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

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.

• 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/MF59 (Biological): 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
• Placebo (Biological): Sodium Chloride for injection, 0.9% delivered IM

Primary outcomes

• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment (Concurrent With First Vaccination) Through 24 Months After Enrollment [Measured through 24 months after first vaccination]: 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.
• Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness [Measured through 3 full days following each vaccination]: 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.
• Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration [Measured through 3 full days following each vaccination]: 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.
• Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms [Measured through 3 full days following each vaccination]: 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.
• Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product [Measured through 30 days after each vaccination]: For participants reporting multiple AEs over the time frame, the maximum relationship is counted.
• Number of Participants Reporting Adverse Events (AEs), by Severity Grade [Measured through 30 days after each vaccination]: 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 12 months after last vaccination]: 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 of Special Interest (AESIs) [Measured through 12 months after last vaccination]: Adverse events of special interest (AESI) were described in Appendix J of the protocol. AESI for this protocol include but are not limited to potential immune-mediated diseases.
• Number of Participants Reporting New Chronic Medical Conditions [Measured through 12 months after last vaccination]: A new chronic medical condition is defined as a new onset or exacerbation of medical condition requiring 2 or more visits to a medical provider during a period of at least 30 days.
• Number of Participants With Early Study Termination Associated With an AE or Reactogenicity [Measured through study completion (through 6 months after confirmation of HIV-1 diagnosis for participants who acquired HIV and through 12 months after last vaccination for the rest)]: From the termination form, early study termination associated with an AE or reactogenicity reasons are tabulated by treatment group.
• Number of Participants With Study Product Discontinuation Associated With an AE or Reactogenicity [Measured through study completion (through 6 months after confirmation of HIV-1 diagnosis for participants who acquired HIV and through 12 months after last vaccination for the rest)]: From the study product discontinuation form, study product discontinuation reasons are tabulated by treatment group.
• Incidence Rate of HIV-1 Infections Diagnosed Following Enrollment and Throughout All Participant Follow-Up [Measured through 36 months after first vaccination]: Per the 23 January 2020 DSMB finding that monitoring boundaries for non-efficacy have been met, Primary outcome 1 has been superseded by this primary outcome. 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.

Secondary outcomes

• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 36 Months Post Enrollment [Measured through 36 months after first vaccination]: 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.
• Incidence Rate of HIV-1 Infection Diagnosed After Month 6.5 Through 24 Months Post Enrollment [Measured after Month 6.5 through 24 months after first vaccination]: 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.
• 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 [Measured 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%.
• Number of Participants With Occurrence of CD4+ and CD8+ T-Cells Expressing IFN-g and/or IL-2 and/or CD40L in Response to HIV Proteins Included in the Vaccine at Month 6.5 [Measured 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%.
• Level 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 [Measured 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. 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%. Summary was calculated among positive responders only.
• Level of CD4+ and CD8+ T-Cells Expressing IFN-g and/or IL-2 and/or CD40L in Response to HIV Proteins Included in the Vaccine at Month 6.5 [Measured 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. 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%. Summary was calculated among positive responders only.
• Number of Participants With Occurrence of Vaccine-induced IgG Binding Antibodies to HIV Proteins at Month 6.5 [Measured at Month 6.5]: Serum IgG responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay, run at 1:50 dilution.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 lt 1 is set to 1,and net MFI > 22,000 is set to 22,000.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.Samples from post-enrollment visits have positive responses if they meet three criteria:(1) net MFI greater than or equal to an antigen-specific response threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI),(2) net MFI values are greater than 3 times baseline net MFI, and (3) experimental antigen MFI values are greater than 3 times baseline MFI.
• Number of Participants With Occurrence of Vaccine-induced IgG3 Binding Antibodies to HIV Proteins at Month 6.5 [Measured at Month 6.5]: Serum IgG3 responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay,run at 1:40 dilution.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 lt 1 is set to 1, and net MFI > 22,000 is set to 22,000.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.Samples from post-enrollment visits have positive responses if they meet three criteria:(1) net MFI greater than or equal to an antigen-specific response threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI), (2) net MFI values are greater than 3 times baseline net MFI, and (3) experimental antigen MFI values are greater than 3 times baseline M
• Number of Participants With Occurrence of Vaccine-induced IgA Binding Antibodies to HIV Proteins at Month 6.5 [Measured at Month 6.5]: Serum IgA responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay,run at 1:10 dilution.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 lt 1 is set to 1, and net MFI > 22,000 is set to 22,000.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.Samples from post-enrollment visits have positive responses if they meet three criteria:(1) net MFI greater than or equal to an antigen-specific response threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI),(2) net MFI values are greater than 3 times baseline net MFI, and (3) experimental antigen MFI values are greater than 3 times baseline MFI.
• Level of Vaccine-induced IgG Binding Antibodies to HIV Proteins at Month 6.5 [Measured at Month 6.5]: Serum IgG responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay, run at 1:50 and 1:100 dilutions. 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 lt 1 is set to 1, and net MFI > 22,000 is set to 22,000. 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. Summary was calculated among positive responders only. The immune response data were also studied for their ability to predict HIV-1 infection through Month 24 (correlates of risk analysis). The comprehensive analysis results are available in Moodie et al 2022 (PubMed ID: 35758878).
• Level of Vaccine-induced IgG3 Binding Antibodies to HIV Proteins at Month 6.5 [Measured at Month 6.5]: Serum IgG3 responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay, run at 1:40 dilution. 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 lt 1 is set to 1, and net MFI > 22,000 is set to 22,000. 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. Summary was calculated among positive responders only. The immune response data were also studied for their ability to predict HIV-1 infection through Month 24 (correlates of risk analysis). The comprehensive analysis results are available in Moodie et al 2022 (PubMed ID: 35758878).
• Level of Vaccine-induced IgA Binding Antibodies to HIV Proteins at Month 6.5 [Measured at Month 6.5]: Serum IgA responses were measured on a Bio-Plex instrument using a standardized custom Luminex assay, run at 1:10 dilution. 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 lt 1 is set to 1, and net MFI > 22,000 is set to 22,000. 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. Summary was calculated among positive responders only. The immune response data were also studied for their ability to predict HIV-1 infection through Month 24 (correlates of risk analysis). The comprehensive analysis results are available in Moodie et al 2022 (PubMed ID: 35758878).
• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 24 Months Among Female Participants [Measured through 24 months after first vaccination]: Vaccine efficacy was calculated as 1 minus the hazard ratio for HIV-1 infection, which was estimated using a Cox proportional-hazards (Cox PH) model and tested using a log-rank test.
• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 24 Months Among Male Participants [Measured through 24 months after first vaccination]: Vaccine efficacy was calculated as 1 minus the hazard ratio for HIV-1 infection, which was estimated using a Cox proportional-hazards (Cox PH) model and tested using a log-rank test.
• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 24 Months Among Female Participants Aged 25 or Younger [Measured through 24 months after first vaccination]: Vaccine efficacy was calculated as 1 minus the hazard ratio for HIV-1 infection, which was estimated using a Cox proportional-hazards (Cox PH) model and tested using a log-rank test.
• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 24 Months Among Female Participants Older Than 25 [Measured through 24 months after first vaccination]: Vaccine efficacy was calculated as 1 minus the hazard ratio for HIV-1 infection, which was estimated using a Cox proportional-hazards (Cox PH) model and tested using a log-rank test.
• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through Month 24 by Genotypic Characteristics of Viral Sequences From HIV-1 Infected Participants at HIV-1 Diagnosis, Such As Signature Site Mutations [Measured through 24 months after first vaccination]: Analysis will only be performed if significant positive evidence of vaccine efficacy from enrollment through 24 months is seen. However, monitoring boundaries for non-efficacy have been met per the 23 January 2020 DSMB finding.
• Number of Participants With Viral Sequences at HIV-1 Diagnosis [Measured through 24 months after first vaccination]: Number of participants in the female mITT cohort with viral sequences were reported. Viral sequencing was conducted on the earliest available plasma specimens with positive HIV-1 RNA PCR tests from study participants who are diagnosed with HIV-1 infection.

Sex: All, ages: 18 Years to 35 Years, accepts healthy volunteers

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

Participant flow

Outcome results

• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment (Concurrent With First Vaccination) Through 24 Months After Enrollment (Primary), Number, events per 100 person-years: Vaccine 0.034; Placebo 0.033 (p 0.84)
• Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness (Primary), Count of participants, Participants: Vaccine 2161; Placebo 2539
• Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration (Primary), Count of participants, Participants: Vaccine 2494; Placebo 2683
• Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms (Primary), Count of participants, Participants: Vaccine 2622; Placebo 2649
• Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product (Primary), Count of participants, Participants: Vaccine 38; Placebo 12
• Number of Participants Reporting Adverse Events (AEs), by Severity Grade (Primary), Count of participants, Participants: Vaccine 161; Placebo 137
• Number of Participants Reporting Serious Adverse Events (SAEs) (Primary), Count of participants, Participants: Vaccine 103; Placebo 95
• Number of Participants Reporting Adverse Events of Special Interest (AESIs) (Primary), Count of participants, Participants: Vaccine 4; Placebo 2
• Number of Participants Reporting New Chronic Medical Conditions (Primary), Count of participants, Participants: Vaccine 54; Placebo 54
• Number of Participants With Early Study Termination Associated With an AE or Reactogenicity (Primary), Count of participants, Participants: Vaccine 9; Placebo 14
• Number of Participants With Study Product Discontinuation Associated With an AE or Reactogenicity (Primary), Count of participants, Participants: Vaccine 8; Placebo 6
• Incidence Rate of HIV-1 Infections Diagnosed Following Enrollment and Throughout All Participant Follow-Up (Primary), Number, events per 100 person-years: Vaccine 0.032; Placebo 0.03 (p 0.66)
• Incidence Rate of HIV-1 Infection Diagnosed After Enrollment Through 36 Months Post Enrollment (Secondary)
• Incidence Rate of HIV-1 Infection Diagnosed After Month 6.5 Through 24 Months Post Enrollment (Secondary), Number, events per 100 person-years: Vaccine 0.03; Placebo 0.026 (p 0.39)
• 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 (Secondary), Count of participants, Participants: Vaccine 65; Placebo 0
• Number of Participants With Occurrence of CD4+ and CD8+ T-Cells Expressing IFN-g and/or IL-2 and/or CD40L in Response to HIV Proteins Included in the Vaccine at Month 6.5 (Secondary), Count of participants, Participants: Vaccine 86; Placebo 0
• Level 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 (Secondary), Median, % T-Cells: Vaccine 0.1 (0.1 to 0.2)
• Level of CD4+ and CD8+ T-Cells Expressing IFN-g and/or IL-2 and/or CD40L in Response to HIV Proteins Included in the Vaccine at Month 6.5 (Secondary), Median, % T-Cells: Vaccine 0.2 (0.1 to 0.3)
• Number of Participants With Occurrence of Vaccine-induced IgG Binding Antibodies to HIV Proteins at Month 6.5 (Secondary), Count of participants, Participants: Vaccine 117; Placebo 0
• Number of Participants With Occurrence of Vaccine-induced IgG3 Binding Antibodies to HIV Proteins at Month 6.5 (Secondary), Count of participants, Participants: Vaccine 74; Placebo 0
• 10 more outcome measures not shown.

Adverse events

Time frame: Serious adverse events, adverse events of special interest, adverse events of STIs, new chronic medical conditions, and adverse events leading to early participant withdrawal or early discontinuation of study product(s) administration were collected through 12 months after the last vaccination received. All other adverse events were collected through 30 days after each vaccination.

Serious adverse events by term

95 more terms not shown.

Other adverse events by term

422 more terms not shown.

• Gray GE, Bekker LG, Laher F, Malahleha M, Allen M, Moodie Z, Grunenberg N, Huang Y, Grove D, Prigmore B, Kee JJ, Benkeser D, Hural J, Innes C, Lazarus E, Meintjes G, Naicker N, Kalonji D, Nchabeleng M, Sebe M, Singh N, Kotze P, Kassim S, Dubula T, Naicker V, Brumskine W, Ncayiya CN, Ward AM, Garrett N, Kistnasami G, Gaffoor Z, Selepe P, Makhoba PB, Mathebula MP, Mda P, Adonis T, Mapetla KS, Modibedi B, Philip T, Kobane G, Bentley C, Ramirez S, Takuva S, Jones M, Sikhosana M, Atujuna M, Andrasik M, Hejazi NS, Puren A, Wiesner L, Phogat S, Diaz Granados C, Koutsoukos M, Van Der Meeren O, Barnett SW, Kanesa-Thasan N, Kublin JG, McElrath MJ, Gilbert PB, Janes H, Corey L; HVTN 702 Study Team. Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults. N Engl J Med. 2021 Mar 25;384(12):1089-1100. doi: 10.1056/NEJMoa2031499. PMID 33761206
• Moodie Z, Dintwe O, Sawant S, Grove D, Huang Y, Janes H, Heptinstall J, Omar FL, Cohen K, De Rosa SC, Zhang L, Yates NL, Sarzotti-Kelsoe M, Seaton KE, Laher F, Bekker LG, Malahleha M, Innes C, Kassim S, Naicker N, Govender V, Sebe M, Singh N, Kotze P, Lazarus E, Nchabeleng M, Ward AM, Brumskine W, Dubula T, Randhawa AK, Grunenberg N, Hural J, Kee JJ, Benkeser D, Jin Y, Carpp LN, Allen M, D'Souza P, Tartaglia J, DiazGranados CA, Koutsoukos M, Gilbert PB, Kublin JG, Corey L, Andersen-Nissen E, Gray GE, Tomaras GD, McElrath MJ. Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk. J Infect Dis. 2022 Aug 24;226(2):246-257. doi: 10.1093/infdis/jiac260. PMID 35758878
• Results publication: Shin E, Bhat AG, Ramanathan M. Large Language Models for Clinical Trial Protocol Assessments. Clin Pharmacol Ther. 2026 Feb;119(2):393-402. doi: 10.1002/cpt.70096. Epub 2025 Oct 21. PMID 41121745
• Results publication: Moodie Z, Li SS, Giorgi EE, Williams LD, Dintwe O, Carpp LN, Chen S, Seaton KE, Sawant SS, Zhang L, Heptinstall J, Liu S, Grunenberg N, Tomaka F, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Ake JA, Vasan S, Pantaleo G, Frank I, Baden LR, Goepfert PA, Keefer M, Chirenje M, Hosseinipour MC, Mngadi K, Laher F, Garrett N, Bekker LG, De Rosa S, Andersen-Nissen E, Kublin JG, Lu S, Gilbert PB, Gray GE, Corey L, McElrath MJ, Tomaras GD. A polyvalent DNA prime with matched polyvalent protein/GLA-SE boost regimen elicited the most robust and broad IgG and IgG3 V1V2 binding antibody and CD4+ T cell responses among 13 HIV vaccine trials. Emerg Microbes Infect. 2025 Dec;14(1):2485317. doi: 10.1080/22221751.2025.2485317. Epub 2025 Apr 7. PMID 40190112
• Results publication: Chihana R, Jin Kee J, Moodie Z, Huang Y, Janes H, Dadabhai S, Roxby AC, Allen M, Kassim S, Naicker V, Innes C, Naicker N, Dubula T, Grunenberg N, Malahleha M, Kublin JG, Bekker LG, Gray G, Kumwenda J, Laher F. Factors associated with reactogenicity to an investigational HIV vaccine regimen in HIV vaccine trials network 702. Vaccine. 2024 Aug 13;42(20):125991. doi: 10.1016/j.vaccine.2024.05.039. Epub 2024 May 21. PMID 38772835
• Results publication: Laher F, Malahleha M, Ramirez S, Brumskine W, Otwombe K, Moodie Z, Allen M. Data quality in an HIV vaccine efficacy clinical trial in South Africa: through natural disasters and with discipline. BMC Med Res Methodol. 2023 Jun 24;23(1):147. doi: 10.1186/s12874-023-01967-9. PMID 37355583
• Results publication: Hanass-Hancock J, Carpenter B, Reddy T, Nzuza A, Gaffoor Z, Goga A, Andrasik M. Participants' characteristics and motivations to screen for HIV vaccine and monoclonal antibody trials in KwaZulu-Natal, South Africa. Trials. 2021 Dec 11;22(1):897. doi: 10.1186/s13063-021-05792-7. PMID 34895272

• Study Protocol and Informed Consent Form (PDF, 2020-05-20)
• Statistical Analysis Plan (PDF, 2020-01-22)

• Glenda Gray, MD, Study chair, Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital