A Study to Assess the Safety and Immune Response to Env-C DNA and Protein Vaccines in Kenya

Study Overview
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Brief Summary
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This is a study of HIV vaccines. A vaccine is a medical product given to prevent certain diseases. The vaccine may educate the body to form a defensive response to try to prevent the disease from the beginning, or preventing it from taking hold of the body. This defensive response is called the immune response. The experimental vaccines in this study are Env-C Plasmid DNA and HIV Env gp145 C690 protein, given with different adjuvants. An adjuvant is a substance added to vaccines that can help make the vaccine more effective by improving the immune response, or by causing the immune response to last longer than it would without the adjuvant. The adjuvants are mixed with the vaccines and injected into muscle or placed on top of the skin. The HIV vaccines contain a piece of genetic material or a protein copied drom the HIV virus cover (Env), but they do not contain the virus itself. The vaccines cannot cause HIV infection or Acquired Immune Deficiency Syndrome (AIDS). The purpose of this study is to find out if the study vaccines with adjuvants cause side effects and are tolerable, whether humans respond (develop immune responses) to the vaccines, and how ling the effects of the study vaccines last. The study will also compare the effects of the study vaccines with adjuvants and adjuvant patch to those of placebo injections and placebo patch. The placebo will consist of saline (sterile saltwater) and will look like study vaccines, be given in the same way, but will have no active vaccine or adjuvant in it. A total of 126 participants will take part in the study and each will have up to 26 clinic visits and will be followed-up for a total of 108 weeks.

Detailed Description
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Antibodies are the most commonly recognized correlate of vaccine protection from infection; however the possible protective HIV antibody levels, which were induced by the modestly protective RV144 vaccine regimen with alum, rapidly decayed. Potentially, a novel, highly selective adjuvant combined with the correctly sequenced HIV antigen could slow antibody decay, increase antibody magnitude and induce antibodies of appropriate functional response. RV460 is an exploratory study that will assess the safety, tolerability, and immunogenicity of a vaccine regimen consisting of priming with an Env-C Plasmid DNA vaccine (with or without novel adjuvants) when given with or without adjuvanted HIV Env gp145 C.6980 protein vaccine and boosting with adjuvanted gp145 C.6980 protein with or without the gp120 DNA vaccine. The study will be carried out in Kericho, Kenya. 126 healthy adults will ben enrolled. Participants will be randomized into one of seven groups which have 15/3 vaccine/placebo recipients per group. Each participant will receive six injections (prim at week 0, 4, 12; boost at week 20, 32 and 56) and will be followed-up for a total of 108 weeks.

Official Title
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A Randomized, Double-Blind Phase 1 Trial to Evaluate the Safety and Immunogenicity of Priming With Env-C Plasmid DNA Vaccine Alone, With Different Adjuvants, or With an Adjuvanted HIV Env gp145 C.6980 Protein Vaccine and Boosting With the Adjuvanted HIV Env gp145 C.6980 Protein Vaccine With or Without the Env-C Plasmid DNA Vaccine in Healthy HIV Uninfected Adults in Kenya

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: Env-C Plasmid DNA
* Biological: HIV Env gp145 C.6980 protein
* Drug: Rehydragel®
* Biological: ALF43
* Biological: dmLT
* Drug: Placebo (IM)
* Drug: Placebo (TCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, male and female participant aged 18 to 40 years and available for 26 months. Must be at low risk for HIV infection per investigator assessment and using the study risk assessment tool. Must be able to understand and complete the informed consent process. Must be capable of reading English or Kiswahili. Must agree to a home visit. Must complete a Test of Understanding (TOU) before enrollment. Must answer 9 out of 10 questions correctly with a maximum of three attempts. Must be in good general health without a clinically significant medical history. HIV-uninfected per diagnostic algorithm within 45 days of enrollment. Laboratory values: Hemoglobin 12.5-18.1 g/dL men 11.0-16.1 g/dL women White Cell Count 2.7-7.7 x 10³ cells/µL men 3.0-9.1 x 10³ cells/µL women Platelets: 125-370 10³ cells/µL men 125-444 10³ cells/µL women ALT and AST: ≤1.25 institutional upper limit of the reference range Creatinine: ≤1.25 institutional upper limit of the reference range Urinalysis: (dipstick) for blood and protein less than 1+ and negative glucose Female-Specific Criteria Negative urine pregnancy test for women at screening, the day of each vaccination, and before any invasive procedure. Already using and commits to continued use of an adequate birth control method for 45 days before to the first vaccination/placebo vaccination, and for at least 90 days after the final vaccine/placebo vaccination. Adequate birth control is defined as follows: Contraceptive medications delivered orally, intramuscularly, vaginally, or implanted, underneath the skin, surgical methods (hysterectomy or bilateral tubal ligation), condoms with spermicide, diaphragms, intrauterine device (IUD), vasectomy in a monogamous partner, or abstinence. Lymph Node Biopsy Inclusion Criteria Body mass index (BMI) <35 Platelets >150,000 International normalized ration (INR) <1.2 Verbal report of no NSAIDS/aspirin for 7 days prior. Negative pregnancy test for participants born female. Exclusion Criteria: A history of: Three or more sexual partners in the previous 24 weeks. Commercial sex work. Non-adherence to condom use in the absence of a long-term monogamous relationship. Intravenous drug use in the previous year. A sexually transmitted infection in the previous 24 weeks. Asplenia: any condition resulting in the absence of a functional spleen. Bleeding disorder diagnosed by a medical doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions). Breastfeeding or pregnant (positive pregnancy test) women or planning to become pregnant during the window between study enrollment and three months after the last vaccination visit. Any past, ongoing, or in remission history of treated or untreated autoimmune disease. Has known active Hepatitis B virus infection (or positive HBsAg). Has known active Hepatitis C infection. History of anaphylaxis or other serious adverse reaction to vaccines or allergies or reactions likely to be exacerbated by any component of the vaccine and placebo, including antibiotics or excipients. Absolute Neutrophil Count (ANC) <1.0 x 10³ cells/µL. Participant has received any of the following substances: Chronic use of therapies that may modify immune response, such as intravenous (IV) immune globulin and systemic corticosteroids (in doses of >20 mg/day prednisone equivalent for periods exceeding 10 days). The following exceptions are permitted and will not exclude study participation: Use of corticosteroid nasal spray for rhinitis; Topical corticosteroids for an acute uncomplicated dermatitis; or A short course (10 days or less, or a single injection) of corticosteroid for a non-chronic condition (based on investigator clinical judgment) at least 2 weeks before enrollment. Blood products within 120 days before HIV screening. Immunoglobulins within 30 days before HIV screening. Any experimental vaccine containing an adjuvant other than aluminum of an adjuvant not approved by the FDA or European Medicines Agency (EMA) as part of a licensed vaccine. CERVARIX vaccine against HPV (containing AS04) Receipt of any investigational HIV vaccine, investigational research agents or vaccine within 30 days before enrollment. Anti-tuberculosis prophylaxis or therapy during the past 90 days before enrollment. Any psychiatric, social condition, occupational reason, or other responsibility that, in the judgment of the investigator, is a contraindication to protocol compliance or impairs a participant's ability to give informed consent. Major psychiatric illness and or substance abuse problems during the past 12 months that, in the opinion of the investigator, would preclude participation. History of atopy or significant skin conditions. Study site employees who are involved in the protocol and or may have direct access to the study-related area. Lymph Node Biopsy Exclusion Criteria History of keloid formation. History of an inguinal hernia, inguinal canal cryptorchidism, varicocele, hydrocele. History of inguinal excisional lymph node biopsy. Final evaluation of eligibility is based on the medical judgment of the investigator. The Protocol Safety Review Team will also remain available to the investigator for consultation if desired.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>|
| Experimental: Group 2: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Biological: ALF43<br>* Adjuvant. Army Liposome Formulation-43% Cholesterol. 200 µg per dose. Administered by intramuscular injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>|
| Experimental: Group 3: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Biological: dmLT<br>* Adjuvant. Recombinant double mutant Escherichia coli heat labile toxin. 50 µg per dose. Transcutaneous application (needle-free skin patch). 1 mL diluted dmLT added to gauze pad at site of injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>Drug: Placebo (TCl)<br>* Transcutaneous application (needle-free skin patch). 0.9% sodium chloride (sterile saline) added to gauze pad at site of injection.<br>|
| Experimental: Group 4: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Biological: ALF43<br>* Adjuvant. Army Liposome Formulation-43% Cholesterol. 200 µg per dose. Administered by intramuscular injection.<br>Biological: dmLT<br>* Adjuvant. Recombinant double mutant Escherichia coli heat labile toxin. 50 µg per dose. Transcutaneous application (needle-free skin patch). 1 mL diluted dmLT added to gauze pad at site of injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>Drug: Placebo (TCl)<br>* Transcutaneous application (needle-free skin patch). 0.9% sodium chloride (sterile saline) added to gauze pad at site of injection.<br>|
| Experimental: Group 5: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Biological: ALF43<br>* Adjuvant. Army Liposome Formulation-43% Cholesterol. 200 µg per dose. Administered by intramuscular injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>|
| Experimental: Group 6: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Biological: ALF43<br>* Adjuvant. Army Liposome Formulation-43% Cholesterol. 200 µg per dose. Administered by intramuscular injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>|
| Experimental: Group 7: Vaccine or Placebo<br>3 doses of prime vaccination or placebo at weeks 0, 4, 12 followed by 3 doses of boost vaccination or placebo at weeks 20, 32, 56 | Biological: Env-C Plasmid DNA<br>* 2 mg per dose. Administered by intramuscular injection.<br>Biological: HIV Env gp145 C.6980 protein<br>* 100 µg per dose. Administered by intramuscular injection.<br>Drug: Rehydragel®<br>* Adjuvant. Aluminum hydroxide fluid gel. 500 µg per dose. Administered by intramuscular injection.<br>Biological: ALF43<br>* Adjuvant. Army Liposome Formulation-43% Cholesterol. 200 µg per dose. Administered by intramuscular injection.<br>Drug: Placebo (IM)<br>* 0.9% sodium chloride (sterile saline). Administered by intramuscular injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of solicited adverse events (AEs), related AEs and serious AEs (SAEs) |  | Thru Week 105 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Magnitude of plasma IgG binding antibodies in response to differing DNA priming regimens | Measured by binding antibody assays. | Thru Week 105 | 
| Durability of plasma IgG binding antibodies in response to differing DNA priming regimens | Measured by binding antibody assays. | Thru Week 105 | 
| Area under the curve (AUC) for plasma IgG binding antibodies in response to differing DNA priming regimens | Measured by binding antibody assays. | Thru Week 105 | 
| Magnitude of plasma IgG binding antibodies between groups with and without Rehydragel® after HIV Env gp145 C.6980 protein boosting | Measured by binding antibody assays. | Thru Week 105 | 
| Durability of plasma IgG binding antibodies between groups with and without Rehydragel® after HIV Env gp145 C.6980 protein boosting | Measured by binding antibody assays. | Thru Week 105 | 
| AUC for plasma IgG binding antibodies between groups with and without Rehydragel® after HIV Env gp145 C.6980 protein boosting | Measured by binding antibody assays. | Thru Week 105 | 
| Presence of plasma IgG binding antibodies | Functional antibodies assessed using rapid fluorometric Antibody-dependent Cell-Mediated Cytotoxicity (ADCC) Assay, Antibody-dependent Cell-mediated Phagocytosis (ADCP), Antibody-dependent Complement (ADC) activation assays, or other functional assays. Neutralizing antibodies assessed using cell line-based and PBMC assays with a panel of viruses from different HIV subtypes, including A, B, C, D, and other circulating recombinant forms (CRFs) such as AE and AG. | Thru Week 105 | 
| Presence of plasma IgA binding antibodies | Functional antibodies assessed using rapid fluorometric Antibody-dependent Cell-Mediated Cytotoxicity (ADCC) Assay, Antibody-dependent Cell-mediated Phagocytosis (ADCP), Antibody-dependent Complement (ADC) activation assays, or other functional assays. Neutralizing antibodies assessed using cell line-based and PBMC assays with a panel of viruses from different HIV subtypes, including A, B, C, D, and other circulating recombinant forms (CRFs) such as AE and AG. | Thru Week 105 | 
| Types of cell-mediated immune responses | Cryopreserved PBMC and lymph nodes will be stimulated with HIV-1-specific antigens and tested using standard (but not limited to) cellular immune assays which may include but are not limited to Intracellular cytokine Staining, ELISPOT, Lymphoproliferation assays, B-cell analysis, T-follicular helper cell and innate immune cell analysis. | Thru Week 105 | 
| Level of cell-mediated immune responses | Cryopreserved PBMC and lymph nodes will be stimulated with HIV-1-specific antigens and tested using standard (but not limited to) cellular immune assays which may include but are not limited to Intracellular cytokine Staining, ELISPOT, Lymphoproliferation assays, B-cell analysis, T-follicular helper cell and innate immune cell analysis. | Thru Week 105 | 
| Types of mucosal humoral responses | Including, but not limited to, plasma IgG and IgA binding antibodies to HIV Env proteins, IgG and IgA subclass, and functional assays. | Thru Week 104 |