The Safety and Immunogenicity of the DNA-GTU Vaccine Administered to HIV-infected Patients on ART vs Placebo

A Randomized Phase I/II Study to Assess the Safety and Immunogenicity of the DNA-GTU Vaccine Administered by Two Novel Routes Compared to Placebo in HIV-infected Patients on Antiretroviral Therapy

CUT*HIVTHER 001 is a randomised placebo-controlled Phase I/II study aimed at exploring the safety and immunogenicity of two different modes of delivery of a GTU® DNA plasmid vaccine (GTU®-multiHIV B clade) in HIV infected volunteers on antiretroviral therapy (ART):

• Transcutaneous (TC) delivery to enhance intramuscular delivery and

• Electroporation (EP) enhanced intramuscular delivery Participants will be randomised 1:1:1 to TC:EP:saline for the purposes of analysis. Half the saline group will receive TC saline and half will receive EP saline.

  30 HIV infected male and female volunteers aged 18-45 years, who have been on ART for at least 6 months with 2 or more HIV plasma viral load measurements < 50 copies HIV RNA/ml prior to enrolment.

The investigational HIV-1 vaccine GTU®-MultiHIV B clade encodes for a MultiHIV antigen which is a synthetic fusion protein consisting of full-length polypeptides of Rev, Nef, Tat, p17 and p24 and containing more than 20 Th and CTL epitopes of protease, reverse transcriptase (RT) and gp160 regions of the HAN2 HIV-1 B clade.

Vaccine is provided in sealed vials at 2mg/ml, and a single 1ml IM injection of 2mg GTU®-MultiHIV DNA IM (into the thigh) is required to deliver a 2mg dose. Individuals in Group 2 will receive a further 0.4mg GTU®-MultiHIV DNA in 0.2ml administered by TC, a novel needle-free method of vaccine delivery.

The investigators are exploring combination regimens with the overall aims of (i) optimising immune responses and (ii) developing safe and well tolerated strategies which will favour the development of T-cell responses that may enhance anti-HIV HIV therapy with the forward looking goal of working towards functional eradication of infection. The investigator proposes to combine the previously used IM and TC methods because preclinical data suggest that the combination of methods will favour the development of CD8 T cell responses. All groups will receive 6.0mg of the vaccine IM given in 3 doses over 12 weeks. Group 1 will receive the 6.0mg IM with electroporation (EP) and Group 2 will receive the 6.0mg IM without EP but together with an additional 1.2mg vaccine TC. The primary immunogenicity endpoint will be to determine whether either intervention group augments the cellular responses to vaccine specific peptides in relation to baseline. It is anticipated that none of subjects receiving saline placebo would have an increase in vaccine specific responses relative to those at baseline. Therefore if the differences between the active groups and saline placebo are sufficiently large, for example 80% responders in a GTU®-MultiHIV DNA active group, <10% in the control group, this would be significant.

Should the regimes prove safe, acceptable and induce significant immunogenicity then the intention is to move one or both regimes into a larger study powered to determine their potential long-term impact on therapy when used in combination with conventional ARV regimens. Proof of concept that DNA vaccination can induce de novo HIV specific responses that are associated with control of viral replication, would justify further investigation of their use in immunotherapies combined with ART intensification and/or anti-latency drugs.

Inclusion Criteria:

1. Male or female
2. Aged between 18 and 45 years on the day of screening
3. BMI between 19-30
4. Available for follow-up for the duration of the study
5. Willing and able to give written informed consent
6. HIV-1 Clade B infection documented by confirmed antibody test
7. Confirmed on 2 separate occasions in the 6 month period prior to enrolment to have viral load < 200 copies HIV RNA/ml whilst on ART
8. Nadir CD4+ > 250 CD4 lymphocytes AND screening CD4 >200 CD4 lymphocytes
9. Willing to avoid UV tanning or strong sun exposure during the immunisation period of the study
10. Willing to avoid all other vaccines within four weeks of scheduled study vaccinations
11. If heterosexually active female, using an effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; consistent record with condoms if using these; physiological or anatomical sterility (in self or partner) from 14 days prior to the first vaccination until 4 months after the last, and willing to undergo urine pregnancy tests prior to each vaccination
12. If heterosexually active male, using an effective method of contraception with their partner from the first day of vaccination until 4 months after the last vaccination

Exclusion Criteria:

1. Pregnant or lactating

2. Use of regular topical treatment on the injection or application site within the last four weeks

3. UV tanning sessions or strong sun exposure within four weeks prior to enrolment

4. Excessive terminal hair growth on the investigational skin areas (to be assessed by reference to a photograph which will be available during screening visit)

5. Individuals in which a skin-fold measurement (cutaneous and subcutaneous tissue) of the upper right or left thigh exceeds 40 mm

6. Clinically relevant abnormality on history or examination including

   • history of grand-mal epilepsy, seizure disorder or any history of prior seizure
   • history of syncope or fainting episodes within 1 year of study entry
   • liver disease including active hepatitis B (surface antigen positive) or C (PCR positive)
   • any skin condition which may interfere with the trial assessment of the injection site
   • haematological, metabolic, gastrointestinal (excluding gastritis) or cardio-pulmonary disorders (excluding mild asthma)
   • a clinically significant abnormality on the ECG
   • autoimmune disease, or use of regular, systemic immunosuppressives in preceding 3 months

7. Known hypersensitivity to any component of the vaccine formulations used in this trial, or have severe or multiple allergies to drugs or pharmaceutical agents

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

   1. local: extensive, indurated redness and swelling involving most of the antero-lateral thigh or the major circumference of the arm, not resolving within 72 hours
   2. general: fever >= 39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours

9. Receipt of live attenuated vaccine within 60 days of enrolment and any vaccine within 30 days of enrolment.

10. Receipt of an experimental vaccine containing HIV antigens at any time in the past

11. Receipt of immunoglobin within 4 months of screening

12. Participation in another trial of a medicinal product, completed less than 30 days prior to enrolment

13. Grade 2 or above routine laboratory parameters. Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia

14. Current use of any electronic stimulation device, such as cardiac demand pacemakers, automatic implantable cardiac defibrillator, nerve stimulators, or deep brain stimulators.

15. Presence of any surgical or traumatic metal implants at the sites of administration

16. Unable to read and speak English to a fluency level adequate for the full comprehension of procedures required in participation and consent.

17. Unlikely to comply with protocol.