A Study of Heterologous Vaccine Regimen of Adenovirus Serotype 26 Mosaic4 Human Immunodeficiency Virus(Ad26.Mos4.HIV), Adjuvanted Clade C gp140 and Mosaic gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender Individuals Who Have Sex With Cis-gender Men and/or Transgender Individuals

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the vaccine efficacy (VE) of a heterologous vaccine regimen utilizing Ad26.Mos4.HIV and aluminum phosphate-adjuvanted Clade C gp140 and Mosaic gp140 for the prevention of HIV-1 infection in HIV-1 seronegative cis-gender men and transgender individuals having sex with cis-gender men and/or transgender individuals.

Detailed Description
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Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that, if left untreated, can progress to acquired immunodeficiency syndrome (AIDS), a condition in which the immune system is severely compromised, leading to life-threatening conditions. Ad26.Mos4.HIV is a tetravalent vaccine composed of Ad26.Mos1.Gag-Pol, Ad26.Mos2.Gag-Pol, Ad26.Mos1.Env, and Ad26.Mos2S.Env. Clade C and Mosaic gp140 HIV bivalent vaccine contains: Clade C gp140, HIV-1 Env gp140 of Clade C, Mosaic gp140, HIV-1 Env gp140, and aluminum phosphate adjuvant. Evidences showed that a combination of vaccination with Ad26.Mos.HIV followed by Ad26.Mos.HIV together with Clade C gp140 protein in aluminum phosphate adjuvant led to highest level of protection observed so far with this vaccine concept. Study comprises of a screening period of 45 days, a 12-month vaccination period and a follow-up period of at least 18 months after fourth vaccination (until Month 30) in participants who remain HIV-1 negative or up to 6 months after diagnosis of HIV-1 infection in participants who become HIV-1 infected. Participants who completed their Month 30 visit will be followed for HIV infection, medically-attended adverse event (MAAEs) and serious adverse events until the end of study (Month 30). Primary analysis of vaccine efficacy will evaluate the number of HIV-1 infections in the vaccine group compared to number of HIV-1 infections in the placebo group between Month 7 and Month X (with 24<=X<=30) in per-protocol population.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled Phase 3 Efficacy Study of a Heterologous Vaccine Regimen of Ad26.Mos4.HIV and Adjuvanted Clade C gp140 and Mosaic gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender Individuals Who Have Sex With Cis-gender Men and/or Transgender Individuals

Conditions
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Healthy

Intervention / Treatment
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* Biological: Ad26.Mos4.HIV
* Biological: Clade C and Mosaic gp140 HIV bivalent vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individual is either cis-gender man having sex with cis-gender men and/or transgender individuals or transgender woman having sex with cis-gender men and/or transgender individuals or transgender man having sex with cis-gender men and/or transgender women or gender non-conforming individual having receptive or insertive anal and/or vaginal condom-less intercourse and who is considered by the site staff to be at increased risk for HIV-1 infection. The potential participants must in the last 6 months have had any condom-less receptive anal or vaginal sex (not included is condom-less anal sex within a mutually monogamous relationship >=12 months if the partner is HIV negative or living with HIV and virally suppressed) or rectal or urethral gonorrhea or chlamydia or incident syphilis or any stimulant use or any other drug and/or substance which in the local context may be associated with increased HIV transmission (example, cocaine, amphetamine) or 5 or more sex partners Potential participant has a negative test result for HIV-1 and HIV-2 infection less than or equal to (<=) 28 days prior to first vaccination Potential participant must be healthy based on medical history, physical examination, and vital sign measurement performed at screening Contraceptive use by participants assigned female at birth and who have not had sexual reassignment surgery should be consistent with local regulations regarding the acceptable methods of contraception for those participating in clinical studies All participants of childbearing potential must have a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test at screening and have a negative urine beta-hCG pregnancy test immediately prior to each study vaccine administration Exclusion Criteria: Potential participants choosing to use PrEP. However, once participants are enrolled and received their first vaccination, and they change their mind regarding PrEP usage, they will be allowed to take PrEP according to the site PrEP plan and will continue to receive further vaccinations. The use of long acting PrEP is disallowed from 24 months prior to Day 1 Potential participant is a recipient of a HIV-vaccine candidate at any time, or a recipient of other experimental vaccine(s) within the last 12 months prior to Day 1. For participants who received an experimental vaccine (except HIV vaccine) more than 12 months prior to Day 1, documentation of the identity of the experimental vaccine must be provided to the HPX3002/HVTN 706 safety review team, who will determine eligibility on a case by-case basis. Exceptions: participants can be included if the vaccine received (except HIV vaccine) was subsequently licensed or authorized for emergency use (example, Emergency Use Authorization (EUA), Emergency Use Listing (EUL), or similar program). Participants with proof of having received only placebo can also be included. Participants who are currently still in an interventional study of such a licensed/emergency use-authorized vaccine are to be excluded from the current study Potential participant has received an HIV-related mAb, whether licensed or investigational, within the last 12 months prior to Day 1. For participants who received an HIV-related mAb more than 12 months prior to Day 1, documentation of the identity of the mAb must be provided to the HPX3002/HVTN 706 safety review team, who will determine eligibility on a case-by-case basis Potential participant has known allergy or history of anaphylaxis or other serious adverse reactions to vaccines Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study vaccination

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group1:Ad26.Mos4.HIV,Clade C and Mosaic gp140 bivalent vaccine<br>Participants will receive adenovirus serotype 26.Mosaic 4.human immunodeficiency virus (Ad26.Mos4.HIV) via intramuscular (IM) injection into the deltoid muscle at months 0 (Day 1) and 3 (preferably the deltoid of the non-dominant upper arm) and, Ad26.Mos4.HIV together with Clade C and Mosaic gp140 HIV bivalent vaccine IM into the deltoid muscle at Months 6 and 12 (different deltoid for each injection). | Biological: Ad26.Mos4.HIV<br>* Participants will receive Ad26.Mos4.HIV via IM injection into the deltoid muscle at months 0 (Day 1), 3, 6 and 12.<br>Biological: Clade C and Mosaic gp140 HIV bivalent vaccine<br>* Participants will receive Clade C and Mosaic gp140 HIV bivalent vaccine as IM injection into the deltoid muscle at Months 6 and 12.<br>|
| Placebo Comparator: Group 2: Placebo<br>Participants will receive placebo into the deltoid muscle on Months 0 (Day 1), 3 (1 injection), 6 and 12 (2 injections). | Biological: Placebo<br>* Participants will receive matching placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine Efficacy (VE) as Derived From Confirmed HIV-1 Infections Diagnosed Between the Month 7 and Month X (with 24 Less Than or Equal to [<=] X <= 30) Visits | Vaccine efficacy is defined as 1-cumulative incidence ratio (vaccine versus placebo) between Month 7 and Month X after first vaccination and is estimated by the transformation of the Nelson-Aalen estimator for the cumulative hazard function after enrollment in the per-protocol (PP) population. Here, month X will be between month 24 and month 30. | From Month 7 up to Month 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Solicited Local and Systemic Adverse Events (AEs) | Number of participants with local solicited adverse events will be evaluated. An adverse event is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product and does not necessarily have a causal relationship with the intervention, therefore it can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that medicinal product. Solicited local AEs include assessment of pain/tenderness, erythema and swelling. Solicited systemic AEs: fatigue, headache, nausea, myalgia, chills, arthralgia, and vomiting will be assessed. | 7 days after each vaccination on Months 0, 3, 6, and 12 | 
| Number of Participants with Unsolicited Adverse Events | Number of Participants with unsolicited AEs will be evaluated. Unsolicited adverse events are all adverse events for which the participant is specifically not questioned in the participant diary. | 28 days after each vaccination on Months 0, 3, 6, and 12 | 
| Number of Participants with Adverse Events of Special Interest (AESIs) | Number of participants with AESIs will be reported. Thrombosis with thrombocytopenia syndrome is considered to be an AESI. | Up to 6 months after the last vaccination (Month 18) | 
| Number of Participants with Medically-attended adverse events (MAAEs) | Number of participants with MAAEs will be evaluated. MAAEs are defined as adverse events with medically attended visits including hospital, emergency room, urgent care clinic, or other visits to or from medical personnel for any reason. | Up to 43 Months (participants will be followed until the last participant reaches Month 30) | 
| Number of Participants with Serious Adverse Events (SAEs) | Number of participants with SAE will be evaluated. An SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. | Up to 43 Months (participants will be followed until the last participant reaches Month 30) | 
| Number of Participants who Discontinue from the Study or Vaccination due to Adverse Events | Number of participants who discontinue from the study or vaccination due to AEs will be evaluated. Participants will be withdrawn from study vaccine administration due to unblinding due to safety reasons, Pregnancy, Confirmed HIV-1 infection, Any related adverse event, Worsening of health status or intercurrent illnesses that in the opinion of the investigator, Required discontinuation from study vaccine, Anaphylactic reaction following vaccination, Serious adverse event or other potentially life-threatening (Grade 4) event that is determined to be related to study vaccine, Chronic or recurrent use of systemic immunomodulators/suppressants, example, cancer chemotherapeutic agents (after discussion with the sponsor), Use of HIV-related monoclonal antibodies (mAbs). | Up to 43 Months (participants will be followed until the last participant reaches Month 30) | 
| Vaccine Efficacy as Derived From Confirmed HIV-1 Infections Diagnosed at VE (0-X months) per Modified Intent-to-Treat (mITT) Population | Vaccine efficacy is defined as 1-cumulative incidence ratio (vaccine versus placebo) between Month 0 and Month X after first vaccination and is estimated by the transformation of the Nelson-Aalen estimator for the cumulative hazard function per mITT populations. Here, month X will be between month 24 and month 30. | Month 0 (Day 1) up to Month 30 | 
| Vaccine Efficacy as Derived From Confirmed HIV-1 Infections Diagnosed at VE (13-X months) per mITT Population | Vaccine efficacy is defined as 1-cumulative incidence ratio (vaccine versus placebo) between Month 13 and Month X after first vaccination and is estimated by the transformation of the Nelson-Aalen estimator for the cumulative hazard function per mITT populations. Here, month X will be between month 24 and month 30. | Month 13 up to Month 30 | 
| Vaccine Efficacy Assessed by Demographic Characteristics | The vaccine efficacy assessed by demographic characteristics diagnosed by HIV-1 infection will be reported. | Month 0 (Day 1) up to Month 30 | 
| Number of Participants who are Ad26 Seropositive | Number of participants who are Ad26 seropositive will be assessed by vector neutralization assay. | Month 0 (Day 1) up to Month 30 | 
| Antibody Titers for Ad26 as Determined by Vector Neutralization Assay | Antibody titers will be determined by vector neutralization assay. | Month 0 (Day 1) up to Month 30 | 
| Sexual Risk Behavior as Assessed by Sexual Activity Questionnaire | Sexual risk behavior collected through sexual activity questionnaire (composed with 36 questions) in which participants will be asked about specific sexual activities. | Month 0 (Day 1) up to Month 30 | 
| Pre-Exposure Prophylaxis (PrEP) Uptake as Measured by Self Report Questionnaire | For HIV-negative participants, participants will be asked whether they use HIV PrEP as part of a self-report questionnaire (composed of 5 questions). | Month 0 (Day 1), 3, 6, 9, 12, 15, 18, 21, 24, 27, 30 and every 3 months post month 30 (up to 48 months) |