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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Biological: AVX101; Other: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 1

Contacts and Locations

Study Locations

• Botswana
  • Gaborone, Botswana
    • Botswana HIV Vaccine Clinical Eval. Ctr, Princess
• South Africa
  • Bertsham, South Africa, 2013
    • Perinatal HIV Research Unit, Chris Hani Baragwanat
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205-1901
      • Johns Hopkins University
  • New York
    • Bronx, New York, United States, 10456
      • New York Blood Center - Bronx
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10003
      • New York Blood Center - Union Square
    • Rochester, New York, United States, 14642-0001
      • University of Rochester
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: AlphaVax, Inc.
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); HIV Vaccine Trials Network
• Investigators: Study Chair: Donald S. Burke, MD, Center for Immunization Research, Johns Hopkins School of Public Health; Study Chair: Salim Abdool Karim, MD, PhD, University of KwaZulu

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2004
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: November 30, 2004
• First Submitted That Met QC Criteria: November 30, 2004
• First Posted (Estimate): December 1, 2004

Study Record Updates

• Last Update Posted (Estimate): July 2, 2012
• Last Update Submitted That Met QC Criteria: June 27, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: HIV Seronegativity; HIV Preventive Vaccine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: HVTN 059