Safety of and Immune Response to an HIV-1 Subtype C Vaccine (AVX101) in HIV Uninfected Adults

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety of and immune response to an alphavirus replicon, HIV-1 subtype C gag vaccine, AVX101, in HIV uninfected adults in the United States, South Africa, and Botswana.

Detailed Description
-----------------
HIV-1 subtype C is the prevailing subtype of HIV found in sub-Saharan Africa and is primarily responsible for the HIV/AIDS epidemic in southern Africa. Thus, development of a preventive subtype C vaccine is critically important in controlling the spread of HIV in this part of the world. This study will determine the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine, AVX101, in HIV uninfected adults. This vaccine utilizes a propagation-defective replicon vector system derived from an attenuated strain of Venezuelan Equine Encephalitis (VEE) virus. The vaccine replicon expresses the gag gene from a South African subtype C isolate of HIV-1. Participants will be recruited in the United States, South Africa, and Botswana. The study will last for 1 year. Participants will be enrolled sequentially, from lowest to highest dose of vaccine, into one of four groups. Groups will begin enrollment only following safety review of the previous group. Participants will be randomly assigned to receive active vaccine or placebo. During the study, participants will receive either 3 injections of one of four possible doses of the vaccine or 3 injections of placebo. Injections will be given at study entry and at Days 28 and 84. At screening, participants will undergo medical history assessment, a complete physical, HIV testing and counseling, and blood and urine collection; they will also be interviewed and asked to complete a questionnaire. After screening, there will be 8 study visits; the visits will occur at Days 14, 28, 42, 84, 98, 168, 273, and 364. Participants will be interviewed and asked to fill out a questionnaire at each study visit; participants will undergo a physical, additional HIV testing and counseling, and blood and urine collection at selected visits.

Official Title
-----------------
A Phase I, Dose Escalation, Safety, and Immunogenicity Trial of an Alphavirus Replicon HIV-1 Subtype C Gag Vaccine (AVX101) in Healthy HIV-1 Uninfected Adult Participants

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Biological: AVX101
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV uninfected At low risk for HIV infection Willing to receive HIV test results Good general health Acceptable methods of contraception for females of reproductive potential Hepatitis B surface antigen negative Anti-hepatitis C virus antibody (anti-HCV) negative or negative HCV PCR if anti-HCV is positive Meets educational requirements of the study Exclusion Criteria: HIV vaccines or placebos in prior HIV vaccine trial Immunosuppressive medications within 168 days prior to first study vaccine administration Blood products within 120 days prior to first study vaccine administration Immunoglobulin within 60 days prior to first study vaccine administration Live attenuated vaccines within 30 days prior to first study vaccine administration Investigational research agents within 30 days prior to first study vaccine administration Subunit or killed vaccines within 14 days prior to first study vaccine administration Allergy treatment with antigen injections within 30 days prior to first vaccine administration Current tuberculosis prophylaxis or therapy Serious adverse reaction to a vaccine. A person who had an adverse reaction to pertussis vaccine as a child is not excluded. Autoimmune disease or immunodeficiency Active syphilis Unstable asthma Type 1 or type 2 diabetes mellitus Thyroid disease requiring treatment in the past 12 months Serious angioedema within the past 3 years Uncontrolled hypertension Bleeding disorder Malignancy unless it has been surgically removed and, in the opinion of the investigator, is not likely to recur during the study period Seizure disorder requiring medication within the past 3 years Asplenia Mental illness that would interfere with compliance with the protocol Other conditions that, in the judgment of the investigator, would interfere with the study Pregnant or breastfeeding

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 x 10^5 IU dose<br>Vaccine dose of 1 x 10^5 IU per injection | Biological: AVX101<br>* Alphavirus replicon particle vaccine expressing HIV Gag antigen<br>|
| Experimental: 1 x 10^6 IU dose<br>Vaccine dose of 1 x 10^6 IU per injection | Biological: AVX101<br>* Alphavirus replicon particle vaccine expressing HIV Gag antigen<br>|
| Experimental: 1 x 10^7 IU dose<br>Vaccine dose of 1 x 10^7 IU per injection | Biological: AVX101<br>* Alphavirus replicon particle vaccine expressing HIV Gag antigen<br>|
| Experimental: 1 x 10^8 IU dose<br>Vaccine dose of 1 x 10^8 IU per injection | Biological: AVX101<br>* Alphavirus replicon particle vaccine expressing HIV Gag antigen<br>|
| Placebo Comparator: Placebo<br>phosphate buffered saline, pH 7.2, HSA, sodium gluconate, and sucrose | Other: placebo<br>* phosphate buffered saline, pH 7.2, HSA, sodium gluconate, and sucrose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade IV adverse events | The sample size at each vaccine dose level was selected such that the stopping rule for not escalating the dose (2 or more vaccine-related Grade IV adverse experiences) would be met with high probability if the true toxicity rate was above 15-20%, and such that dose escalation would occur with high probability if the true toxicity rate was less than 5%. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local and systemic adverse events | Reactogenicity assessments were performed for all participants before and after each injection, beginning 25 to 45 minutes post injection and continuing daily for 7 days. Assessments performed included systemic reactogenicity (body temperature, malaise and/or fatigue, myalgia, headache, chills, arthralgia, nausea, vomiting) and local reactogenicity (injection site pain, tenderness, erythema or induration, and axillary lymph node tenderness or enlargement). | 7 days after each dose | 
| Binding antibodies by ELISA | Binding antibodies to commercially available Gag protein (P55 Gag; Quality Biologicals) were assessed by ELISA using single serum dilutions (1/50 or 1/100) on samples taken at baseline, two weeks after the second and third vaccinations and at the final visit. Samples that were positive in the initial ELISA were tested by endpoint titration ELISA using six 2- to 7-fold serial dilutions of serum beginning at a 1/50 or 1/100 dilution. Magnitude of responses is reported as the difference in optical density (OD) in antigen-containing and non-antigen containing wells at the 1:50 dilution. | 1 year | 
| Chromium release CTL assay | A standard 51Cr-release CTL assay was performed on fresh peripheral blood mononuclear cells (PBMC) at baseline and 2 weeks after the second and third vaccinations, using a 50:1 effector to target (E:T) ratio. | 3 months | 
| IFN-gamma ELISpot assay | Bulk T cell responses were assessed by IFN-γ ELISpot, using cryopreserved PBMC collected at baseline and 2 weeks after the second and third vaccinations, and stimulated overnight with Gag peptide pools at 200,000 cells per well. | 3 months | 
| Antibodies to VEE virus | Neutralizing antibodies to VEE virus were measured in serum obtained at baseline, 2 weeks after the second and third vaccinations and at the final visit. | 1 year | 
| Replication-competent viral vector viremia | Any participant who reported a fever greater than 38oC, or other moderate symptoms consistent with a viral illness (e.g. headache or malaise) during the 7 days following vaccination, or neurological symptoms (e.g. nuchal rigidity, ataxia, convulsions, coma, paralysis) within the window of the 2-week post vaccination visit, provided a serum sample to confirm the absence of replication-competent VEE viremia. | 2 weeks after each vaccine dose | 
| Intracellular cytokine staining (ICS) assay | Flow cytometry was used to examine HIV-specific CD4+ and CD8+ T cell responses using ICS, following stimulation with Gag peptides that span the protein sequence encoded by the vaccine construct. ICS assays were performed at baseline and 2 weeks after the second and third vaccinations. | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV Seronegativity, HIV Preventive Vaccine