Pivotal Phase 2b/3 ALVAC/Bivalent gp120/MF59 HIV Vaccine Prevention Safety and Efficacy Study in South Africa

National Institute of Allergy and Infectious Diseases (NIAID)5,404 enrolled

Overview

This study will evaluate the preventive vaccine efficacy, safety, and tolerability of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 in HIV-seronegative South African adults over 24 months and potentially up to 36 months from enrollment.

This study will evaluate the preventive vaccine efficacy, safety, and tolerability of the ALVAC-HIV vaccine + Bivalent Subtype C gp120 protein adjuvanted with MF59 in HIV-seronegative South African adults over 24 months from enrollment. Participants will be randomized to receive ALVAC-HIV (vCP2438), or placebo, by intramuscular injection at weeks 0 and 4; they will receive ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59, or placebo, by IM injection at weeks 12, 24, and 52. In addition to the vaccination visits, participants will attend study visits at weeks 26, 39, 54, 65, 78, 91, 104, 117, 130, 142, and 156. All study visits, including vaccination visits, will include HIV risk reduction counseling, a physical exam, and an interview/questionnaire. and pregnancy testing for participants capable of becoming pregnant. Select study visits will include a medical history review, physical exam, blood collection, urine collection, HIV testing, and pregnancy testing for participants capable of becoming pregnant. As of February 3, 2020, vaccinations for this study were suspended. Participants have been asked to continue attending follow-up visits for 12 months after the last vaccination they received. Participants who become HIV infected will be followed for 6 months after diagnosis.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

5,404

Conditions

HIV Infections

Interventions

ALVAC-HIV (vCP2438)BIOLOGICAL

Expresses the gene products ZM96 gp120 (clade C strain) linked to the sequences encoding the HIV-1 transmembrane anchor (TM) sequence of gp41 (28 amino acids clade B LAI strain) and gag and pro (clade B LAI strain). It is formulated as a lyophilized vaccine for injection at a dose \> 10\^6 cell culture infectious dose 50% (CCIDv50) and \< 1 × 10\^8 CCIDv50 (nominal dose of 10\^7 CCIDv50) and is reconstituted with 1 mL of sterile sodium chloride solution (NaCl 0.4%) delivered IM

Bivalent Subtype C gp120/MF59BIOLOGICAL

Subtype C TV1.C gp120 Env and 1086.C gp120 Env proteins, each at a dose of 100 mcg, mixed with MF59 adjuvant (an oil-in-water emulsion) and delivered IM

PlaceboBIOLOGICAL

Sodium Chloride for injection, 0.9% delivered IM

Eligibility

Sex: ALLMin age: 18 YearsMax age: 35 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria * Age of 18 to 35 years * Sexually active, defined as having had sexual intercourse at least twice in the past 30 days prior to screening, and is considered by the site staff to be at risk for HIV infection. * Access to a participating HVTN 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 prior to first vaccination with verbal demonstration of understanding of all questions. * Agrees not to enroll in another study of an investigational research agent until the participant is unblinded or their study participation ends, whichever occurs last * Good general health as shown by medical history, physical exam, and screening laboratory tests * Willingness to receive HIV test results * Willingness to discuss HIV infection risks and willing to receive HIV risk reduction counseling. * Alanine aminotransferase (ALT) \< 2.5 times the institutional upper limit of normal * Negative HIV-1 and -2 blood test within 30 days prior to enrollment: Sites may use locally available assays that have been approved by HVTN Laboratory Operations. * Volunteers who were born female: negative serum or urine beta human chorionic gonadotropin (β-HCG) 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 (Appendix B and Appendix C) for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through 3 months after the last vaccination. Effective contraception is defined as using 2 methods of birth control. These include 1 of the following methods: * Condoms (male or female) * Diaphragm or cervical cap PLUS 1 of the following methods: * Intrauterine device (IUD), * Hormonal contraception (in accordance with applicable national contraception guidelines), or * 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 * Any other contraceptive method approved by the protocol safety review team; * Or not be of reproductive potential, such as having been diagnosed with premature menopause (with no menses for 1 year) or having undergone hysterectomy, bilateral oophorectomy, or tubal ligation. * Volunteers who were born female must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until 3 months after the last vaccination Exclusion Criteria * Blood products received within 90 days before first vaccination * Investigational research agents received within 30 days before first vaccination * 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 study * Pregnant or breastfeeding * HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 702 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 for vaccines that have subsequently undergone licensure. For volunteers who have received control/placebo in an experimental vaccine trial, the protocol safety review team 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 protocol safety review team on a case-by-case basis. * Live attenuated vaccines other than influenza vaccine received within 30 days before first vaccination or scheduled within 14 days after injection (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) * 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 oral/parenteral corticosteroids at doses \< 2 mg/kg/day and length of therapy \< 11 days with completion at least 30 days prior to enrollment.) * Serious adverse reactions to vaccines or to vaccine components such as eggs, egg products, or neomycin 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 non-anaphylactic adverse reaction to pertussis vaccine as a child.) * Immunoglobulin received within 60 days before first vaccination * Immunodeficiency * 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. * Active tuberculosis (TB) disease * Uncontrolled hypertension: systolic blood pressure (SBP) ≥ 160 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg * Bleeding disorder (diagnosed by a doctor) contraindicating IM injection and/or blood draws, based on investigator's judgment * 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) * History of hereditary angioedema, acquired angioedema, or idiopathic angioedema

Locations (14)

Walter Sisulu University HIV Vaccine Research Unit CRS

Mthatha, Eastern Cape, South Africa

Kliptown Soweto CRS

Johannesburg, Gauteng, South Africa

Aurum Tembisa CRS

Johannesburg, Gauteng, South Africa

Outcomes

Primary Outcomes

Incidence Rate of HIV-1 Infection Diagnosed After Enrollment (Concurrent With First Vaccination) Through 24 Months After Enrollment

Vaccine efficacy was calculated as 1 minus the hazard ratio for HIV-1 infection, which was estimated using a sex-stratified Cox proportional-hazards (Cox PH) model and tested using a sex-stratified log-rank test. Vaccine efficacy was also measured using a ratio of cumulative incidences (CIR) of HIV-1 infection in the vaccine group as compared with the placebo group, which was calculated using Nelson-Aalen cumulative hazard estimates and tested using a Wald test.

Time frame: Measured through 24 months after first vaccination

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.

Time frame: Measured through 3 full days following each vaccination

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

Time frame: Measured through 3 full days following each vaccination

Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms

Time frame: Measured through 3 full days following each vaccination

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

For participants reporting multiple AEs over the time frame, the maximum relationship is counted.

Data from ClinicalTrials.gov

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Secondary Outcomes

Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 36 Months Post Enrollment

This outcome measure is the same as Primary Outcome 12, which was added after pre-established criteria for vaccine non-efficacy had been met. Analysis was not repeated but the outcome is listed for completeness.

Time frame: Measured through 36 months after first vaccination

Incidence Rate of HIV-1 Infection Diagnosed After Month 6.5 Through 24 Months Post Enrollment

Time frame: Measured after Month 6.5 through 24 months after first vaccination

Number of Participants With Occurrence of CD4+ and CD8+ T-Cells Expressing IFN-g and/or IL-2 in Response to HIV Proteins Included in the Vaccine at Month 6.5

PBMC samples are stimulated with synthetic peptide pools or left unstimulated as negative control. Response magnitude is % cells expressing IFN-g and/or IL-2 after stimulation minus % cells expressing markers after no stimulation. Contingency table is constructed to assess response: stimulation (peptide/none) vs. marker expression (yes/no). One-sided Fisher's exact test is applied, testing if number of cells positive for the marker is equal in stimulated vs. unstimulated cells. Bonferroni-Holm adjustment is made over peptide pools. Response is positive if adjusted p-value le 0.00001. Data are excluded if blood draw date was outside visit window, participant was HIV-infected (post-infection samples), PBMC viability/T-cell count were low or negative control was high. Any Env is the maximum of ZM96 gp120, 1086 gp120, and TV1 gp120. Any HIV is the sum of Any Env and LAI Gag. Negative magnitudes are censored at 0 before calculating sum; if the sum is lt 0.01, it is set to 0.01%.