Inclusion Criteria
General and Demographic Criteria
1. At least 18 years old at screening and up to 55 years old on day of enrollment.
2. Access to a participating HVTN CRS and willingness to be followed for the planned duration of the study.
3. Demonstrates an understanding of the study and is able and willing to provide informed consent.
4. Agrees not to enroll in another study of an investigational agent during participation in the trial. If a potential participant is already enrolled in another clinical trial, approvals are required prior to enrollment into HVTN 606.
5. In good general health according to the clinical judgment of the site investigator.
6. Physical examination and laboratory results without clinically significant findings that would interfere with assessment of safety or reactogenicity in the clinical judgment of the site investigator.
7. Willing to not donate blood, sperm, or other tissues until after the last required protocol clinic visit.
8. CMV seropositive.
9. Systolic blood pressure of 90 to \< 140 mmHg and diastolic blood pressure of 50 to \< 90 mmHg at screening visit. The average blood pressure between the screening visit and the enrollment visit must be below 140 mmHg systolic and 90 mmHg diastolic. A single measurement ≥ 160 systolic mmHg or 100 mmHg diastolic during the current study evaluation is exclusionary.
10. Male volunteers with partners of pregnancy potential must agree to have their partners use contraception through the end of the study (does not include long-term follow-up).
11. For Part A only: Women who are not of pregnancy potential or male volunteers. Any individual may be enrolled if they are not of pregnancy potential.
12. For Part B only: Women volunteers who are of pregnancy potential must
* Be willing to use an approved method of highly effective contraception from 14 days before enrollment through the end of the study
* Refrain from egg donation and in vitro fertilization from the time of study product administration through the end of the study
* Have negative serum 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 of study product administration. Women who are NOT of pregnancy potential due to having undergone hysterectomy or salpingectomy or tubal ligation or bilateral oophorectomy (verified by medical records) are not required to undergo pregnancy testing.
* Also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit
13. Willingness to receive HIV and TB test results.
14. Hemogram/complete blood count (CBC)
• Hemoglobin: ≥ 11.0 g/dL for women, ≥ 13.0 g/dL for men
Note: If receiving exogenous hormones for more than 6 consecutive months with dosing equivalent to parenteral testosterone ≥1000 mg every 12 weeks or estradiol valerate ≥2 mg/week, determine hemoglobin eligibility based on the exogenous hormone reported.
15. White blood cell count = 2,500 to 12,000 cells/mm3 (WBC over 12,000/mm3 is not exclusionary if further evaluation shows general good health and if approval is granted).
• Platelets = 125,000 to 550,000 cells/mm3.
16. Chemistry panel:
* Alanine aminotransferase (ALT) \< 1.25 × upper limit of institutional reference range
* Aspartate aminotransferase (AST) (\< 1.25 × upper limit of normal (ULN)) based on institutional normal range
* Serum creatinine ≤ 1.1 × ULN based on institutional normal range
* Direct bilirubin levels \< 7.7 mic mol/L (0.45mg/dL) and total bilirubin \< 22.5 mic mol/L (1.3 mg/dL) (volunteers known to have Gilbert's Syndrome with an abnormal total bilirubin are not excluded)
* Gamma-glutamyl transferase (GGT) \< 1.1 × ULN based on institutional normal range
17. Negative HIV-1 and -2 blood test by one of the following options:
* Negative European Conformity (CE)-marked or FDA-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA) or
* Negative results on 2 different brands of HIV rapid tests (one of which must be CE-marked or FDA-approved) Note: For participants with vaccine-induced seropositivity (VISP) from previous HIV vaccine study product(s), a negative result from a HVTN HIV diagnostics testing laboratory within 14 days prior to enrollment.
18. Negative hepatitis B surface antigen (HBsAg).
19. Negative anti-hepatitis C virus antibodies (anti-HCV), or negative HCV nucleic acid test if the anti-HCV is positive.
20. All volunteers must use condoms for the duration of the study . ALL volunteers regardless of sex, reproductive status, or sex of partner(s) must use condoms as a barrier method to mitigate against potential VIR-1778 transmission to their partner(s) (in the event that shedding occurs).
Exclusion criteria
1. Known significant exposure to TB in the 2 years prior to enrollment, as determined by the site investigator based on potential participant report and available medical records.
Note: Significant exposure is defined as close contact with a person who has active TB and has not completed TB treatment. Close contact is defined as sleeping in the same contiguous house/dwelling, and/or working or socializing in close proximity in an enclosed space frequently (eg, several times a week).
2. History of prior active TB disease, as determined by the site investigator based on participant report and available medical, laboratory, or radiographic records.
3. Current anti-TB prophylaxis or therapy.
4. Evidence of active TB disease as determined by the site investigator.
5. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires approval.
6. Pregnant or breastfeeding.
7. Receipt of investigational research agents with a half-life of 7 or fewer days within 4 weeks prior to enrollment. If a potential participant has received investigational agents with a half-life of more than 7 days (or unknown half-life) within the past year, approval is required for enrollment.
8. Use of (val)acyclovir, (val)ganciclovir, letermovir, foscarnet, or another antiviral with anti-CMV activity within 30 days prior to the first vaccination. Chronic or suppressive use of (val)acyclovir is not permitted. Short-term use (defined as less than 10 days) of (val)acyclovir is permitted at standard doses provided there have been no more than 2 courses of (val)acyclovir over the last 6 months. Topical use is not exclusionary.
9. Investigational TB vaccine(s) or CMV-based vaccine received in prior vaccine trials or BCG vaccination outside infancy. For volunteers who have received control/placebo in a TB vaccine trial, eligibility will be determined on a case-by-case basis.
10. Investigational non-TB vaccine(s) or non-CMV vaccine received within the last 1 year in a prior vaccine trial. Exceptions may be made for vaccines that have subsequently undergone licensure by the FDA or by the national regulatory authority where the volunteer is enrolling. For volunteers who have received control/placebo in an experimental vaccine trial, eligibility will be determined on a case-by-case basis. For volunteers who have received an experimental vaccine(s) greater than 1 year ago, eligibility for enrollment will be determined on a case-by-case basis.
11. Receipt of any of the following within 4 weeks prior to enrollment:
* Live replicating vaccine
* Any mRNA-based vaccine with FDA licensure, FDA EUA, or WHO EUL
* ACAM2000 vaccine \> 28 days prior with a vaccination scab still present
12. Receipt of any vaccines that are not covered in the exclusion criterion #10 within 14 days prior to enrollment. Please note this includes replication-incompetent vaccines such as the Jynneos vaccine for the prevention of mpox (formerly known as monkeypox) disease.
13. Initiation of Ag-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiated immunotherapy within the previous year requires PSRT approval.
14. Congenital or acquired immunodeficiency, including systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator, such as glucocorticoid use, ≥ prednisone 10 mg/day within 3 months prior to enrollment.
15. Autoimmune disease, current or history of (not exclusionary: mild, well-controlled psoriasis).
16. Asthma exclusion criteria:
Asthma is exclusionary if the volunteer has ANY of the following:
* Required either oral or parenteral corticosteroids for an exacerbation 2 or more times within the past year; OR
* 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 but sought urgent/emergent care solely for asthma medication refills or coexisting conditions unrelated to asthma); OR
* Uses a short-acting rescue inhaler more than 2 days/week for acute asthma symptoms (ie, not for preventive treatment prior to athletic activity); OR uses medium-to-high-dose inhaled corticosteroids (greater than 250 mcg fluticasone or therapeutic equivalent per day), whether in single-therapy or dual-therapy inhalers (ie, with a long-acting beta agonist \[LABA\]); OR
* Uses more than 1 medication for maintenance therapy daily. Inclusion of anyone on a stable dose of more than 1 medication for maintenance therapy daily for greater than 2 years requires PSRT approval.
17. Asplenia or functional asplenia.
18. Active duty and reserve US military personnel.
19. Any other chronic or clinically significant condition that, in the clinical judgment of the investigator, would jeopardize the safety or rights of the study participant, including but not limited to: clinically significant forms of substance use or alcohol use disorder(s), serious psychiatric disorders, any suicide attempt within the past 1 year (if between 1 and 2 years, eligibility will be considered on a case-by case basis), or cancer that, in the clinical judgment of the site investigator, has potential for recurrence (excluding basal cell carcinoma).
20. Diabetes mellitus (DM) type 1 or type 2. Not exclusionary: Type 2 DM controlled with diet alone (and confirmed by HgbA1c ≤ 8% within the last 6 months) or a history of isolated gestational diabetes are not exclusionary. Enrollment of individuals with type 2 DM that is well controlled on hypoglycemic agent(s) may be considered on a case-by-case basis, provided that the HgbA1c is ≤ 8% within the last 6 months (sites may draw these at screening).
21. Bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions) diagnosed by a clinician, or current therapeutic systemic anticoagulation for any clinical indication. Systemic anticoagulation includes oral anticoagulants (eg, warfarin, dabigatran, rivaroxaban, apixaban, edoxaban), injectable anticoagulants (eg, low-molecular-weight heparin, unfractionated heparin), or other similar prescription anticoagulants. Other conditions previously treated with systemic anticoagulants for any therapeutic (non-prophylactic) indication may be considered on a case-by-case basis.
22. Investigator concern for difficulty with venous access based on clinical history and physical examination. For example, persons with a history of intravenous drug use or substantial difficulty with previous blood draws.
23. Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.
24. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any related vaccine or component of the study-vaccine regimen (eg, Histidine, Trehalose-dihydrate).
25. History of angioedema: Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.
26. History of generalized urticaria within the past year.
27. Have intimate contact with immunocompromised individuals. Intimate contacts are defined as individuals who come into contact with the study participant through sexual relations or mucosal kissing or who share personal items that may be in contact with the participant's body fluids.
28. Have intimate contact with a pregnant partner or a partner planning to become pregnant during the course of the study.
29. Healthcare provider who routinely comes into unmasked contact with immunosuppressed patients or pregnant women.
30. Person with primary caregiving interactions with children less than 2 years of age, as determined by the site investigator.
31. Childcare worker who routinely provides care to children under the age of 2 years old.
