A Phase 1 Trial of a Gorilla Adenovirus Vectored Networked Epitopes Vaccine, Administered to Healthy Adults Living Without and with HIV

A Phase 1 Randomized Double Blinded Placebo Controlled, Dose Ranging Trial, of a Gorilla Adenovirus Vectored Networked Epitopes Vaccine (GRAdHIVNE1 Vaccine), Administered to Healthy Adults Living without HIV and Living with HIV, in Southern Africa

This is a Phase 1 trial for the GRAdHIVNE1 vaccine, designed to evaluate safety, tolerability, and immunogenicity in healthy individuals (PLWoH) including healthy People Living with HIV (PLWH). This study builds on insights from prior T-cell vaccine trials and pre-clinical non-human primate studies, which demonstrated that robust CD8+ T cell responses, are crucial for viral control but require broad, polyfunctional responses that can also effectively counteract HIV's diversity and immune evasion strategies. Inclusion of PLWoH and PLWH in this study is important for safety, tolerability and immunogenicity data that can inform further development of the vaccine for prevention and therapeutic use. Prior clinical trials, using adenovirus vectors and exploring different vaccine approaches, demonstrated safety and potential immunogenic benefits in PLWH, despite not achieving sustained viral suppression post-treatment interruption Understanding these dynamics is key to evaluating the full therapeutic potential of vaccine induced immune responses in controlling HIV as well as inform the potential of the vaccine in aborting the establishment of a disseminated infection in the setting of prevention.

Eligibility Criteria:
Inclusion Criteria:

1. At least 18 years of age on the day of screening and has not reached his or her 51st birthday on the day of signing the Informed Consent Document.
2. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
3. In the opinion of the Principal Investigator or designee and based on Assessment of Informed Consent Understanding results, has understood the information provided and potential impact and/or risks linked to administration of the investigational product; written informed consent will be obtained from the participant before any study-related procedures are performed.
4. All sexually active female participants capable of becoming pregnant must commit to use an effective method of contraception from 21 days prior to receiving the IP until 4 months following the last IP administration, including:

   1. Intrauterine device, or contraceptive implant
   2. Hormonal contraception
   3. Successful vasectomy in the male partner (considered successful if a woman reports that a male partner has \[1\] documentation of azoospermia by microscopy (\&lt; 1 year ago), or \[2\] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post-vasectomy)
5. Women who have undergone a hysterectomy, bilateral oophorectomy, or tubal ligation, as well as those who are postmenopausal (\&gt;45 years of age with amenorrhea for at least 2 years, or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone \[FSH\] level \&gt;40 IU/L) will not be required to use contraceptives.
6. Willing to forgo donations of blood, or any other tissues during the study.

   Additional Inclusion criteria for PLWH
7. Confirmed HIV infection (HIV Ab+ or HIV RNA+) by documentation in the medical records or in-clinic HIV testing on screening visit.
8. CD4 ≥ 500 cells/µl at screening.
9. Currently on ART, and documentation of continuous combination ART (cART) for at least 12 months with suppression of plasma HIV-1 viral load \&lt; 50 copies / ml for greater than 6 months prior to trial entry, measured on at least 2 independent occasions that can include the screening viral load. cART is defined as a regimen including ≥ 2 compounds, e.g., 2 nucleoside reverse transcriptase inhibitors plus either non-nucleoside reverse transcriptase inhibitor or protease inhibitor or integrase inhibitor.
10. Viral load \&lt; 50 copies / ml at time of screening (within 28 days prior to IP administration).
11. Must commit to adhering to a suppressive ART regimen for the duration of the study

Exclusion Criteria:

1. Any clinically significant acute or chronic medical condition, other than HIV infection (in Part B only), that is considered progressive or in the opinion of the investigator makes the participant unsuitable for participation in the study.
2. For the PLWH (Part B), history of AIDS-defining illness or CD4 \&lt; 200 cells/µl.
3. If female, pregnant, lactating or planning a pregnancy during the period of screening through completion of the study.
4. In the past 6 months a history of alcohol or substance use, judged by the Investigator to potentially interfere with participant study compliance. Bleeding disorder that was diagnosed by a physician (e.g., Factor deficiency, coagulopathy or platelet disorder that requires special precautions). Note: A participant who states that he or she has easy bruising or bleeding but does not have a formal diagnosis and has intramuscular injections and blood draws without any adverse experience, is eligible.

6. History of a splenectomy. 7. Previous receipt of an adenovirus vectored vaccine. 8. Receipt of live attenuated vaccine or other vaccine within the previous 60 days or planned receipt within 180 days after administration of IP. Receipt of blood transfusion or blood derived products within the previous 3 months.

9. Participation in another clinical trial of an investigational product currently, within the previous 3 months or expected participation during this study. 10. Prior receipt of an investigational HIV vaccine candidate, monoclonal antibody or polyclonal immunoglobulin (note: receipt of placebo in a previous HIV vaccine or monoclonal antibody trial will not exclude a participant from participation if documentation is available and the Medical Monitor gives approval). 11. History of severe local or systemic reactogenicity to vaccines (e.g., anaphylaxis, respiratory difficulties, angioedema). 12. Psychiatric condition that compromises safety of the participant and precludes compliance with the protocol. Specifically excluded are persons with history of psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.

13. If, in the opinion of the Principal Investigator or designee, it is not in the best interest of the participant to participate in the trial. 14. Seizure disorder: a participant who has had a seizure in the last 3 years is excluded. (Not excluded: a participant with a history of seizures who has neither required medications nor had a seizure for 3 years.) 15. Infectious disease: chronic hepatitis B infection (HbsAg positive), current hepatitis C infection (HCV Ab positive and/ or HCV RNA) or treatment for hepatitis C infection in the past year, or active syphilis (RPR confirmed by TPHA). 16. A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy.

17. Active, serious infections (other than HIV infection in PLWH) requiring parenteral antibiotic, antiviral or antifungal therapy within 30 days prior to enrollment. 18. Any of the following abnormal laboratory parameters at screening:

a. Haematology i. Haemoglobin \&lt;10.5 g/dL in females; haemoglobin \&lt;11.0 g/dL in males ii. Absolute Neutrophil Count (ANC): ≤1000/mm3 iii. Absolute Lymphocyte Count (ALC): \&lt; 650/mm3 iv. Platelets: \&lt; 125,000 mm3 or ≥ 550,000/mm3 b. Chemistry i. Creatinine ≥1.1 x ULN ii. AST ≥1.25 x ULN iii. ALT ≥1.25 x ULN iv. Total bilirubin ≥1.25 x ULN v. Alkaline phosphatase ≥1.25 x ULN vi. Albumin ≤ 3.0 g/dL or ≤ 30 g/L c. Urinalysis i. Clinically significant abnormal dipstick confirmed by microscopy ii. Protein = 1+ or more iii. Blood = 1+ or more (not due to menses) 19. Any clinically relevant abnormality on history or examination including history of immunodeficiency or autoimmune disease, other than HIV among the PLWH; use of systemic corticosteroids, immunosuppressive, anticancer, or other medications considered significant by the investigator within the previous 6 months.

Eligibility Criteria Specific to PLWoH (Part A) People living without HIV(PLWoH) at screening, must be deemed to be at low risk of HIV infection and willing to maintain low-risk behavior for the duration of the trial per the guidelines for determining low likelihood of acquiring HIV.

The following guidelines should be applied by the investigator to identify potential vaccine trial participants with a low likelihood of acquiring HIV. These guidelines are based on behavior within the last 12 months prior to enrollment. Some participants may not be appropriate for enrollment even if they meet these guidelines, and more stringent criteria may be applied based on the site Principal Investigator's (PI) discretion. These guidelines should be supplemented and interpreted with local epidemiological information about HIV prevalence. The site PI may review with the Medical Monitor and/or the Protocol Safety Review Team (PSRT) a participant's likelihood of acquiring HIV