Evaluating the Safety and Immunogenicity of MTBVAC in Adolescents and Adults Living With and Without HIV in South Africa

Inclusion Criteria:

• Age of 12 through 55 years, on the day of enrollment.

• Access to a participating HVTN or ACTG CRS and willingness to be followed for theplanned duration of the study.

• For volunteers 18 years of age or older: ability and willingness to provide informedconsent.

• For volunteers less than 18 years of age: parent or legal guardian is willing andable to provide informed consent for potential participant's study participation; inaddition, when applicable per ethics committee policies and procedures, potentialparticipant is willing and able to provide written assent for study participation.

• Assessment of Understanding (AoU): volunteer demonstrates understanding of thisstudy and completes a questionnaire prior to vaccination with verbal demonstrationof understanding of all questionnaire items answered incorrectly.

• Prior receipt of BCG vaccine in infancy as determined by the site investigator.

• Agrees not to enroll in another study of an investigational study product untilafter the last scheduled clinic visit. If a potential participant is alreadyenrolled in another clinical trial, approvals from the other trial sponsor and theHVTN 605/A5421 PSRT are required prior to enrollment into HVTN 605/A5421.

• Good general health as shown by medical history, physical exam, and screeninglaboratory tests and assessed by the site investigator.

• Willingness to receive HIV-related test results.

• For volunteers living without HIV:

1. Negative HIV-1 and -2 blood test: Non-US sites may use locally available assaysthat have been approved by HVTN Laboratory Operations

2. Assessed by the clinic staff as having a low likelihood of acquiring HIV and iscommitted to maintaining behavior that is consistent with a lower likelihood ofacquiring HIV through the last required protocol clinic visit

3. Willingness to discuss their potential for HIV acquisition and is amenable toHIV risk reduction counseling

• For volunteers living with HIV:

1. For both Cohorts 2 and 3: Completed one course of tuberculosis preventivetreatment (TPT) as determined by the site investigator.Documented HIV viral suppression (Plasma HIV levels < 50 copies/mL) collectedat least three months and up to 15 months prior to enrollment (with nointervening HIV-1 RNA results ≥ 50 copies/mL) and from screening labs.Has been receiving at least 6 months of ART prior to enrollment, as determinedby the site investigator

2. For Cohort 2: WHO HIV clinical stage 1 or 2 prior to initiation (orre-initiation in case of treatment interruption/default) of ART.

CD4+ T-cell count of ≥ 200 cells/mm3 (during screening) 3. For Cohort 3: Advanced HIV disease (defined as CD4 count less than 200 cells/mm3 or WHO HIV clinical stage 3 or 4) prior to initiation (or re-initiation) of ART. Advanced HIV defined as CD4 count less than 200 cells/mm3 or WHO stage 3 or 4. Current CD4+ T-cell count of ≥ 100 cells/ mm3 (during screening)

• Laboratory Inclusion Values - Has normal or Grade 1 results of all of the followingat screening:

Hemoglobin (≥ 9.5 g/dL or ≥ 5.88 mmol/L for males and females less than 13 years of age; ≥ 9.5 g/dL or ≥ 5.88 mmol/L for females 13 years of age and older; ≥ 10.0 g/dL or ≥ 6.19 mmol/L for males 13 years of age and older); White blood cell count (≥ 2000 cells/mm3 or ≥ 2.000 × 109 cells/L); Platelet count (≥ 100,000 cells/mm3 or ≥ 100.000 × 109 cells/L); Creatinine (≤ 1.3 × upper limit of normal [ULN]); Alanine aminotransferase (ALT) (< 2.5 × ULN); Aspartate aminotransferase (AST) (< 2.5 × ULN)

• Negative Hepatitis B surface antigen (HBsAg).

• Negative anti-Hepatitis C virus Abs (anti-HCV), or negative HCV nucleic acid test ifthe anti-HCV is positive

• For volunteers assigned female sex at birth (AFAB) or intersex at birth and are ofreproductive potential (hereafter referred to as "of pregnancy potential"): negativeserum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test at screening (ie, prior to randomization) and prior to study product administration on the day ofstudy product administration. Persons who are NOT of pregnancy potential includinghaving reached menopause (no menses for 1 year) or having undergone hysterectomy orbilateral oophorectomy, or tubal ligation (verified by medical records) are notrequired to undergo pregnancy testing.

• Reproductive status: A volunteer of pregnancy potential:

1. Must agree to use effective contraception for sexual activity that could leadto pregnancy from at least 21 days prior to enrollment until 10 weeks aftervaccination.

2. Volunteers of pregnancy potential must also agree not to seek pregnancy throughalternative methods, such as artificial insemination, or in vitro fertilizationuntil 10 weeks after vaccination.

3. Volunteers of pregnancy potential must also agree not to undergo oocyteretrieval.

Exclusion Criteria:

• Weight less than 40 kg

• Known significant exposure to TB or receipt of tuberculin skin test in the sixmonths prior enrollment, as determined by the site investigator based on potentialparticipant/parent/guardian report and available medical records. [Note: Significantexposure is defined as close contact with a person who has active TB and has notcompleted TB treatment. Close contact is defined as sleeping in the same contiguoushouse/dwelling, and/or working or socializing in close proximity in an enclosedspace frequently (eg, several times a week).]

• History of prior active TB disease, as determined by the site investigator based onparticipant/parent/guardian report and available medical, laboratory or radiographicrecords.

• Evidence of active TB disease as determined by the site investigator based onparticipant/parent/guardian report and available medical records, results fromphysical examination, two-view chest X-ray, and M.tb nucleic acid testing from anexpectorated sputum, including a review of any available radiography; and, forvolunteers living with HIV and a CD4 count <200 cells/mm3, a positive urine LAMtest.

• Receipt of TB preventive therapy within 28 days prior to enrollment or expected toinitiate TB preventive therapy during the study as determined by the siteinvestigator based on participant/parent/guardian report and available medicalrecords Note: Clinical indication for receipt of TB preventive therapy will bedetermined by the site investigator consistent with local standard guidelines.Potential participants on TB preventive therapy during screening may be enrolledonce the exclusionary timeframes indicated above have elapsed. If the screeningperiod is exceeded while this requirement is being met, a new screening attemptshould be initiated.

• For volunteers living with HIV: current active AIDS-defining condition as determinedby the site investigator based on participant/parent/guardian report and availablemedical records

• Blood products received within 120 days before vaccination.

• Investigational study products (non-vaccine) received within 28 days beforevaccination.

• Pregnant or breastfeeding.

• Investigational TB vaccine(s) received in a prior TB vaccine trial or BCGvaccination outside infancy. For volunteers who have received control/placebo in aTB vaccine trial, the HVTN 605/A5421 PSRT will determine eligibility on acase-by-case basis.

• Investigational non-TB vaccine(s) received within the last 1 year in a prior vaccinetrial. Exceptions may be made by the HVTN 605/A5421 PSRT for vaccines that havesubsequently undergone licensure by the FDA or by the national regulatory authoritywhere the volunteer is enrolling. For volunteers who have received control/placeboin an experimental vaccine trial, the HVTN 605/A5421 PSRT will determine eligibilityon a case-by-case basis. For volunteers who have received an experimental vaccine(s)greater than 1 years ago, eligibility for enrollment will be determined by the HVTN 605/A5421 PSRT on a case-by-case basis.

• Live attenuated vaccines received within 28 days before first vaccination orscheduled within 28 days after injection (eg, measles, mumps, and rubella [MMR];oral polio vaccine [OPV]; varicella; yellow fever; live attenuated influenzavaccine).

• Any vaccines that are not live attenuated vaccines and were received within 14 daysprior to first vaccination (eg, tetanus, pneumococcal, Hepatitis A or B).

• Allergy treatment with antigen injections within 28 days before first vaccination orthat are scheduled within 14 days after first vaccination.

• Immunosuppressive medications received within 168 days before first vaccination (Notexclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3]topical corticosteroids for mild, uncomplicated dermatologic condition; or [4] asingle course of oral/parenteral prednisone or equivalent at doses < 60 mg/day andlength of therapy < 11 days with completion at least 30 days prior to enrollment).

• Serious adverse reactions to vaccines or to vaccine components including history ofanaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema,and/or abdominal pain. (Not excluded from participation: a volunteer who had anon-anaphylactic adverse reaction to pertussis vaccine as a child).

• Immunoglobulin received within 90 days before vaccination.

• Autoimmune disease, current or history (Not exclusionary: mild, well-controlledpsoriasis)

• Immunodeficiency (Not exclusionary: HIV).

• Clinically significant medical condition, physical examination findings, clinicallysignificant abnormal laboratory results, or past medical history with clinicallysignificant implications for current health. A clinically significant condition orprocess includes but is not limited to:

1. A process that would affect the immune response,

2. A process that would require medication that affects the immune response,

3. Any contraindication to repeated injections or blood draws,

4. A condition that requires active medical intervention or monitoring to avertgrave danger to the volunteer's health or well-being during the study period,

5. A condition or process for which signs or symptoms could be confused withreactions to vaccine, or

6. Any condition specifically listed among the exclusion criteria below.

• Any medical, psychiatric, occupational, or other condition that, in the judgment ofthe investigator, would interfere with, or serve as a contraindication to, protocoladherence, assessment of safety or reactogenicity, or a volunteer's ability to giveinformed consent, including but not limited to clinically significant substance oralcohol use disorder.

• Psychiatric condition that precludes compliance with the protocol. Specificallyexcluded are persons with psychoses within the past 3 years, ongoing risk forsuicide, or history of suicide attempt or gesture within the past 3 years.

• Asthma exclusion criteria:

Asthma is exclusionary if the participant has ANY of the following:

1. Required either oral or parenteral corticosteroids for an exacerbation 2 or moretimes within the past year; OR 2. Needed emergency care, urgent care,hospitalization, or intubation for an acute asthma exacerbation within the past year (eg, would NOT exclude individuals with asthma who meet all other criteria butsought urgent/emergent care solely for asthma medication refills or coexistingconditions unrelated to asthma); OR 3. Uses a short-acting rescue inhaler more than 2 days/week for acute asthma symptoms (ie, not for preventive treatment prior toathletic activity); OR 4. Uses medium-to-high-dose inhaled corticosteroids (greaterthan 250 mcg fluticasone or therapeutic equivalent per day), whether insingle-therapy or dual-therapy inhalers (ie, with a long-acting beta agonist [LABA]); OR Uses more than 1 medication for maintenance therapy daily. Inclusion ofanyone on a stable dose of more than 1 medication for maintenance therapy daily forgreater than 2 years requires PSRT approval.

• Diabetes mellitus type 1 or type 2. (Not exclusionary: type 2 cases controlled withdiet alone or a history of isolated gestational diabetes. For these cases, controlshould be confirmed with an appropriate laboratory test (eg, fasting glucose, HbA1c)based on a specimen collected during screening.)

• Hypertension:

1. If a person has been found to have elevated blood pressure or hypertensionduring screening or previously, exclude for blood pressure that is not wellcontrolled. Well-controlled blood pressure is defined in this protocol asconsistently < 140 mm Hg systolic and < 90 mm Hg diastolic, with or withoutmedication, with only isolated, brief instances of higher readings, which mustbe ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these volunteers, bloodpressure must be < 140 mm Hg systolic and < 90 mm Hg diastolic at enrollment.

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

• Bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorderrequiring special precautions)

• Malignancy (Not excluded from participation: Volunteer who has had malignancyexcised surgically and who, in the investigator's estimation, has a reasonableassurance of sustained cure, or who is unlikely to experience recurrence ofmalignancy during the period of the study).

• Seizure disorder: History of seizure(s) within past three years. Also exclude ifvolunteer has used medications in order to prevent or treat seizure(s) at any timewithin the past 3 years.

• Asplenia: any condition resulting in the absence of a functional spleen.

• History of angioedema or anaphylaxis (Not exclusionary: angioedema or anaphylaxiswith known trigger and no episodes within five years.)

• History of generalized urticaria within past five years.