Study to Assess Safety and Ability to Induce Immune Responses of HIV-1 Vaccines M3 and M4 Given Alone or in Combination in HIV-infected Adults
Condition: HIV-1 Infection
MeSH terms: Infections
Intervention: MVA.tHIVconsv3; MVA.tHIVconsv4; Placebo
Intervention description: viral-vector, MVA, expressing immunogens derived from conserved yet immunogenic regions of HIV-1; viral-vector, MVA, expressing immunogens derived from conserved yet immunogenic regions of HIV-1; The appropriate amount of Sodium Chloride for Injection USP, 0.9% will be drawn into a syringe.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomized 7(M3):7(M4):7(M3+M4):3(Placebo) to one of four study arms, and receive study treatment or placebo at Day 0.
Masking: Double (Participant, Investigator)
Masking description: This is a double-blind study in which both the participant and the investigator are blinded to what the participant receives.
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: HIV-1; Infection; Suppressed; ART; Vaccines; Alone; Combination; Immunogenicity

Summary:

      This is a double blind, randomized, placebo-controlled, parallel design, study in which 24
      HIV-infected participants with durable viral suppression will be randomly assigned to receive
      vaccination with MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), M3+M4 combined, or placebo.
      Participants will be randomized 7:7:7:3 to one of four study arms, and receive study
      treatment or placebo at Day 0. Each enrolled participant will complete the study in
      approximately 33.5 weeks (8.4 months).

      The purpose of this study is to find out:

        -  If it is safe for people to receive injections of two investigational HIV vaccines,
           called MVAtHIVconsv3 and MVAtHIVconsv4 alone or in combination.

        -  If giving participants these vaccine doses will increase their immune system's ability
           to kill HIV virus.
    

Eligibility criteria:

        Inclusion Criteria:

          1. HIV infection documented by any licensed rapid HIV test or HIV enzyme or
             chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
             confirmed by a licensed Western blot or a second antibody test by a method other than
             the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral assay.

             A reactive initial rapid test should be confirmed by either another type of rapid
             assay or an E/CIA that is based on a different antigen preparation and/or different
             test principle (e.g., indirect versus competitive), or a Western blot or a plasma
             HIV-1 RNA viral load.

             WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention)
             guidelines mandate that confirmation of the initial test result must use a test that
             is different from the one used for the initial assessment.

          2. Ages ≥ 18 to ≤ 65 years old

          3. Able and willing to give written informed consent.

          4. Able and willing to provide adequate locator information.

          5. Able and willing to comply with time requirements for protocol-specified visits and
             evaluations.

          6. Able and willing to commit to all study visits including follow-up through Day 168
             (Week 24).

          7. Continuous ART prior to screening, defined as not missing more than 9 total days and
             never more than 4 consecutive days in the last 3 months.

          8. On a stable ART regimen defined as no changes in any ART medication within the 30 days
             prior to screening.

          9. Permitted ART regimens include:

               -  1) At least 3 ART agents (not counting ritonavir or cobicistat as one of the
                  agents if less than a 200mg total daily dose). One of the agents must include an
                  integrase inhibitor, NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors), or
                  a boosted-PI (protease inhibitor).

             OR

               -  2) Two ART agents in which one of the agents is either a boosted protease
                  inhibitor or an integrase inhibitor.

             NOTE: Other potent fully suppressive antiretroviral combinations will be considered on
             a case-by-case basis.

             NOTE: Changes in drug formulation or dose are allowed (e g, TDF to TAF, ritonavir to
             cobicistat or separate ART agent dosing to fixed-dose combination), but none within 30
             days prior to screening.

             NOTE: Prior changes in, or elimination of, medications for easier dosing schedule,
             intolerance, toxicity, an improved side effect profile or within a drug class are
             permitted if an alternative suppressive regimen was maintained, but not within 30 days
             prior to screening.

         10. Ability and willingness of participant to continue ART throughout the study.

         11. Plasma HIV-1 RNA <50 copies/mL at 3 time points in the previous 24 months prior to
             screening and never ≥50 copies/mL on 2 consecutive time points in the last 24 months.

         12. At least 1 documented HIV-1 RNA result <50 copies/mL ≥24 months but ≤ 36 months prior
             to screening.

         13. Plasma HIV-1 RNA level <50 copies/mL on an FDA-approved HIV RNA assay performed at a
             US CLIA Certified Laboratory (or its equivalent) at screening.

         14. CD4 cell count ≥ 350 cells/mm3, performed at any US laboratory that has a CLIA
             certification or its equivalent at screening.

         15. Hepatitis C (HCV) antibody negative result at screening or, if the participant is HCV
             antibody positive, a negative HCV RNA at screening.

         16. Hepatitis B surface antigen (HBsAg) negative at screening.

         17. Adequate vascular access for leukapheresis.

         18. Able and willing to receive IM injections without difficulty.

         19. All women must have a negative serum pregnancy test at screening regardless of
             reproductive potential.

             Note: The serum pregnancy test must have a sensitivity of at least 25 mIU/mL.

         20. All participants must agree not to participate in a conception process (e.g., active
             attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization,
             egg donation) while on study and for 4 months after their vaccination.

             Note: Women of child bearing potential is defined as women who have not been
             post-menopausal for at least 24 consecutive months, i.e., who have had menses within
             the preceding 24 months, or women who have not undergone surgical sterilization,
             specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy

         21. All men and women participating in sexual activity that could lead to pregnancy must
             agree to consistently use at least one of the following forms of birth control for at
             least 21 days prior to Visit 4 (Day 0) and for 4 months after their vaccination:

               -  Condoms (male or female) with or without a spermicidal agent

               -  Diaphragm or cervical cap with spermicide

               -  Intrauterine device (IUD)

               -  Tubal ligation

               -  Hormone-based contraceptive

             NOTE: For female participants receiving ritonavir or cobicistat, estrogen-based
             contraceptives are not reliable and an alternative method should be suggested.

         22. Men and women who are not of reproductive potential are eligible without requiring the
             use of contraceptives. Acceptable documentation detailing sterilization and menopause
             are specified below.

             Note: Men who have sex with men only will not be required to use contraception.

             Written or oral documentation communicated by clinician or clinician's staff of one of
             the following:

               -  Physician report/letter

               -  Operative report or other source documentation in the patient record (a
                  laboratory report of azoospermia is required to document successful vasectomy)

               -  Discharge summary

               -  Follicle stimulating hormone-release factor (FSH) measurement elevated into the
                  menopausal range as established by the reporting laboratory

         23. Agrees not to enroll on another study of an investigational research agent during the
             study period.

             NOTE: Investigational research agent is defined as any unlicensed investigational drug
             not yet approved for use in humans.

         24. Willingness to defer routine vaccination except for influenza and COVID-19 from within
             the previous 28 days of screening through 28 days after vaccination at Day 0.

             NOTE: Potential participants should delay enrollment on study until 14 days after
             receiving the influenza and/or COVID-19 vaccine.

         25. Adequate organ function as indicated by the following laboratory values:

        Hematological: Absolute neutrophil count (ANC) ≥ 1,000 /mcL; Platelets ≥ 100,000/mcL;
        Hemoglobin ≥ 12 g/dL (male) and ≥ 11.5 g/dL (females)

        Coagulation: Prothrombin Time or INR<1.1 x ULN (upper limit of normal)

        Chemistries: Serum potassium levels within normal limits; Serum magnesium levels1; Glucose
        - Screening serum glucose ≤ Grade 1 (fasting or non-fasting)

        1 = LLN for Mg++ per the clinical laboratory's normal range used for this study is a grade
        1 event per the DAIDS Toxicity Table and is allowed for eligibility.

        Renal: Creatinine clearance determined by the CKD-Epi equation - eGFR > 60mL/min

        Hepatic: Serum total bilirubin - Total bilirubin <1.1 x ULN. If total bilirubin is
        elevated, direct bilirubin must be <2 x ULN

        If the participant is on an atazanavir -containing therapy then a direct bilirubin should
        be measured instead of the total bilirubin and must be ≤1.0mg/dL.

        AST (SGOT) and ALT (SGPT)<1.25 X ULN Alkaline Phosphatase <1.25 X ULN

        Urinalysis: Protein < 2+; Blood < 2+ (for women, before or after menses) LLN = lower limit
        of normal; UPN = upper limit of normal; WNL = within limit of normal

        Exclusion Criteria:

          1. If the HIV provider or study investigator is unable, as assessed by the study PI or
             protocol team, to construct a fully active alternative regimen based on previous
             resistance testing and/or treatment history.

          2. Women of childbearing age/potential must not be breast feeding, pregnant, or planning
             pregnancy any time from enrollment to 4 months after vaccination at Day 0.

          3. Body Mass Index (BMI) ≥40 kg/m2

          4. Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without
             clear documentation of treatment).

             NOTE: In cases of untreated syphilis, participant may rescreen following documentation
             of adequate treatment of syphilis.

          5. Current treatment for HCV with antiviral therapy or participants who have received HCV
             treatment within 6 months prior to screening.

          6. HIV RNA ≥150 copies/mL in the 6 months prior to screening.

          7. Received any infusion blood product, immune globulin, or hematopoetic growth factors
             within 6 months prior to screening.

          8. Use of any of the following within 90 days prior to screening: immunomodulatory,
             cytokine, or growth stimulating factors such as systemic cytotoxic chemotherapy, ,
             immune globulin, interferon, cyclosporine, methotrexate, azathioprine, anti-CD25
             antibody, IFN, interleukins, interleukin-2 (IL-2), hydroxyurea, thalidomide,
             sargramostim (granulocyte macrophage-colony stimulating factor [GM-CSF]), growth
             factors, dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex,
             polyribonucleoside, or diticarb sodium, coumadin, warfarin, or other Coumadin
             derivative anticoagulants.

          9. Intent to use immunomodulators (e.g., IL-2, IL-12, interferons or TNF modifiers)
             during the course of the study.

         10. Use of systemic corticosteroids or topical steroids over a total area exceeding 15 cm2
             within 30 days prior to screening, or anticipated need for periodic use of
             corticosteroids during the study.

             NOTE: For participants receiving ritonavir or cobicistat, (either as a booster or
             protease inhibitor [PI]) as part of their ART regimen, the concomitant use of
             oral/systemic/topical/inhaled/ intranasal corticosteroids is prohibited.

         11. Use of any prior HIV vaccine (prophylactic and/or therapeutic) or HIV immunotherapy.

             Note: exceptions allowed for antibody therapies per PI review and approval.

             Note: exceptions allowed for IGHID 11627 (UNC IRB 17-0468; NCT 03212989) per PI review
             and approval provided there is greater than 12 months since receipt of study-provided
             treatment.

         12. Any experimental non-HIV vaccination within 1 year prior to screening.

             NOTE: the receipt of an FDA Emergency Use Authorization (EUA) sanctioned COVID-19
             vaccine is not considered exclusionary and should be reviewed with the protocol PI on
             a case-by-case basis.

         13. Prior immunization with a recombinant Adenovirus or MVA vaccine

             Note: Prior immunization with smallpox vaccine is not exclusionary.

             NOTE: This exclusion INCLUDES COVID-19 vaccines with adenovirus vector (i.e., Janssen
             and AstraZeneca).

         14. Live attenuated vaccines received within 60 days prior to screening (i.e., varicella;
             measles, mumps, rubella [MMR]; yellow fever, oral polio, shingles).

             NOTE: Individuals who require vaccination will delay screening for the study until 60
             days after receiving the injection.

         15. History of prior IgG therapy or immunization with any experimental immunogens
             (antibodies) within 6 months of screening.

         16. Use of any investigational treatment within 6 months prior to screening, with the
             exception of Phase II studies of antiretroviral agents.

             NOTE: Co-enrollment with other studies under an IND using an FDA approved medication
             that are not otherwise listed as prohibited will be considered on a case-by-case
             basis.

             NOTE: The receipt of an FDA Emergency Use Authorization (EUA) sanctioned COVID-19
             vaccine or treatment will be reviewed with the protocol PI and will be considered on a
             case-by-case basis.

         17. For any serious illness requiring systemic treatment or hospitalization, the
             participant must either complete therapy or be clinically stable on therapy, in the
             opinion of the site investigator, for at least 90 days prior to screening.

         18. Treatment for an active HIV-related opportunistic infection within 90 days prior to
             screening.

         19. History of malignancy within the last 5 years.

             NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous
             cell skin cancer) is not exclusionary with documentation of topical treatment or of
             complete resection at least 3 months prior to screening).

         20. Immune deficiency other than that caused by HIV infection.

         21. Any medical, psychiatric, occupational or other condition that, in the judgment of the
             investigator, would interfere with, or serve as a contraindication to, protocol
             adherence or assessment of safety.

         22. Hypertension - Exclude for blood pressure consistently > 150 mm Hg systolic and >100
             mm Hg diastolic.

             Note: Elevated BP occurring during research leukapheresis procedures completed within
             the past 12 months are excluded from this requirement. Isolated elevations must be
             noted as acceptable and signed by study PI or designee.

         23. History of auto-immune disease, including Type I diabetes mellitus, with specific
             exception of:

               -  Vitiligo

               -  Resolved childhood atopic dermatitis

               -  Psoriasis (with the exception of psoriatic arthritis) not requiring systemic
                  treatment (within the past 2 years).

               -  Grave's disease with subsequent return to a euthyroid state (clinically and by
                  laboratory testing).

         24. Seizure disorder: History of seizure(w) within the past 3 years. Also exclude if
             participant has used medications in order to prevent or treat seizure(s) at any time
             within the past 3 years.

         25. History of unexplained syncope or fainting episodes within 12 months of study
             screening.

         26. History of Asplenia - absence of normal spleen function as indicated by:

               -  Splenectomy

               -  Sickle cell disease

         27. Bleeding disorder including factor deficiency, coagulopathy or platelet disorder that
             requires special precautions (easy bruising without a formal diagnosis is not
             exclusionary).

         28. Allergy to eggs and/or egg products.

         29. History of anaphylaxis or severe adverse reaction to vaccines including symptoms such
             as hives, respiratory difficulty, angioedema, and/or abdominal pain.

         30. History of hereditary angioedema, acquired angioedema or idiopathic angioedema.

         31. Known or suspected hypersensitivity to any vaccine component.

         32. Unstable asthma (e.g. sudden acute attacks occurring without an obvious trigger) or
             asthma requiring:

               -  Daily steroid or long acting beta-agonist prevention

               -  Hospitalization in the last two years

         33. Depo-provera injection at the site of administration (upper left or right medial
             deltoid muscles) within the 3 months prior to screening, if other deltoid is not an
             option.

         34. History of allergy to latex.

         35. Active chronic skin problems such as eczema or psoriasis.

         36. Known psychiatric or substance abuse disorder/dependence that, in the opinion of the
             site investigator, would interfere with cooperation with the requirements of the
             trial.

         37. Compulsorily detained (involuntarily incarcerated) for treatment of either a
             psychiatric illness or a physical illness, e.g., infectious disease.

         38. Prisoner recruitment and participation is not permitted.

         39. Inability to communicate effectively with study personnel.