Safety and Immunogenicity Study of tgAAC09, an HIV Vaccine in an Adeno-associated Virus (AAV) Capsid

Study Overview
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Brief Summary
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This phase 2 study will evaluate the safety, immunogenicity and optimal timing of two injections at three dose levels of the tgAAC09 vaccine in healthy volunteers. Study volunteers will receive two intramuscular injections of tgAAC09 or placebo at Months 0 and 6 (groups A, C, E and G) or at Months 0 and 12 (groups B, D and F) and be followed for a total of 18 months following the first injection with the exception of group G in which volunteers will be followed for 12 months after the first injection (6 months after the second injection). This study will explore whether boosting is possible, and compare a shorter and more practical six-month time interval with a twelve-month time interval.

Detailed Description
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The study design will also assess the effect of the presence of anti-AAV2 capsid neutralizing antibodies at the time of vaccination on the safety and immunogenicity of tgAAC09. Since the prevalence of pre-existing neutralizing antibodies to AAV2 capsid is high (IAVI and Targeted Genetics, data on file), this protocol amendment adds Group G which is composed of volunteers who have documented pre-existing anti-AAV2 capsid neutralizing antibodies titers ≤ 1/8. This will assure that there are sufficient numbers of volunteers with and without antibodies for a useful comparison.

Official Title
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Phase II, Placebo-controlled, Double-blind, Dose-escalation/Dose-optimization Trial to Evaluate Safety and Immunogenicity of tgAAC09, an HIV Vaccine Containing Clade C Gag-PR-ΔRT DNA in an Adeno-associated Virus (AAV) Capsid

Conditions
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Human Immunodeficiency Virus Infections, HIV Infections

Intervention / Treatment
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* Biological: tgAAC09
* Biological: tgAAC09
* Biological: tgAAC09
* Other: Formulation buffer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female Age at least 18 years on the day of screening and no greater than 50 years on the day of the first study injection Willing to comply with the requirements of the protocol and available for follow up for the planned duration of the study Able and willing to give informed consent. Willing to undergo HIV testing, counseling and receive results If sexually active female of child-bearing potential (not menopausal or anatomically sterile), willing to use an effective method of contraception (hormonal contraceptives; intrauterine contraceptive device (IUCD); condoms; anatomical sterility in self or partner) from screening until at least four months after last study injection and willing to undergo urine pregnancy tests at screening, prior to each injection and four months after the last injection If sexually active male, willing to use a method of contraception (such as condoms) from screening until four months after the last study injection Exclusion Criteria: HIV-1 or HIV-2 infection Active tuberculosis Clinically relevant abnormality on history or examination including history of immunodeficiency, or cancer, or autoimmune disorder Use of systemic corticosteroids, immunosuppressive or anticancer medications in the last six months Chronic condition that, in the opinion of the investigator or the designated trial physician, would make the volunteer unsuitable for the study Any of the following abnormal laboratory parameters: Hemoglobin <9.0 g/dL (females), <12.0 g/dL (males) Absolute Neutrophil Count (ANC): ≤ 999/mm3 Absolute Lymphocyte Count (ALC): ≤ 500/mm3 Platelets: decreased ≤ 90,000 or increased ≥ 550,000/mm3 Creatinine: > 1.4 x ULN AST: >3.0 x ULN ALT: >3.0 x ULN Urine dipstick: blood = 2+ or more (except in menstruating females); protein = 2+ or more Any of the following high-risk behaviors: Had unprotected vaginal or anal sex with a known HIV positive person in the past six months Had unprotected vaginal or anal sex with a casual partner (i.e. no continuing established relationship) in the past six months Engaged in sex work for money or drugs in the past six months Used injection drugs illegally in the past six months Acquired a sexually transmitted infection (STI) in the past six months If female, pregnant, lactating or planning a pregnancy within four months after last study injection Receipt of live attenuated vaccine within 30 days or other vaccine within 14 days of the first study injection Receipt of blood transfusion or blood products six months prior to the first study injection Participation in another clinical trial of an investigational product currently or within last 12 weeks of first study injection or expected participation during this study Prior receipt of an investigational HIV vaccine History of severe local or systemic reaction to vaccination(s) or history of severe allergic reactions History of major neurological or psychiatric disorders Positive for hepatitis B surface antigen, active untreated syphilis (confirmed by treponemal test such as TPHA in addition to nontreponemal test such as RPR) or other active sexually transmitted diseases

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Number of Vaccine Recipients: 10 Dosage level 3 x 10^10 DRP Month 0 + 6 | Biological: tgAAC09<br> <br> |
| Experimental: Group B<br>Number of Vaccine Recipients: 10 Dosage level 3 x 10^10 DRP Month 0+12 | Biological: tgAAC09<br> <br> |
| Experimental: Group C<br>Number of Vaccine Recipients: 10 Dosage level 3 x 10^11 DRP Month 0+6 | Biological: tgAAC09<br> <br> |
| Experimental: Group D<br>Number of Vaccine Recipients: 10 Dosage level 3 x 10^11 DRP Month 0+12 | Biological: tgAAC09<br> <br> |
| Experimental: Group E<br>Number of Vaccine Recipients: 10 Dosage level 3 x 10^12 DRP Month 0+6 | Biological: tgAAC09<br> <br> |
| Experimental: Group F<br>Number of Vaccine Recipients: 10 Dosage level 3 x 10^12 DRP Month 0+12 | Biological: tgAAC09<br> <br> |
| Experimental: Group G<br>Number of Vaccine Recipients: 10 Preselected for baseline AAV neutralization titers of <1/8 Dosage level 3 x 10^12 DRP Month 0+6 | Biological: tgAAC09<br> <br> |
| Placebo Comparator: Placebo<br>3 volunteers will receive placebo matched to each experimental group. | Other: Formulation buffer<br>* Sterile isotonic buffered salt solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: proportion of volunteers with severe local and systemic reactions, proportion of volunteers with other SAEs (including laboratory abnormalities) related to study vaccine, number of volunteers with SAEs related to study vaccine |  | 18 months | 
| Proportion of volunteers with HIV-1 specific T- cell responses quantified by γ-IFN ELISPOT and magnitude of the response, and proportion of volunteers with HIV-1 specific binding antibodies and magnitude of the response |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: high versus low or negative titres of neutralizing antibodies to AAV2 at the time of each vaccination |  | 18 months | 
| Immunogenicity: proportion of volunteers with HIV-1 specific T- cell responses by γ-IFN CFC or other T-cell assays |  | 18 months | 
| Immunogenicity endpoints in volunteers with high versus low or negative titres of neutralizing antibodies to AAV2 at the time of each vaccination |  | 18 months | 
| Immunogenicity endpoints in volunteers with versus without four-fold or greater increase in titres of neutralizing antibodies to AAV2 after vaccination |  | 18 months | 
| Immunogenicity endpoints after the second study injection, compared with the first study injection |  | 18 months | 
| Immunogenicity endpoints after the second study injection following a twelve-month interval compared to a six-month interval |  | 18 months | 
| Vaccine biodistribution: presence and persistence of vaccine in peripheral blood mononuclear cells (PBMC), saliva, nasal swabs, urine and semen or cervical/vaginal secretions |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HIV seronegativity, preventative vaccine