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

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.

Inclusion criteria

• Confirmed HIV-1 infection
• On combined antiretroviral treatment (defined as ≥ 3 antiretroviral drugs) initiated within 6 months of estimated time of HIV-1 acquisition.
• Willing and able to be adherent to their cART regimen for the duration of the study.
• 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.
• Being on the same cART regimen for at least 4 weeks at screening visit.
• 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).
• Stable CD4 counts ≥ 400 cells per mm^3 for the last 6 months at screening visit.
• Availability of stored biological sample (including PBMC and plasma) before any cART initiation.
• Aged at least 18 years on the day of screening and no greater than 60 years on the day of the first vaccination.
• Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
• In the opinion of the principal investigator or designee, the patient has understood the information provided and capable of giving written informed consent.
• 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.
• 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.
• Willing to accept blood draws and collect stool at time points specified in the Schedule of Procedures.
• Willing to forgo donating blood during the study.

Exclusion criteria

• Pregnancy or lactating.
• Presence of resistance drug mutations in a pre-cART genotype.
• Reported periods of suboptimal adherence to cART.
• History of past antiretroviral treatment interruptions longer than 2 weeks.
• Participation in another clinical trial within 12 weeks of study entry (at screening visit).
• Any AIDS-defining disease or progression of HIV-related disease.
• History of autoimmune disease.
• History or clinical manifestations of any physical or psychiatric disorder which could impair the subject's ability to complete the study.
• Receipt of approved vaccines within 2 weeks of study entry and along the duration of the trial.
• History of anaphylaxis or severe adverse reaction to vaccines.
• Previous immunisation with any experimental immunogens.
• Receipt of blood products within 6 months of study entry.
• Treatment for cancer or lymphoproliferative disease within 1 year of study entry.
• 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.
• 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).
• 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
• Complete refusal to cART interruption