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

This is a Phase 1, single site, pilot study to evaluate the safety and immunogenicity of the
M3 and M4 vaccines administered alone or in combination in HIV-infected participants
suppressed on ART.

This is a double blind, randomized, placebo-controlled, parallel design study to evaluate the
safety and immunogenicity of viral-vector, MVA, expressing immunogens, tHIVconsv3 (M3) and
tHIVconsv4 (M4), derived from conserved yet immunogenic regions of HIV-1. The participant
population is HIV-1 infected adults suppressed on ART with plasma HIV-1 RNA <50 copies/mL.

Hypotheses: The administration of M3 or M4 or M3+M4 together will be safe in HIV-1-infected
participants suppressed on ART. The simultaneous administration of M3 with M4 (M3+M4) will
result in both an increase in total magnitude of HIV-1-specific T cell responses and increase
the breadth of T cells targeting conserved regions of HIV-1 compared with either M3 or M4
vaccination alone.

The vaccine and placebo doses will be administered to all participants as an IM
(intramuscular) injection in the deltoid muscle of the non-dominant arm, unless a participant
requests vaccination in their dominant arm. Participants continue their baseline ART regimen
throughout the study. Randomized assignment 8:8:8:3 occurs at Day 0 to one of four arms as
provided below:

Arm 1 - 8 participants - Treatment: M3 - Dose (pfu): 2x10-8 - Route: IM; Arm 2 - 8
participants - Treatment: M4 - Dose (pfu): 2x10-8 - Route: IM; Arm 3 - 8 participants -
Treatment: M3+M4 - Dose (pfu): 1x10-8, each vaccine - Route: IM; Arm 4 - 3 participants -
Treatment: Placebo/saline - Dose: N/A - Route: IM; M3 = MVA.tHIVconsv3; M4 = MVA.tHIVconsv4;
pfu = plaque forming units; IM = intramuscular

The primary safety outcome is the occurrence of at least one ≥ Grade 3 Adverse Event (AE)
including signs/symptoms, lab toxicities, and/or clinical events that are possibly, probably,
or definitely related to study treatment through 28 days following vaccination. The primary
safety analysis will be blinded through Day 28 after the last dose of vaccine/placebo and the
second leukapheresis is completed by the last participant.

Screening, Enrollment, and Leukapheresis. The participant reviews and signs the informed
consent (ICF). Participants meeting eligibility requirements enroll and undergo one
leukapheresis procedure between Day -60 and Day 0. The leukapheresis procedure collects white
blood cells allowing for completion of detailed immunologic and virologic assays with minimal
blood loss. Participants have the option to consent to a lymph node FNA/biopsy; participants
choosing this option will complete the pre-vaccine FNA/biopsy between Day -60 and Day 0 and a
post-vaccine FNA/biopsy between Day 7 and Day 21.

Randomization, Study Treatment, Follow-up Assessment, and Leukapheresis. Randomization occurs
at Day 0 when a randomization identification number (RID) will be assigned. All participants
receive a vaccine or placebo dose as an IM injection. Post vaccination safety assessments
occur via clinical evaluations, and lab testing/evaluations. The study will collect research
assays at designated visits.

At Day 28, all participants will undergo their 2nd leukapheresis. This procedure can be
completed between Day 21 through Day 35. The leukapheresis product will be used for
immunologic and virologic research assays post vaccine/placebo. Participants will be followed
for immunogenicity assessments through Day 70 and safety assessments through Day 168 (Week
24) following the administration of vaccine/placebo at Day 0.

Note: The post-vaccine leukapheresis must be done as close to Day 28 as possible. There may
be a rare situation where the completion of the procedure in the 2-week visit window will not
be possible. As soon as the study coordinator becomes aware of this scenario, the study
coordinator should notify the study PI (or designee) to schedule the procedure outside the
study window, preferably earlier (between Days 14 and 28). If the procedure can only be done
after Day 35, participants should complete the Day 28 visit with collection of a 42.5 mL ACD
sample at that visit.

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 ≤ 45 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 Week 24.

7. Continuous ART prior to screening, defined as not missing more than 4 total days and
never more than 2 consecutive days in the last 3 months.

8. On a stable ART regimen defined as no changes in any ART medication within the 3
months 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 3
months 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).

14. CD4 cell count ≥ 350 cells/mm3, performed at any US laboratory that has a CLIA
certification or its equivalent.

15. No history of auto-immune disease, auto-immune manifestations or chronic inflammatory
conditions including but not limited to inflammatory bowel diseases, scleroderma,
severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus,
rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insufficiency,
autoimmune thyroiditis, hypophysitis, or sarcoidosis.

Note: The following conditions are not exclusionary: vitiligo, resolved childhood
atopic dermatitis, Graves' disease with subsequent return to a euthyroid state
(clinically and by laboratory testing).

16. Hepatitis C (HCV) antibody negative result at screening or, if the participant is HCV
antibody positive, a negative HCV RNA at screening.

17. Hepatitis B surface antigen (HBsAg) negative at screening.

18. Adequate vascular access for leukapheresis.

19. Able and willing to receive IM injections without difficulty.

20. All women must have a negative serum pregnancy test at screening regardless of
reproductive potential.

21. 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

22. 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.

23. 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

24. Agrees not to enroll on another study of an investigational research agent during the
study period.

25. Willingness to defer routine vaccination except for influenza from screening through
28 days after vaccination at Day 0.

26. 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 levels ≥ 1.4
mEq/L; Glucose - Screening serum glucose ≤ Grade 1 (fasting or non-fasting)

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)

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).

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).

12. Any experimental non-HIV vaccination within 1 year prior to screening.

13. Prior immunization with a recombinant Adenovirus or MVA vaccine

14. Prior immunization with small pox vaccine.

15. Live attenuated vaccines received within 60 days prior to screening (i.e., varicella;
measles, mumps, rubella [MMR]; yellow fever, oral polio, shingles).

16. Receipt of other vaccines, excluding influenza vaccine, within the previous 28 days of
screening.

17. History of prior IgG therapy or immunization with any experimental immunogens
(antibodies) within 6 months of screening.

18. 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.

19. 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.

20. Treatment for an active HIV-related opportunistic infection within 90 days prior to
screening.

21. 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 complete resection at
least 3 months prior to enrollment).

22. Immune deficiency other than that caused by HIV infection.

23. 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.

24. Hypertension

- If a person has been found to have elevated blood pressure or hypertension during
screening or previously, exclude for blood pressure that is not well controlled.
Well-controlled blood pressure is defined as consistently ≤ 140 mm Hg systolic
and ≤ 90 mm Hg diastolic, with or without medication, with only isolated, brief
instances of higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg
diastolic. For these participants, blood pressure must be ≤ 140 mm Hg systolic
and ≤ 90 mm Hg diastolic at enrollment.

- If a person has NOT been found to have elevated blood pressure or hypertension
during screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg
at enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment.

Note: Elevated BP occurring during research leukapheresis procedures completed within
the past 12 months are excluded from this requirement. Other isolated incidences of
elevated BP should be reviewed by study PI to determine whether exclusionary. Isolated
elevations must be noted as acceptable and signed by study PI or designee.

25. Seizure disorder or any history of prior seizure.

26. History of unexplained syncope or fainting episodes within 12 months of study
screening.

27. History of Asplenia - absence of normal spleen function as indicated by:

- Splenectomy

- Sickle cell disease

28. Bleeding disorder including factor deficiency, coagulopathy or platelet disorder that
requires special precautions (easy bruising without a formal diagnosis is not
exclusionary).

29. Allergy to eggs and/or egg products.

30. History of anaphylaxis or severe adverse reaction to vaccines including symptoms such
as hives, respiratory difficulty, angioedema, and/or abdominal pain.

31. History of hereditary angioedema, acquired angioedema or idiopathic angioedema.

32. Known or suspected hypersensitivity to any vaccine component.

33. 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

34. Extensive tattoos or depo-provera injection at the site of administration (upper left
or right medial deltoid muscles).

35. History of allergy to latex.

36. Active chronic skin problems such as eczema or psoriasis.

37. 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.

38. Compulsorily detained (involuntarily incarcerated) for treatment of either a
psychiatric illness or a physical illness, e.g., infectious disease.

39. Prisoner recruitment and participation is not permitted.

40. Inability to communicate effectively with study personnel.