Safety and Immunogenicity Study of a DNA Priming and MVA Boosting Strategy of HIV Vaccine

• Adverse events (local and system reactogenicity) [ Time Frame: 44 weeks ] [ Designated as safety issue: Yes ]
  The safety of immunization will be assessed by clinical features and standard clinical chemistry and hematological tests. Safety endpoints: Adverse events will be assessed using a standard format for soliciting local and systemic reactogenicity to the vaccine and collection of unsolicited adverse events. Solicited reactogenicity will be evaluated for 7 days following each vaccination. All other AE will be collected from the time of first injection until the end of the study follow-up period.
• Immunogenicity [ Time Frame: 44 weeks ] [ Designated as safety issue: No ]

  The primary immunogenicity endpoint will be determined by the interferon gamma (IFN-gama) enzyme linked immunospot (ELISPOT) assay.

  Secondary immunogenicity endpoints will include cellular immune responses determined by intracellular cytokine staining and T cell proliferation assays as well as binding antibody and neutralizing antibody responses.

While antiretroviral drugs have shown great promise in reducing HIV replication and thus in reducing HIV/AIDS associated morbi-mortality and HIV transmission, the cost is substantial and side effects are a potentially limiting factor. Development of an effective safe-affordable vaccine is likely to be the best way to stop further virus spread. The study aims to determine safety and immunogenicity of the DNA-vaccine at a dose of 600µg and 1200µg delivered id in combination with MVA-CMDR boost im.

• Biological: DNA HIVIS and MVA-CMDR
  600 µg i.d. (separate plasmids pools) of DNA priming at weeks 0, 4 and 12; 108 pfu i.m. MVA boosting at weeks 24 and 36
• Biological: DNA HIVIS and MVA-CMDR
  1200 µg i.d. (separate plasmids pools) of DNA priming at weeks 0, 4 and 12 ; 108 pfu i.m. MVA boosting at weeks 24 and 36
• Biological: Saline solution
  2 x 0.1 ml of saline solution i.d at weeks 0, 4 and 12 ; saline solution i.m at weeks 24 and 36
• Biological: Saline solution
  2 x 0.2 ml of saline solution i.d at weeks 0, 4 and 12 ; saline solution i.m at weeks 24 and 36

• Active Comparator: IA
  600 µg i.d. (separate plasmids pools) of DNA priming at weeks 0, 4 and 12 108 pfu i.m. MVA boosting at weeks 24 and 36
  Intervention: Biological: DNA HIVIS and MVA-CMDR
• Placebo Comparator: IB
  2 x 0.1 ml of saline solution i.d at weeks 0, 4 and 12 saline solution i.m at weeks 24 and 36
  Intervention: Biological: Saline solution
• Active Comparator: IIA
  1200 µg i.d. (separate plasmids pools) of DNA priming at weeks 0, 4 and 12;108 pfu i.m. MVA boosting at weeks 24 and 36
  Intervention: Biological: DNA HIVIS and MVA-CMDR
• Placebo Comparator: IIB
  2 x 0.2 ml of saline solution i.d at weeks 0, 4 and 12 ; saline solution i.m at weeks 24 and 36
  Intervention: Biological: Saline solution

Inclusion Criteria:

1. Age: 18 to 26 years
2. Willing to undergo HIV (Human Immunodeficiency Virus) counseling and testing
3. Have a negative antigen/antibody or antibody ELISA for HIV infection
4. Able to give informed consent
5. Satisfactory completion of an assessment of understanding prior to enrolment defined as 89% correct answers after three opportunities to take the test
6. Basic abilities to read and write
7. Resident in Maputo, and willing to remain so for the duration of the study

8. At low risk of HIV infection, defined as the absence of an identifiable risk factor/ behavior (their presence is therefore an exclusion criteria):

   • sexual partner with HIV
   • sexual partner with unknown HIV serostatus who is also unwilling to use protective condoms consistently in all sexual relations
   • sexual partner is known to be at high risk for HIV
   • more than one sexual partner in the last 6 months
   • history of being an alcoholic [as medically defined or more than 35 units /week]
   • history of Sexually Transmitted Infection (STI) within past 6 months
9. Verbal assurances that adequate birth control methods are used not to conceive/father a child during the study and up to 3 months after the last vaccine injection.
10. Women shall have a negative urine pregnancy test
11. Be willing to practice safe sex for the duration of the study to avoid sexually transmitted infections including HIV
12. Good health as determined by medical history, physical examination, clinical judgment and by key laboratory parameters as judged by the study physician.

13. Laboratory criteria:

    • Hemoglobin >10.5g/dl
    • White blood cell count <13,000/mm3
    • Neutrophils >1,300/mm3
    • Lymphocytes >1.000/ mm3
    • Platelets >120,000/ mm3
    • Random Blood Glucose < 6.44 mmol/L; if elevated, then a Fasting Blood Glucose < 6.11mmol/L (according to DAIDS Table for Lab Criteria)
    • Bilirubin <1.25 x uln
    • Alanine transaminase (ALT) <1.25 x uln
    • Urine dipstick for protein and blood: negative or trace. (If either is ¿ 1+, complete urinalysis (UA) will be performed.

Exclusion Criteria:

1. At risk of HIV infection as mentioned above in the inclusion criteria
2. Active tuberculosis or other systemic infectious process elicited by review of systems, physical examination and laboratory detection
3. A history of immunodeficiency, chronic illness requiring continuous or frequent medical intervention
4. Autoimmune disease by history and physical examination
5. Hives or recurrent hives and severe eczema
6. A history of psychiatric, medical (including traditional medicine) and/or substance abuse problems during the past 6 months that the investigator believes would adversely affect the volunteer's ability to participate in the trial
7. History of epilepsy, or currently taking anti-epileptics
8. Received blood or blood products or immunoglobulins in the past 3 months
9. Receiving immunosuppressive therapy such as systemic corticosteroids or cancer chemotherapy
10. Use of experimental therapeutic agents within 30 days of study entry
11. Reception of any live, attenuated vaccine within 60 days of study entry.
12. Abnormality in Electrocardiogram (ECG) that could indicate risk or make interpretation of vaccine effects difficult according to the study operating procedures
13. Previously received an HIV vaccine candidate

14. History of severe local or general reaction to vaccination defined as:

    • Local: Extensive, indurate redness and swelling involving most of the major circumference of the arm, not resolving within 72 hours
    • General: Fever >= 39.5 0C within 48 hours; anaphylaxis; bronchospasm; laryngeal edema; collapse; convulsions or encephalopathy within 72 hours
15. Being a lactating mother
16. Study site employees who are involved in the protocol and may have direct access to the immunogenicity results
17. Unlikely to comply with protocol as judged by the principal investigator or his designate.

• Swedish Institute for Communicable Disease Control, Sweden
• European and Developing Countries Clinical Trials Partnership (EDCTP)