Safety and Immunogenicity Study of DNA.HTI, MVA.HTI and ChAdOx1.HTI in HIV-1-positive Patients (AELIX-002)

The AELIX-002 study aims to evaluate the safety and the immunogenicity of an heterologous prime-boost regimen with DNA.HTI, MVA.HTI and ChAdOx1.HTI in early diagnosed and treated HIV-1 positive individuals, males and females,18-60 years of age.

AELIX Therapeutics has developed a novel immunogen, which was designed to be used as a a therapeutic HIV vaccine that could help HIV infected individuals to control viral replication in the absence of antiretroviral treatment. HIVACAT T cell immunogen (HTI) is a novel T cell immunogen covering the most vulnerable regions of HIV. The encoding DNA sequence that has been inserted in various vaccine vectors, including viral and non-viral vectors. Administration of the HTI immunogen is implemented through a heterologous prime-boost approach. The aim of the sequential administration of the therapeutic vaccines is to achieve a so-called "functional cure," in which HIV-infected participants can control viral replication in the absence of ART.

The AELIX-002 Phase I study will evaluate the safety and immunogenicity of an heterologous regime with DNA.HTI, MVA.HTI and ChAdOx1.HTI in HIV-1 positive participants on suppressive antiretroviral treatment who started Combination Antiretroviral Therapy (cART) within the first 6 months of confirmed HIV-1 acquisition. In Phase A, participants were randomized to receive active vaccine or placebo in a double blinded fashion. There was a sentinel group of three participants; two received active vaccine and one received placebo (0.9% normal saline). During the sentinel phase of the study only one participant was enrolled per day. Two weeks later and in the absence of any related SAE or ≥ Grade 3 adverse event lasting \>72h after vaccination in any of the 3 sentinel participants, six individuals in the remaining cohort were enrolled (in blocks of 3 patients per day) and the final six participants one week later, also in blocks of 3 participants per day. On each vaccination day, 2 participants received active IMP and 1 received placebo (2:1).

After the first 15 participants (3 sentinel and 12 non-sentinel) have reached week 22 visit and a favourable report from the Safety Monitoring Committee has been released, transition to Phase B was performed to include 30 participants (Group 3). Participants were recruited sequentially and without following blocks of pre-defined number of vaccines and placebos per immunization day.

At week 32, all participants were invited to participate in an extension sub-study (Roll-over Phase) to assess long-term safety, tolerability and immunogenicity of DNA.HTI and MVA.HTI administrations until start of Phase C. There were no interventions during this extension Roll over Phase.

After a favourable SMC report, transition to Phase C occurred. During Roll-over Phase participants in Phase A/B were offered to participate in Phase C. Participants who received active treatment (DDDMM) in Phase A/B will continue to receive active treatment (CCM) in Phase C, while participants who received placebo in Phase A/B will continue to receive placebo (PPP). Treatment allocation remained blind. Eight weeks after the third MVA.HTI/placebo administration, all participants will undergo an Analytical Treatment Interruption (ATI) of up to 24 weeks of duration. At visit Phase C week 56 (end-of-ATI visit), or before according to pre-specified criteria, cART will be resumed, and participants will be followed during a safety period of 12 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Confirmed HIV-1 infection
2. On combined antiretroviral treatment (defined as ≥ 3 antiretroviral drugs) initiated within 6 months of estimated time of HIV-1 acquisition.
3. Willing and able to be adherent to their cART regimen for the duration of the study.
4. Optimal virological suppression for at least 1 year defined as maintained pVL below the limit of detection (based on current available assays, 20, 40 or 50 copies/ml) allowing for isolated blips.
5. Being on the same cART regimen for at least 4 weeks at screening visit.
6. Nadir CD4 count ≥ 200 cells per mm3. Isolated lower counts at the moment of acute HIV-1 infection will be allowed only if appropriate immune recovery was followed after cART initiation (as is criteria 7).
7. Stable CD4 counts ≥ 400 cells per mm\^3 for the last 6 months at screening visit.
8. Availability of stored biological sample (including PBMC and plasma) before any cART initiation.
9. Aged at least 18 years on the day of screening and no greater than 60 years on the day of the first vaccination.
10. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
11. In the opinion of the principal investigator or designee, the patient has understood the information provided and capable of giving written informed consent.
12. If heterosexually active female; using an effective method of contraception (hormonal contraception, intra-uterine device (IUD), or anatomical sterility in self or partner) from 14 days prior to the first vaccination until at least 12 weeks after the last vaccination; all female volunteers must be willing to undergo urine pregnancy tests at time points specified in the Schedule of Procedures.
13. If heterosexually active male; willing to use an effective method of contraception (anatomical sterility in self) or agree on the use of an effective method of contraception by his partner (hormonal contraception, intra-uterine device (IUD), or anatomical sterility) from the day of the first vaccination until 12 weeks after the last vaccination.
14. Willing to accept blood draws and collect stool at time points specified in the Schedule of Procedures.
15. Willing to forgo donating blood during the study.

Exclusion Criteria:

1. Pregnancy or lactating.
2. Presence of resistance drug mutations in a pre-cART genotype.
3. Reported periods of suboptimal adherence to cART.
4. History of past antiretroviral treatment interruptions longer than 2 weeks.
5. Participation in another clinical trial within 12 weeks of study entry (at screening visit).
6. Any AIDS-defining disease or progression of HIV-related disease.
7. History of autoimmune disease.
8. History or clinical manifestations of any physical or psychiatric disorder which could impair the subject's ability to complete the study.
9. Receipt of approved vaccines within 2 weeks of study entry and along the duration of the trial.
10. History of anaphylaxis or severe adverse reaction to vaccines.
11. Previous immunisation with any experimental immunogens.
12. Receipt of blood products within 6 months of study entry.
13. Treatment for cancer or lymphoproliferative disease within 1 year of study entry.
14. Any other current or prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study.
15. Current or recent use (within last 3 months) of interferon or systemic corticosteroids or other immunosuppressive agents (use on inhaled steroids for asthma or topic steroids for localized skin conditions are permitted).
16. Any laboratory abnormalities including:

    Haematology
    * Haemoglobin \< 10.0 g/dl
    * Absolute Neutrophil Count (ANC) ≤ 1,000 /mm3
    * Absolute Lymphocyte Count (ALC) ≤ 600 /mm3
    * Platelets ≤100,000 /mm3, ≥ 550,000 /mm3

    Biochemistry
    * Creatinine \> 1.3 x ULN
    * Aspartate aminotransferase (AST) \> 2.5 x ULN
    * Alanine aminotransferase (ALT) \> 2.5 x ULN

    Microbiology
    * Positive for hepatitis B surface antigen,
    * Positive for hepatitis C antibody, unless confirmed clearance of HCV infection (spontaneous or following treatment)
    * Positive serology indicating active syphilis requiring treatment
17. Complete refusal to cART interruption