Safety of an HIV Vaccine (AVX101) in HIV Uninfected Volunteers in the United States and South Africa

A Phase I Safety and Immunogenicity Trial of an Alphavirus Replicon HIV Subtype C Gag Vaccine (AVX101, Alphavax, Inc.) in Healthy HIV-1 Uninfected Adult Volunteers

The purpose of this study is to see if different doses of an experimental HIV vaccine are safe and to study how the immune system responds to the vaccine. The vaccine will be tested in healthy, HIV uninfected volunteers. AVX101 contains only one of the many substances that HIV needs to make more copies of itself; therefore, the vaccine cannot cause HIV or AIDS.

Study Overview

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

Detailed Description

This study was designed to evaluate the safety and immunogenicity of an alphavirus replicon HIV subtype C gag vaccine. 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.

This study evaluated the AVX101 vaccine in healthy, HIV uninfected volunteers in both the United States and South Africa. Participants will be randomized to receive either vaccine or placebo at study entry and again at Months 1 and 3. The study was originally designed to enroll four groups of participants in both the US and South Africa, with successive groups receiving increasing doses of the vaccine, but was later amended to enroll only two groups. Twelve US participants (US Group 1) were randomized to receive either vaccine or placebo. After a review of initial safety data from this group, 12 South African participants (SA Group 1) were randomized to receive the same vaccine dose as US Group 1 or placebo, while 12 US participants (US Group 2) were randomized to receive the next higher vaccine dose or placebo. Review of safety data from SA Group 1 and US Group 2 was used to inform the decision to begin enrollment into SA Group 2 .

Participants had nine study visits over 12 months. Study visits included clinical evaluation, urine and blood tests, and HIV tests. After each injection, participants were asked to record their temperature and any symptoms each day for 7 days and report them to the clinic staff.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Durban, South Africa
    • SAAVI Vaccine Research Unit
  • Soweto, South Africa
    • Chris Hani Baragwanath Hospital
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205-1901
      • Johns Hopkins University
  • New York
    • Bronx, New York, United States, 10456
      • New York Blood Ctr- Union Square
    • New York, New York, United States, 10032
      • Columbia University
    • Rochester, New York, United States, 14642-0002
      • University of Rochester Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria

• HIV negative
• 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
• Access to participating site and available for follow-up during the 12 month study

Exclusion Criteria

• HIV vaccines or placebos in prior HIV vaccine trial
• Measurable anti-VEE antibody
• High risk for HIV infection according to HVTN Risk Criteria
• 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
• Current tuberculosis prophylaxis or therapy
• Active syphilis
• Serious adverse reaction to vaccines. A person who had an adverse reaction to pertussis vaccine as a child is not excluded.
• Autoimmune disease or immunodeficiency
• Unstable asthma
• Type 1 or Type 2 Diabetes Mellitus
• Thyroid disease requiring treatment
• 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 judgement of the investigator, would interfere with the study
• Pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: placebo; phosphate buffered saline, pH 7.2, HSA, sodium gluconate, and sucrose
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 10^4 IU dose; Vaccine dose of 1 x 10^4 IU per injection	Biological: AVX101; Alphavirus replicon particle vaccine expressing HIV Gag antigen

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
Lymphoproliferation assay	A lymphocyte proliferation assay in response to purified Gag protein and/or Gag peptides was performed on cryopreserved PBMC collected at baseline, 2 weeks after the second and third vaccinations, and at the final visit.	1 year

Collaborators and Investigators

• Sponsor: AlphaVax, Inc.
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); HIV Vaccine Trials Network
• Investigators: Study Chair: Donald Burke, MD, Johns Hopkins University; Study Chair: Salim Abdool Karim, MD, PhD, University of Natal, Durban, South Africa

Publications and helpful links

General Publications

• Strauss JH, Strauss EG. The alphaviruses: gene expression, replication, and evolution. Microbiol Rev. 1994 Sep;58(3):491-562. doi: 10.1128/mr.58.3.491-562.1994. Erratum In: Microbiol Rev 1994 Dec;58(4):806.
• 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.
• Pushko P, Parker M, Ludwig GV, Davis NL, Johnston RE, Smith JF. Replicon-helper systems from attenuated Venezuelan equine encephalitis virus: expression of heterologous genes in vitro and immunization against heterologous pathogens in vivo. Virology. 1997 Dec 22;239(2):389-401. doi: 10.1006/viro.1997.8878.
• Pushko P, Bray M, Ludwig GV, Parker M, Schmaljohn A, Sanchez A, Jahrling PB, Smith JF. Recombinant RNA replicons derived from attenuated Venezuelan equine encephalitis virus protect guinea pigs and mice from Ebola hemorrhagic fever virus. Vaccine. 2000 Aug 15;19(1):142-53. doi: 10.1016/s0264-410x(00)00113-4.
• Davis NL, Caley IJ, Brown KW, Betts MR, Irlbeck DM, McGrath KM, Connell MJ, Montefiori DC, Frelinger JA, Swanstrom R, Johnson PR, Johnston RE. Vaccination of macaques against pathogenic simian immunodeficiency virus with Venezuelan equine encephalitis virus replicon particles. J Virol. 2000 Jan;74(1):371-8. doi: 10.1128/jvi.74.1.371-378.2000. Erratum In: J Virol 2000 Apr;74(7):3430.

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (Actual): July 1, 2005
• Study Completion (Actual): July 1, 2005

Study Registration Dates

• First Submitted: July 7, 2003
• First Submitted That Met QC Criteria: July 7, 2003
• First Posted (Estimate): July 8, 2003

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-1; AIDS Vaccines; HIV Preventive Vaccine; Dose-Response Relationship, Immunologic; Injections, Subcutaneous; Gene Products, gag
• 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 040