Evaluating the Safety and Immunogenicity of HIV Clade C DNA Vaccine and MF59- or AS01B-Adjuvanted Clade C Env Protein Vaccines in Various Combinations in Healthy, HIV-Uninfected Adults

Evaluating the Safety and Immunogenicity of HIV Clade C DNA Vaccine and MF59- or AS01B-Adjuvanted Clade C Env Protein Vaccines in Various Combinations in Healthy, HIV-Uninfected Adults

A Phase 1/2a Clinical Trial to Evaluate the Safety and Immunogenicity of HIV Clade C DNA, and of MF59®- or AS01B-Adjuvanted Clade C Env Protein in Various Combinations, in Healthy, HIV-Uninfected Adult Participants

This study will evaluate the safety and immune response to the DNA-HIV-PT123 vaccine used in combination with one of two protein vaccines (Bivalent Subtype C gp120/MF59 or Bivalent Subtype C gp120/AS01B) in healthy, HIV-uninfected adults.

The purpose of this study is to evaluate the safety, tolerability, and immune response of the DNA-HIV-PT123 vaccine when used in combination with one of two protein vaccines: Bivalent Subtype C gp120/MF59 (Protein/MF59) or Bivalent Subtype C gp120/AS01B (Protein/AS01B). These protein vaccines may boost the immune response to the DNA vaccine. The study will enroll healthy, HIV-uninfected adults. Participants will be randomly assigned to one of eight groups, and each group will receive a different sequence of vaccines during the study. Groups 1 and 4 will receive the DNA-HIV-PT123 vaccine, the Protein/MF59 vaccine, and placebo. Groups 2, 3, 5, 6, and 7 will receive the DNA-HIV-PT123 vaccine, the Protein/AS01B vaccine, and placebo. Group 8 will only receive placebo. All participants will receive their assigned vaccines at Months 0, 1, 3, and 6. Each of these visits will include three injections. Follow-up visits will occur at Week 2 and Months 1.5, 3.5, 6.25, 6.5, 9, and 12. Study visits will include a physical examination, an interview and/or questionnaire, HIV testing and HIV risk reduction counseling, and urine and blood collection. Participants may optionally choose to provide stool, rectal fluid, cervical fluid, or semen samples. Participants will be contacted 6 months after the last scheduled visit by phone, text message, or e-mail for information about their health.

Participants will receive the DNA-HIV-PT123 vaccine in their left deltoid at Months 0, 1, 3, and 6. They will receive placebo in their right deltoid at Months 0 and 1, and placebo and the Protein/MF59 vaccine in their right deltoid at Months 3 and 6.

Participants will receive the DNA-HIV-PT123 vaccine in their left deltoid at Months 0, 1, 3, and 6. They will receive placebo in their right deltoid at Months 0 and 1, and placebo and the Protein/AS01B vaccine in their right deltoid at Months 3 and 6.

Participants will receive the DNA-HIV-PT123 vaccine in their left deltoid at Months 0, 1, 3, and 6. They will receive placebo in their right deltoid at Months 0 and 1, and placebo and the Protein/AS01B vaccine in their right deltoid at Months 3 and 6.

Participants will receive the DNA-HIV-PT123 vaccine in their left deltoid at Months 0, 1, and 6 and placebo in their left deltoid at Month 3. They will receive placebo and the Protein/MF59 vaccine in their right deltoid at Months 0, 1, and 6 and placebo in their right deltoid at Month 3.

Participants will receive the DNA-HIV-PT123 vaccine in their left deltoid at Months 0, 1, and 6 and placebo in their left deltoid at Month 3. They will receive placebo and the Protein/AS01B vaccine in their right deltoid at Months 0, 1, and 6 and placebo in their right deltoid at Month 3.

Participants will receive the DNA-HIV-PT123 vaccine in their left deltoid at Months 0, 1, and 6 and placebo in their left deltoid at Month 3. They will receive placebo and the Protein/AS01B vaccine in their right deltoid at Months 0, 1, and 6 and placebo in their right deltoid at Month 3.

Participants will receive placebo in their left deltoid at Months 0, 1, 3, and 6. They will receive placebo and the Protein/AS01B vaccine in their right deltoid at Months 0, 1, and 6 and placebo in their right deltoid at Month 3.

Contains a mixture of three DNA plasmids in a 1:1:1 ratio, each at 1.33 mg: 1) clade C 96ZM651 gag, 2) clade C 96ZM651 gp140, and 3) clade C CN54 pol-nef, delivered at a total dose of 4 mg, administered by intramuscular (IM) injection to the left deltoid as a single 1 mL dose.

Clade C TV1.C gp120 Env and clade C 1086.C gp120 Env, each at a dose of 100 mcg, mixed with MF59 adjuvant, administered by IM injection to the right deltoid as a single 0.5 mL dose.

Clade C TV1.C gp120 Env and clade C 1086.C gp120 Env, mixed with AS01B adjuvant, administered by IM injection to the right deltoid as a single 0.75 mL dose. Groups 2 and 5 will receive a 100 mcg dose. Groups 3, 6, and 7 will receive a 20 mcg dose.

Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 [March 2017]. The maximum grade observed for each symptom over the time frame is presented.

Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 [March 2017]. The maximum grade observed for each symptom over the time frame is presented.

Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 [March 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.

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 New Chronic Conditions (Requiring Medical Intervention for ≥ 30 Days)

There were no new chronic conditions (requiring medical intervention for ≥ 30 days) reported by any participant.

There were no early study terminations associated with an AE or reactogenicity reported by any participant.

From the study product discontinuation form, study product administration reasons are tabulated by treatment arm.

For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population.

For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population.

For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population.

For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population.

For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population.

The numbers (percentages) of participants with local laboratory values recorded as meeting Grade 1 AE criteria or above as specified in the DAIDS AE Grading Table were tabulated by treatment group for each post vaccination timepoint.

Occurrence and Level of HIV-specific Total IgG Binding Antibody Response Breadth and Magnitude - Positive Response Rates.

IgG binding antibody breadth assays were not run. Instead, IgG was assayed against a smaller panel of antigens. Serum IgG responses were measured on a Bio-Plex instrument using a 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 minus reference antigen MFI. Net MFI below 1 is set to 1, and Net MFI above 22,000 is set to 22,000. Samples from post-baseline visits have positive responses if they meet three criteria: (1) net MFI >= antigen-specific threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI), (2) net MFI > 3 times baseline net MFI, and (3) experimental antigen MFI > 3 times baseline 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 and Level of HIV-specific Total IgG Binding Antibody Response Breadth and Magnitude - Magnitudes.

IgG binding antibody breadth assays were not run. Instead, IgG was assayed against a smaller panel of antigens.Serum IgG responses were measured on a Bio-Plex instrument using a 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 minus reference antigen MFI. Net MFI below 1 is set to 1, and Net MFI above 22,000 is set to 22,000. Samples from post-baseline visits have positive responses if they meet three criteria: (1) net MFI >= antigen-specific threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI), (2) net MFI > 3 times baseline net MFI, and (3) experimental antigen MFI > 3 times baseline 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 and Level of Anti -V1/V2 Scaffold IgG Binding Antibody Responses - Positive Response Rates.

Serum IgG responses were measured on a Bio-Plex instrument using a 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 minus reference antigen MFI. Net MFI below 1 is set to 1, and Net MFI above 22,000 is set to 22,000. Samples from post-baseline visits have positive responses if they meet three criteria: (1) net MFI >= antigen-specific threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI), (2) net MFI > 3 times baseline net MFI, and (3) experimental antigen MFI > 3 times baseline 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.

Serum IgG responses were measured on a Bio-Plex instrument using a 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 minus reference antigen MFI. Net MFI below 1 is set to 1, and Net MFI above 22,000 is set to 22,000. Samples from post-baseline visits have positive responses if they meet three criteria: (1) net MFI >= antigen-specific threshold (defined as the maximum of 100 and the 95th percentile of baseline net MFI), (2) net MFI > 3 times baseline net MFI, and (3) experimental antigen MFI > 3 times baseline 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.

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. Any Env magnitude is the maximum of gp120 and Env ZM96 magnitude; Any Pol is the sum of CN54 magnitude; and Any HIV is the sum of Gag ZM96, Nef CN54, Any Pol, and Any Env. 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.

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. Any Env magnitude is the maximum of gp120 and Env ZM96 magnitude; Any Pol is the sum of CN54 magnitude; and Any HIV is the sum of Gag ZM96, Nef CN54, Any Pol, and Any Env. 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.

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. Any Env magnitude is the maximum of gp120 and Env ZM96 magnitude; Any Pol is the sum of CN54 magnitude; and Any HIV is the sum of Gag ZM96, Nef CN54, Any Pol, and Any Env. 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.

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. Any Env magnitude is the maximum of gp120 and Env ZM96 magnitude; Any Pol is the sum of CN54 magnitude; and Any HIV is the sum of Gag ZM96, Nef CN54, Any Pol, and Any Env. 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.

Inclusion Criteria: General and Demographic Criteria Age of 18 to 40 years Access to a participating 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; completes a questionnaire prior to first vaccination with verbal demonstration of understanding of all questionnaire items answered incorrectly Agrees not to enroll in another study of an investigational research agent before the last required protocol clinic visit Willing to be contacted by phone, text message, or e-mail 6 months after completion of the scheduled clinic visits 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. 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: ALT, 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 FDA-approved enzyme immunoassay (EIA). Non-US sites may use locally available assays that have been approved by HVTN Laboratory Operations. 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 (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: United States 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 through the last required protocol clinic visit. Effective contraception for participants in the United States is defined as using any 1 or more of the following methods: Condoms (male or female) with or without a spermicide, Diaphragm or cervical cap with spermicide, Intrauterine device (IUD), Hormonal contraception, 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 HVTN 108 protocol safety review team (PSRT) 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. Southern Africa 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 through the last required protocol clinic visit. Effective contraception for participants in Southern Africa 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: 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 HVTN 108 PSRT 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 Other Volunteers 21 years of age and older who were born female consenting to provide cervical samples: Pap smear within: the 3 years prior to enrollment with the latest result reported as normal or atypical squamous cells of undetermined significance (ASCUS), or the 5 years prior to enrollment, with the latest result reported as normal, or ASCUS with no evidence of high risk human papillomavirus (HPV). If no pap smear was done within the last 3 years (or within the last 5 years, if high risk HPV testing was performed), the volunteer must be willing to undergo a pap smear with the result reported as normal or ASCUS prior to sample collection. 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: 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 108 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 108 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 HVTN 108 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 108 PSRT 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) Allergy treatment with antigen injections within 30 days before first vaccination or that are scheduled 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 oral/parenteral corticosteroids at doses less than 2 mg/kg/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 US 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.

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