Safety, Tolerability, and Immunogenicity Study of Homologous Ad26 Mosaic Vector Vaccine Regimens or Heterologous Ad26 Mosaic and MVA Mosaic Vector Vaccine Regimens With Glycoprotein 140 (gp140) for Human Immunodeficiency Virus (HIV) Prevention

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of various regimens containing adenovirus serotype 26-Mosaic -Human Immunodeficiency Virus (Ad26.Mos.HIV), Modified Vaccinia Ankara (MVA)-Mosaic, and/or HIV type 1 Clade C glycoprotein 140 drug product (gp140 DP) components and to compare envelope binding antibody responses between the different vaccine regimens.

Detailed Description
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This is a multicenter (more than 1 hospital or medical school team work on a study), randomized (the study drug is assigned by chance), parallel group (each group of participants will be treated at the same time), placebo-controlled (study in which the experimental treatment or procedure is compared to a pretend treatment with no drug in it to test if the drug has a real effect), and double-blind (neither physician nor participant knows the treatment that the participant receives) study. All eligible participants will be randomly assigned to receive 1 of the 8 vaccine regimens. Participants will receive study vaccines (Ad26.Mos.HIV, MVA-Mosaic, gp140 DP, and placebo) 4 times as per assigned regimen. The study comprises a Screening Period (up to 4 weeks), a Vaccination Period (participants will be vaccinated at Baseline (Week 0), Week 12, Week 24 and Week 48), and a Follow-up Period (up to 48 weeks). A long-term follow-up period (approximately 2 years after Week 96) will continue for participants randomized to the regimen subsequently selected for future studies, based on analysis of Week 28 data. If Week 28 data are inconclusive, Week 52 data will be considered for regimen selection. If no clear decision can be made, the extended follow-up period could include participants from more than 1 group for assessing durability of immune responses. Participants' safety will be monitored throughout the study.

Official Title
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A Phase 1/2a Trial to Evaluate the Safety/Tolerability and Immunogenicity of Homologous Ad26 Mosaic Vector Regimens or Ad26 Mosaic and MVA Mosaic Heterologous Vector Regimens, With High-Dose, Low-Dose or no Clade C gp140 Protein Plus Adjuvant for HIV Prevention

Conditions
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Healthy

Intervention / Treatment
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* Biological: Ad26.Mos.HIV
* Biological: MVA-Mosaic
* Biological: gp140 DP Low-dose
* Biological: gp140 DP High-dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be healthy on the basis of physical examination, medical history, electrocardiogram (ECG) and laboratory criteria, and vital signs measurement performed at Screening Participants are negative for human immunodeficiency virus (HIV) infection at Screening All female participants of childbearing potential must have a negative serum (beta human chorionic gonadotropin) at Screening, and a negative urine pregnancy test pre-dose on Week 0, 12, 24, and 48 A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction until 3 months after receiving the last dose of study vaccine. A man must agree not to donate sperm until 3 months after receiving the last dose of study vaccine Participants are assessed by the clinic staff as being at low risk for HIV infection Exclusion Criteria: Participant has chronic active hepatitis B or active hepatitis C, active syphilis infection, chlamydia, gonorrhea, or trichomonas. Active syphilis documented by exam or serology unless positive serology is due to past treated infection In the 12 months prior to enrollment, participant has a history of newly acquired herpes simplex virus type 2 (HSV-2), syphilis, gonorrhea, non-gonococcal urethritis, chlamydia, pelvic inflammatory disease, trichomonas, mucopurulent cervicitis, epididymitis, proctitis, lymphogranulomavenereum, chancroid, or hepatitis B Participant has any clinically significant acute or chronic medical condition that in the opinion of the investigator would preclude participation (for example, history of seizure disorders, bleeding/clotting disorder, autoimmune disease, active malignancy, poorly controlled asthma, active tuberculosis or other systemic infections) Participant has had major surgery within the 4 weeks prior to study entry or planned major surgery through the course of the study Participant has had a thyroidectomy, or thyroid disease requiring medication during the last 12 months Participant has a history of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with permanent sequelae, clinically significant arrhythmia (including any arrhythmia requiring medication, treatment, or clinical follow up) Participant has an ECG (per examination and interpretation of a cardiologist) with clinically significant findings, or features that would interfere with the assessment of myo/pericarditis, including any of the following: a) conduction disturbance (complete left or complete right bundle branch block or nonspecific intraventricular conduction disturbance with QRS >=120 millisecond [ms], PR interval >=220 ms, any 2nd or 3rd degree AV block, or QTc prolongation [>450 ms]); b) significant repolarization (ST segment or T wave) abnormality; c) significant atrial or ventricular arrhythmia, frequent atrial or ventricular ectopy (for example frequent premature atrial contractions, 2 premature ventricular contractions in a row); d) ST elevation consistent with ischemia, or evidence of past or evolving myocardial infarction Participant has a history of anaphylaxis or other serious adverse reactions to vaccines or vaccine products, or neomycin or streptomycin or egg products

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Participants will receive adenovirus serotype 26-Mosaic -Human Immunodeficiency Virus (Ad26.Mos.HIV) vaccine at Week 0 and 12; followed by Ad26.Mos.HIV vaccine + HIV type 1 Clade C glycoprotein 140 drug product (gp140 DP) vaccine containing 250 microgram (mcg) of total protein mixed with adjuvant (aluminum phosphate) at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Biological: gp140 DP High-dose<br>* The gp140 DP vaccine containing 250 mcg of total protein, mixed with aluminum phosphate adjuvant, per 0.5 mL injection administered intramuscularly.<br>|
| Experimental: Group 2<br>Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12; followed by Ad26.Mos.HIV vaccine + gp140 DP vaccine containing 50 mcg of total protein mixed with adjuvant at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Biological: gp140 DP Low-dose<br>* The gp140 DP vaccine containing 50 mcg of total protein, mixed with aluminum phosphate adjuvant (0.425 mg aluminum), per 0.5 mL injection administered intramuscularly.<br>|
| Experimental: Group 3<br>Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12; followed by Ad26.Mos.HIV vaccine + placebo injection at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Drug: Placebo<br>* Normal saline, 0.5 mL injection administered intramuscularly.<br>|
| Experimental: Group 4<br>Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12; followed by modified Vaccinia Ankara (MVA)-Mosaic vaccine + gp140 DP vaccine containing 250 mcg of total protein mixed with adjuvant at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Biological: MVA-Mosaic<br>* Recombinant live attenuated MVA virus-vectored vaccine that has been genetically engineered to express 2 mosaic Gag, Pol, and Env sequences (Mosaic 1 and Mosaic 2). Total dose is 10^8 plaque-forming unit per 0.5 mL injection administered intramuscularly.<br>Biological: gp140 DP High-dose<br>* The gp140 DP vaccine containing 250 mcg of total protein, mixed with aluminum phosphate adjuvant, per 0.5 mL injection administered intramuscularly.<br>|
| Experimental: Group 5<br>Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12; followed by MVA-Mosaic vaccine + gp140 DP vaccine containing 50 mcg of total protein mixed with adjuvant at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Biological: MVA-Mosaic<br>* Recombinant live attenuated MVA virus-vectored vaccine that has been genetically engineered to express 2 mosaic Gag, Pol, and Env sequences (Mosaic 1 and Mosaic 2). Total dose is 10^8 plaque-forming unit per 0.5 mL injection administered intramuscularly.<br>Biological: gp140 DP Low-dose<br>* The gp140 DP vaccine containing 50 mcg of total protein, mixed with aluminum phosphate adjuvant (0.425 mg aluminum), per 0.5 mL injection administered intramuscularly.<br>|
| Experimental: Group 6<br>Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12; followed by MVA-Mosaic vaccine + placebo injection at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Biological: MVA-Mosaic<br>* Recombinant live attenuated MVA virus-vectored vaccine that has been genetically engineered to express 2 mosaic Gag, Pol, and Env sequences (Mosaic 1 and Mosaic 2). Total dose is 10^8 plaque-forming unit per 0.5 mL injection administered intramuscularly.<br>Drug: Placebo<br>* Normal saline, 0.5 mL injection administered intramuscularly.<br>|
| Experimental: Group 7<br>Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12; followed by gp140 DP vaccine containing 250 mcg of total protein mixed with adjuvant + placebo injection at Week 24 and 48. | Biological: Ad26.Mos.HIV<br>* Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelop (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5*10^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly.<br>Biological: gp140 DP High-dose<br>* The gp140 DP vaccine containing 250 mcg of total protein, mixed with aluminum phosphate adjuvant, per 0.5 mL injection administered intramuscularly.<br>Drug: Placebo<br>* Normal saline, 0.5 mL injection administered intramuscularly.<br>|
| Placebo Comparator: Group 8<br>Participants will receive 1 placebo injection at Week 0 and 12; followed by 2 placebo injections at Week 24 and 48. | Drug: Placebo<br>* Normal saline, 0.5 mL injection administered intramuscularly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Solicited Local Adverse Events (AEs) Post Vaccination | Solicited local AEs (at injection site) included erythema, induration, swelling, itching and warmth were collected within 7 days after vaccination. | Up to Week 49 (7 days post any dose) | 
| Percentage of Participants With Solicited Systemic Adverse Events (AEs) Post Vaccination | Solicited systemic AEs included fever (defined as body temperature of 38.0-degree celsius or higher), headache, fatigue, myalgia, nausea, vomiting were collected within 7 days after vaccination. | Up to Week 49 (7 days post any dose) | 
| Percentage of Participants With Unsolicited Adverse Events Post Vaccination | Unsolicited AEs were defined as events that participants experienced but were not specifically asked about. | Up to Week 52 (28 days post vaccination) | 
| Number of Participants With Serious Adverse Events (SAEs) Post Vaccination | An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the study vaccine. An AE can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. A SAE is any AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect and is a suspected transmission of any infectious agent via a medicinal product. | Serious adverse events (SAEs) were reported up to Week 336 for Group 1 and 2 and up to Week 96 for the other groups (Group 3, 4, 5, 6, 7, and 8). Other adverse events (AEs) were reported for the main study period up to Week 96 for all the groups | 
| Percentage of Responders for Envelop (Env) Clade A, B and C-specific Binding Antibody Titers at Week 28 | The Env Clade A (92UG037.1), B (1990a), and C (Con C), (C97ZA.012)- specific binding antibody titer were assessed using enzyme-linked immunosorbent assay (ELISA). The response was defined as post-baseline value greater than (>) lower limit of quantification (LLOQ) if baseline less than (<) LLOQ or missing or defined as post-baseline value >3-fold increase from baseline if baseline greater than or equal to (>=) LLOQ. The lower limits of quantification (LLOQs) for this assay were 625, 156.25, 625, and 156.25 endotoxin units per milliliter (EU/mL) for Clade A (92UG037.1), Clade B (1990a), Clade C (Con C), and Clade C (C97ZA.012) respectively. | Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders for Clade C (C97ZA.012) Env Enzyme-linked Immunosorbent Assay (ELISA) Immunoglobulin G1 (IgG1), IgG2, IgG3 and IgG4 Glycoprotein (gp) 140 Binding Antibody | Vaccine-induced binding antibody IgG1, IgG2, IgG3 and IgG4 subclass responses were investigated using Clade C (C97ZA.012) specific ELISAs. The response was defined as post-baseline value >LLOQ if baseline <LLOQ or missing or defined as post-baseline value >3-fold increase from baseline if baseline >=LLOQ. The LLOQs for this assay were 12.3, 28.7, 12.4, and 13.2 for IgG1, IgG2, IgG3 and IgG4 respectively. Samples taken after Week 48 (W48) from PPI set, who missed 4th vaccine or deviated schedule were excluded. As planned, the data reported for this endpoint at specified time points only for each reported category. | Week 28, 52 and 96 | 
| Percentage of Responders for Env ELISA Including Consensus C and Mos1 Antigens | The response was defined as post-baseline value >LLOQ if baseline <LLOQ or missing or defined as post-baseline value >3-fold increase from baseline if baseline >=LLOQ. The LLOQ for this assay is a 50 percent (%) inhibitory concentration (IC50) of 20 (fold-dilution). The lower limits of quantification (LLOQs) for this assay were 625 and 78.125 EU/mL for Clade C (Con C) and Mos1 respectively. Samples taken after W48 from PPI set, who missed 4th vaccine or deviated schedule were excluded. As planned, the data reported for this endpoint at specified time points only for each reported category. | Week 28, 52 and 96 | 
| Percentage of Responders for Env Antibody-dependent Cellular Phagocytosis (ADCP) gp Antibody | The functionality of vaccine-induced antibody responses was investigated by the determination of ADCP. The response was defined as post-baseline value > limit of detection (LOD) if baseline <LOD or missing or defined as post-baseline value >3-fold increase from baseline if baseline >=LOD. The lower limits of detection (LODs) for this assay were 5.16, 6.43, 6.49, 4.32 and 4.28 (phagocytic score) for Clade A (92UG037.1), Clade B (1990a), Clade C (Con C), Clade C (C97ZA.012), and Mos1, respectively. Samples taken after W48 from PPI set, who missed 4th vaccine or deviated schedule were excluded. As planned, the data reported for this endpoint at specified time points only for each reported category of Clade A, B, C and Mos 1. | Week 16, 26, 28, 52, 78, and 96 | 
| Percentage of Responders for Human Immunodeficiency Virus Neutralizing Antibody (HIV nAb) | The functionality of vaccine-induced antibody responses was investigated by the determination of nAb activity in a virus neutralization assay (VNA) using TZM-bl cells and Env-pseudotyped viruses. The response was defined as post-baseline value >LLOQ. The LLOQ for this assay is an inhibitory concentration (IC50) of 20 (fold-dilution). Data reported for the responses against Tier 1 HIV strain Clade C (MW965.26) was reported. Samples taken after W48 from PPI set, who missed 4th vaccine or deviated schedule were excluded. As planned, the data reported for this endpoint at specified time points only for each reported category. | Week 28 and 52 | 
| Percentage of Responders for Binding Antibody Multiplex Assay (BAMA) IgG1-IgG4 and IgA and IgG-t Breadth Antibody | The human immunodeficiency virus (HIV)-1 BAMA employs flow-cytometric-based technology that also utilizes antibody and antigen interactions to test for the presence of specific antibodies in an unknown sample with the added advantage of multiplexing the antigens of interest. Positive and negative control standards were run with each assay to ensure specificity. The positivity threshold was determined per antigen based on the plus (+) 3 standard deviation (SD) on the non-specific background. Sample values had to be greater than or equal to this value and had to be 3-fold over the baseline values with a minimum median fluorescent intensities (MFI) value of 100. Samples taken after W48 from PPI set, who missed 4th vaccine or deviated schedule were excluded. As planned, the data reported for this endpoint at specified time points only for each reported category. | Week 16, 28, 52, 78, and 96 | 
| Percentage of Responders With Interferon-gamma (IFN-gamma) T Cell Responses Enzyme-linked Immunospot Assay (ELISpot) | Frozen peripheral blood mononuclear cell (PBMCs) were analyzed by interferon-gamma (IFN-gamma) (ELISpot). The response was defined as post-baseline value >P95 if baseline <P95 or missing or defined as post-baseline value >3-fold increase from baseline if baseline >=P95. The threshold for ELISpot test was based on the 95th percentile (P95) from the baseline values of participants on that test in the study. Samples taken after W48 from PPI set, who missed 4th vaccine or deviated schedule were excluded. As planned, the data reported for this endpoint at specified time points only for each reported category. | Week 26, 50, 78 and 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy, Acquired Immuno-Deficiency Syndrome, Acquired Immunodeficiency Syndrome Virus, adenovirus serotype 26, Ad26.Mos.HIV, Modified Vaccinia Ankara, Glycoprotein, Adjuvant, Vaccine, Placebo