoff is 10 for TZM-bl cells. Titers below the limit of detection (\<10) were set to 5.
Occurrence of Vaccine-induced Binding Antibodies to HIV Proteins Measured by the Binding Antibody Multiplex Assay (BAMA)	Measured at 2 weeks after the third vaccination	Serum HIV-1-specific IgG responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay. The readout is background-subtracted mean fluorescent intensity (MFI), with background adjustment for an antigen-specific 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. Samples from post-enrollment visits have positive responses if they meet three conditions: (1) net MFI greater than or equal to an antigen-specific response threshold (defined as the maximum of 100 and the 95th percentile of pre-vaccination net MFI), (2) net MFI values are greater than 3 times pre-vaccination net MFI, and (3) experimental antigen MFI values are greater than 3 times pre-vaccination MFI. Data are excluded if the blood draw date was outside the allowable window, a participant was HIV-infected, or the reference antigen exceeds 5000 MFI.
Occurrence of HIV-specific CD4+ and CD8+ T-cell Responses to the HIV Proteins Included in the Vaccine. Measured by Flow Cytometry.	Measured at 2 weeks after the third vaccination	PBMC samples are stimulated with synthetic peptide pools or left unstimulated as a negative control. For each sample, T-cell subset, and peptide pool, response magnitude is % cells expressing markers after peptide stimulation minus % cells expressing markers after no stimulation. A contingency table is constructed to assess response: stimulation (peptide/none) vs. marker expression (yes/no). A one-sided Fisher's exact test is applied, testing if the number of cells positive for the marker is equal in the stimulated vs. unstimulated cells. A discrete Bonferroni adjustment is made over the peptide pools. Response is positive if p\<=0.00001. Data are excluded if the blood draw date was outside the visit window, the participant was HIV-infected, PBMC viability or T-cell count were low, or negative control was high.
Levels of CD4+ and CD8+ T Cells Responses to the HIV Proteins Included in the Vaccine. Measured by Flow Cytometry.	Measured at 2 weeks after the third vaccination	PBMC samples are stimulated with synthetic peptide pools or left unstimulated as a negative control. For each sample, T-cell subset, and peptide pool, response magnitude is % cells expressing markers after peptide stimulation minus % cells expressing markers after no stimulation. A contingency table is constructed to assess response: stimulation (peptide/none) vs. marker expression (yes/no). A one-sided Fisher's exact test is applied, testing if the number of cells positive for the marker is equal in the stimulated vs. unstimulated cells. A discrete Bonferroni adjustment is made over the peptide pools. Response is positive if p\<=0.00001. Data are excluded if the blood draw date was outside the visit window, the participant was HIV-infected, PBMC viability or T-cell count were low, or negative control was high.

Trial Locations

Locations (3)

New York Blood Center CRS; 🇺🇸 New York, New York, United States

Columbia P&S CRS; 🇺🇸 New York, New York, United States

Penn Prevention CRS; 🇺🇸 Philadelphia, Pennsylvania, United States