Clinical trial NCT02404311: A Safety and Immune Response Study of 2 Experimental HIV Vaccines
Official title: A Phase 1-2 Randomized, Double-blind, Placebo-controlled Clinical Trial of Clade C ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected Adults at Low Risk of HIV Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infection
Keywords: HIV
AIDS
Vaccine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: HIV Vaccine Trials Network
name: Bill and Melinda Gates Foundation
name: Medical Research Council
name: Sanofi Pasteur, a Sanofi Company
name: GlaxoSmithKline
First posted: 2015-03-31
Enrollment: 252
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The HIV Vaccine Trials Network (HVTN) is doing a study to test a new HIV vaccine combination. HIV is the virus that causes AIDS.

252 people are taking part in this study at multiple sites. The US National Institutes of Health (NIH) is paying for the study.

The investigators are doing this study to answer several questions.

* Are the study vaccines safe to give to people?
* Are people able to take the study vaccines without becoming too uncomfortable?
* How do people's immune systems respond to the study vaccines? (Your immune system protects you from disease.)

Detailed description: The HIV Vaccine Trials Network (HVTN) is doing a study to test a new HIV vaccine combination. HIV is the virus that causes AIDS. The investigators are doing this study to answer several questions:

* Are the study vaccines safe to give to people?
* Are people able to take the study vaccines without becoming too uncomfortable?
* How do people's immune systems respond to the study vaccines? (Your immune system protects you from disease.)

The study uses 2 different vaccines: ALVAC-HIV (vCP2438) and bivalent gp120/MF59. These are experimental HIV vaccines -- the investigators do not know whether the vaccines will be safe to use in people, or whether they will work to prevent HIV infection. These vaccines are used only in research studies.

The ALVAC vaccine is made out of canarypox virus, which infects birds but cannot grow in human cells. This virus has small bits of man-made DNA inserted into it. DNA is a natural substance found in all living things, including people and some viruses. The canarypox virus helps get the DNA into the body's cells. The DNA then tells those cells to make small amounts of proteins that look like some of the ones found in HIV.

A study in South Africa, HVTN 097, gave a similar ALVAC vaccine to about 80 participants. So far, no one has had serious health problems.

The Protein vaccine has man-made pieces of a protein found on the outside of HIV. These protein pieces are mixed with an adjuvant called MF59. An adjuvant is something added to the vaccine to help the immune system respond better. MF59 has been included with other vaccines that have been given to over 50,000 people in clinical trials without causing any serious health problems.

This combination of study vaccines has not been given to people before. However, similar ALVAC and protein vaccines have been given to more than 10,000 people in clinical trials without causing any serious health problems. Also, over 300 people have received a similar combination of ALVAC and protein vaccines with the MF59 adjuvant in clinical trials without having any serious health problems.

The study is in 2 parts, Part A and Part B. Part B continues the study in order to learn how well boosting the study vaccines improves immune responses. 252 people took part in Part A of this study at multiple sites. Those who continue to meet eligibility requirements are invited to continue in Part B.

The US National Institutes of Health (NIH) is paying for the study. For people who continue to Part B, the study requires about 23 clinic visits in 4 years.

Eligibility criteria: Inclusion Criteria:

* Age of 18 to 40 years
* 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; 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
* 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 amenable to HIV risk reduction counseling
* Assessed by the clinic staff as being at "low risk" for HIV infection (per Low Risk Guidelines for South African sites) and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit
* Hemoglobin ≥ 11.0 g/dL for volunteers who were born female, ≥ 13.0 g/dL for volunteers who were born male
* WBC = 3,300 to 12,000 cells/mm3
* Total lymphocyte count ≥ 800 cells/mm3
* Remaining differential either within institutional normal range or with site physician approval
* Platelets = 125,000 to 550,000/mm3
* Chemistry panel: ALT, AST, and ALP \< 1.25 times the institutional upper limit of normal; creatinine ≤ institutional upper limit of normal.
* Negative HIV-1 and -2 blood test: 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
* 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).
* Volunteers who were born female: negative urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of initial vaccination or negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test within 24 hours prior to initial vaccination. Persons who are NOT of reproductive potential due to having undergone total hysterectomy with 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 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 South Africa is defined as using 2 methods, including the following:
  * Condoms (male or female), or
  * Diaphragm or cervical cap,

PLUS 1 of the following methods:

* Intrauterine device (IUD),
* Hormonal contraception (in accordance with Republic of South Africa: National Contraception Clinical Guidelines),
* 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 100 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

Exclusion Criteria:

* Blood products received within 120 days before first vaccination
* Investigational research agents received within 30 days before first vaccination
* Body mass index (BMI) ≥ 40; or BMI ≥ 35 with 2 or more of the following: systolic blood pressure \> 140 mm Hg, diastolic blood pressure \> 90 mm Hg, current smoker, known hyperlipidemia
* Intent to participate in another study of an investigational research agent or any study that includes HIV testing during the planned duration of the HVTN 100 study
* Pregnant, breastfeeding, or lactating
* HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 100 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 by the South Africa Medicines Control Council (MCC). For volunteers who have received control/placebo in an experimental vaccine trial, the HVTN 100 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 100 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
* Immunosuppressive medications received within 168 days before first vaccination. (Not excluded from participation: \[1\] 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 nonanaphylactic adverse reaction to pertussis vaccine as a child.)
* Immunoglobulin received within 60 days before first vaccination
* Autoimmune disease
* Immunodeficiency
* 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 or moderate, well-controlled asthma. (Symptoms of asthma severity as defined in the most recent 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 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 ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these volunteers, blood pressure must be ≤ 140 mm Hg systolic and ≤ 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 ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment.
* Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions)
* Malignancy (Not excluded: 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 three 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.

Primary outcomes:
measure: Part A: Number of Participants Reporting Local Reactogenicity Signs and Symptoms During the Primary Vaccine Regimen
timeFrame: Measured through 3 days after participants' last vaccination at Month 0,1,3, and 6
measure: Part A: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms During the Primary Vaccine Regimen
timeFrame: Measured through 3 days after each vaccination at Month 0, 1, 3, and 6
measure: Part A: Number of Participants With Early Study Termination Associated With an AE or Reactogenicity
timeFrame: Measured through Month 18
measure: Part A: Number of Participants With Study Product Discontinuation Associated With an AE or Reactogenicity
timeFrame: Measured through the Month 12 vaccination
measure: Part A: Chemistry and Hematology Laboratory Results With Grade 1 or Higher
timeFrame: Measured during screening for part A, and 2 weeks after each vaccination at Month 0, 1, 3, 6, and 12
measure: Part A Chemistry Laboratory Measures: Alkaline Phosphatase, AST, and ALT
timeFrame: Time Frame: Measured during screening for part A, and 2 weeks after each vaccination at Month 0, 1, 3, 6, and 12
measure: Part A Chemistry Laboratory Measures: Hemoglobin, Creatinine
timeFrame: Time Frame: Measured during screening for part A, and 2 weeks after each vaccination at Month 0, 1, 3, 6, and 12
measure: Part A Hematology Laboratory Measures: WBC, Platelets, Lymphocytes, Neutrophils
timeFrame: Measured during screening for part A, and 2 weeks after each vaccination at Month 0, 1, 3, 6, and 12
measure: Part A: Occurrence of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) After the Primary Vaccine Regimen, Measured by HIV-1 Multiplex Antibody Assay
timeFrame: Measured at Month 6.5
measure: Part A: Level of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) After the Primary Vaccine Regimen, Measured by HIV-1 Multiplex Antibody Assay
timeFrame: Measured at Month 6.5
measure: Part A: Occurrence of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins After the Primary Vaccine Regimen
timeFrame: Measured at Month 6.5
measure: Part A: Level of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins After the Primary Vaccine Regimen
timeFrame: Measured at Month 6.5
measure: Part A: Occurrence of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine After the Primary Vaccine Regimen. Measured by Flow Cytometry.
timeFrame: Measured at Month 6.5
measure: Part A: Level of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine After the Primary Vaccine Regimen.
timeFrame: Measured at Month 6.5
measure: Part B: Number of Participants Reporting Local Reactogenicity Signs and Symptoms in the Extension Study
timeFrame: Measured through 3 days after the Month 30 vaccination
measure: Part B: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms in the Extension Study
timeFrame: Measured through 3 days after the Month 30 vaccination
measure: Part B: Number of Participants With Early Study Termination Associated With an AE or Reactogenicity
timeFrame: Measured through Month 36
measure: Part B: Chemistry and Hematology Laboratory Results of Grade 1 or Higher
timeFrame: Time Frame: Measured during screening for part B, and 2 weeks after vaccination at Month 30
measure: Part B Chemistry Laboratory Measures: Alkaline Phosphatase, AST, and ALT
timeFrame: Measured during screening for part B, and 2 weeks after vaccination at Month 30
measure: Part B Chemistry Laboratory Measures: Hemoglobin, Creatinine
timeFrame: Measured during screening for part B, and 2 weeks after vaccination at Month 30
measure: Part B Chemistry Laboratory Measures: WBC, Platelets, Lymphocytes, Neutrophils
timeFrame: Measured during screening for part B, and 2 weeks after vaccination at Month 30
measure: Part B: Occurrence of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins in the Extension Study
timeFrame: Measured at Month 30.5
measure: Part B: Level of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins in the Extension Study
timeFrame: Measured at Month 30.5
measure: Part B: Occurrence of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) in the Extension Study
timeFrame: Measured at Month 30.5
measure: Part B: Level of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) in the Extension Study
timeFrame: Measured at Month 30.5
measure: Part B: Occurrence of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine in the Extension Study
timeFrame: Measured at Month 30.5
measure: Part B: Level of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine in the Extension Study
timeFrame: Measured at Month 30.5
Secondary outcomes:
measure: Part A: Frequency of Severe Local Reactogenicity Signs and Symptoms, Through the Fifth Vaccination
timeFrame: Measured through 3 days after each vaccination at Month 0, 1, 3, 6, and 12
measure: Part A: Frequency of Severe Systemic Reactogenicity Signs and Symptoms, Through the Fifth Vaccination
timeFrame: Measured through 3 days after each vaccination at Month 0, 1, 3, 6, and 12
measure: Part A: Compare the Occurrence of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) After the Fourth Versus the Fifth Vaccination
timeFrame: Measured at Month 6.5 and 12.5
measure: Part A: Compare the Level of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) After the Fourth Versus the Fifth Vaccination
timeFrame: Measured at Month 6.5 and 12.5
measure: Part A: Compare the Occurrence of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins After the Fourth Versus the Fifth Vaccination
timeFrame: Measured at Month 6.5 and 12.5
measure: Part A: Compare the Level of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins After the Fourth Versus the Fifth Vaccination
timeFrame: Measured at Month 6.5 and 12.5
measure: Part A: Compare the Occurrence of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine After the Fourth Versus the Fifth Vaccinations
timeFrame: Measured at Month 6.5 and 12.5
measure: Part A: Compare the Level of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine After the Fourth Versus the Fifth Vaccinations
timeFrame: Measured at Month 6.5 and 12.5
measure: Part B: Occurrence of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) in the Extension Study, at 6 Months After the Month 30 Vaccination
timeFrame: Measured at Month 30 and 36
measure: Part B: Level of IgG Ab Binding to gp120 Env Proteins Contained in the Vaccine (ZM96, TV1.C, 1086.C) in the Extension Study, at 6 Months After the Month 30 Vaccination
timeFrame: Measured at Month 30 and 36
measure: Part B: Occurrence of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins in the Extension Study, at 6 Months After the Month 30 Vaccination
timeFrame: Measured at Month 30 and 36
measure: Part B: Level of IgG Binding Antibodies to 3 V1V2-scaffolded Env Proteins in the Extension Study, at 6 Months After the Month 30 Vaccination
timeFrame: Measured at Month 30 and 36
measure: Part B: Occurrence of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine in the Extension Study, at 6 Months After the Month 30 Vaccination
timeFrame: Measured at Month 30 and 36
measure: Part B: Level of CD4+ T Cell Responses to the HIV Proteins Included in the Vaccine in the Extension Study, at 6 Months After the Month 30 Vaccination
timeFrame: Measured at Month 30 and 36
Other outcomes:
Locations:
city: Durban
country: South Africa
facility: CAPRISA eThekwini CRS
state: KwaZulu-Natal
city: Durban
country: South Africa
facility: Isipingo CRS
state: KwaZulu-Natal
city: Cape Town
country: South Africa
facility: Emavundleni Desmond Tutu HIV Centre CRS
state: Western Cape
city: Klerksdorp
country: South Africa
facility: Aurum Institute for Health Research
city: Soweto
country: South Africa
facility: Perinatal HIV Research Unit
Study officials:
affiliation: HIV Vaccine Trials Network
name: Linda-Gail Bekker, MBChB, DTMH, DCH, FCP(SA), PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: Laher F, Moodie Z, Cohen KW, Grunenberg N, Bekker LG, Allen M, Frahm N, Yates NL, Morris L, Malahleha M, Mngadi K, Daniels B, Innes C, Saunders K, Grant S, Yu C, Gilbert PB, Phogat S, DiazGranados CA, Koutsoukos M, Van Der Meeren O, Bentley C, Mkhize NN, Pensiero MN, Mehra VL, Kublin JG, Corey L, Montefiori DC, Gray GE, McElrath MJ, Tomaras GD. Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines. PLoS Med. 2020 Feb 24;17(2):e1003038. doi: 10.1371/journal.pmed.1003038. eCollection 2020 Feb.
citation: Zhao LP, Fiore-Gartland A, Carpp LN, Cohen KW, Rouphael N, Fleurs L, Dintwe O, Zhao M, Moodie Z, Fong Y, Garrett N, Huang Y, Innes C, Janes HE, Lazarus E, Michael NL, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Robb ML, De Rosa SC, Corey L, Gray GE, Seaton KE, Yates NL, McElrath MJ, Frahm N, Tomaras GD, Gilbert PB. Landscapes of binding antibody and T-cell responses to pox-protein HIV vaccines in Thais and South Africans. PLoS One. 2020 Jan 30;15(1):e0226803. doi: 10.1371/journal.pone.0226803. eCollection 2020.
citation: Bekker LG, Moodie Z, Grunenberg N, Laher F, Tomaras GD, Cohen KW, Allen M, Malahleha M, Mngadi K, Daniels B, Innes C, Bentley C, Frahm N, Morris DE, Morris L, Mkhize NN, Montefiori DC, Sarzotti-Kelsoe M, Grant S, Yu C, Mehra VL, Pensiero MN, Phogat S, DiazGranados CA, Barnett SW, Kanesa-Thasan N, Koutsoukos M, Michael NL, Robb ML, Kublin JG, Gilbert PB, Corey L, Gray GE, McElrath MJ; HVTN 100 Protocol Team. Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial. Lancet HIV. 2018 Jul;5(7):e366-e378. doi: 10.1016/S2352-3018(18)30071-7. Epub 2018 Jun 18.