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

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
AVX101
placebo
Sponsored by
AlphaVax, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV Infections focused on measuring HIV Seronegativity, HIV Preventive Vaccine

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Johns Hopkins University
  • New York Blood Center - Bronx
  • New York Blood Center - Union Square
  • Columbia University
  • University of Rochester
  • Vanderbilt University
  • Botswana HIV Vaccine Clinical Eval. Ctr, Princess
  • Perinatal HIV Research Unit, Chris Hani Baragwanat

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

1 x 10^5 IU dose

1 x 10^6 IU dose

1 x 10^7 IU dose

1 x 10^8 IU dose

Placebo

Arm Description

Vaccine dose of 1 x 10^5 IU per injection

Vaccine dose of 1 x 10^6 IU per injection

Vaccine dose of 1 x 10^7 IU per injection

Vaccine dose of 1 x 10^8 IU per injection

phosphate buffered saline, pH 7.2, HSA, sodium gluconate, and sucrose

Outcomes

Primary Outcome Measures

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%.

Secondary Outcome Measures

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).
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.
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.
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.
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.
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.
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.

Full Information

First Posted
November 30, 2004
Last Updated
June 27, 2012
Sponsor
AlphaVax, Inc.
Collaborators
HIV Vaccine Trials Network, National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00097838
Brief Title
Safety of and Immune Response to an HIV-1 Subtype C Vaccine (AVX101) in HIV Uninfected Adults
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2012
Overall Recruitment Status
Completed
Study Start Date
October 2004 (undefined)
Primary Completion Date
September 2009 (Actual)
Study Completion Date
September 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AlphaVax, Inc.
Collaborators
HIV Vaccine Trials Network, National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
HIV Seronegativity, HIV Preventive Vaccine

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
96 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1 x 10^5 IU dose
Arm Type
Experimental
Arm Description
Vaccine dose of 1 x 10^5 IU per injection
Arm Title
1 x 10^6 IU dose
Arm Type
Experimental
Arm Description
Vaccine dose of 1 x 10^6 IU per injection
Arm Title
1 x 10^7 IU dose
Arm Type
Experimental
Arm Description
Vaccine dose of 1 x 10^7 IU per injection
Arm Title
1 x 10^8 IU dose
Arm Type
Experimental
Arm Description
Vaccine dose of 1 x 10^8 IU per injection
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
phosphate buffered saline, pH 7.2, HSA, sodium gluconate, and sucrose
Intervention Type
Biological
Intervention Name(s)
AVX101
Intervention Description
Alphavirus replicon particle vaccine expressing HIV Gag antigen
Intervention Type
Other
Intervention Name(s)
placebo
Intervention Description
phosphate buffered saline, pH 7.2, HSA, sodium gluconate, and sucrose
Primary Outcome Measure Information:
Title
Grade IV adverse events
Description
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%.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Local and systemic adverse events
Description
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).
Time Frame
7 days after each dose
Title
Binding antibodies by ELISA
Description
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.
Time Frame
1 year
Title
Chromium release CTL assay
Description
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.
Time Frame
3 months
Title
IFN-gamma ELISpot assay
Description
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.
Time Frame
3 months
Title
Antibodies to VEE virus
Description
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.
Time Frame
1 year
Title
Replication-competent viral vector viremia
Description
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.
Time Frame
2 weeks after each vaccine dose
Title
Intracellular cytokine staining (ICS) assay
Description
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.
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Donald S. Burke, MD
Organizational Affiliation
Center for Immunization Research, Johns Hopkins School of Public Health
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Salim Abdool Karim, MD, PhD
Organizational Affiliation
University of KwaZulu
Official's Role
Study Chair
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205-1901
Country
United States
Facility Name
New York Blood Center - Bronx
City
Bronx
State/Province
New York
ZIP/Postal Code
10456
Country
United States
Facility Name
New York Blood Center - Union Square
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Rochester
City
Rochester
State/Province
New York
ZIP/Postal Code
14642-0001
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Botswana HIV Vaccine Clinical Eval. Ctr, Princess
City
Gaborone
Country
Botswana
Facility Name
Perinatal HIV Research Unit, Chris Hani Baragwanat
City
Bertsham
ZIP/Postal Code
2013
Country
South Africa

12. IPD Sharing Statement

Citations:
PubMed Identifier
12120997
Citation
Davis NL, West A, Reap E, MacDonald G, Collier M, Dryga S, Maughan M, Connell M, Walker C, McGrath K, Cecil C, Ping LH, Frelinger J, Olmsted R, Keith P, Swanstrom R, Williamson C, Johnson P, Montefiori D, Johnston RE. Alphavirus replicon particles as candidate HIV vaccines. IUBMB Life. 2002 Apr-May;53(4-5):209-11. doi: 10.1080/15216540212657.
Results Reference
background
PubMed Identifier
12120996
Citation
Williamson AL. The development of HIV-1 subtype C vaccines for Southern Africa. IUBMB Life. 2002 Apr-May;53(4-5):207-8. doi: 10.1080/15216540212648.
Results Reference
background
PubMed Identifier
12639249
Citation
Williamson C, Morris L, Maughan MF, Ping LH, Dryga SA, Thomas R, Reap EA, Cilliers T, van Harmelen J, Pascual A, Ramjee G, Gray G, Johnston R, Karim SA, Swanstrom R. Characterization and selection of HIV-1 subtype C isolates for use in vaccine development. AIDS Res Hum Retroviruses. 2003 Feb;19(2):133-44. doi: 10.1089/088922203762688649.
Results Reference
background
PubMed Identifier
11727528
Citation
Schlesinger S. Alphavirus vectors: development and potential therapeutic applications. Expert Opin Biol Ther. 2001 Mar;1(2):177-91. doi: 10.1517/14712598.1.2.177.
Results Reference
background
PubMed Identifier
22914365
Citation
Wecker M, Gilbert P, Russell N, Hural J, Allen M, Pensiero M, Chulay J, Chiu YL, Abdool Karim SS, Burke DS; HVTN 040/059 Protocol Team; NIAID HIV Vaccine Trials Network. Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults. Clin Vaccine Immunol. 2012 Oct;19(10):1651-60. doi: 10.1128/CVI.00258-12. Epub 2012 Aug 22.
Results Reference
derived

Learn more about this trial

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

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