A Clinical Study to Evaluate the Safety and Immunogenicity of a Higher Dose of the Study Vaccine, VIR-1388, in HCMV-seropositive Adult Participants Without HIV

Inclusion Criteria: 1. At least 18 years old at screening and up to 55 years old on day of enrollment. 2. Access to a participating clinical research site 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. 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. 11. Women who are not of pregnancy potential or male volunteers. Any individual may be enrolled if they are not of pregnancy potential 12. Willingness to receive HIV test results. 13. Hemogram/complete blood count (CBC) Hemoglobin: * ≥ 11.0 g/dL for women * ≥ 13.0 g/dL for men 14. White blood cell (WBC) 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). 15. Platelets = 125,000 to 550,000 cells/mm3. 16. Alanine aminotransferase (ALT) \< 1.25 × upper limit of institutional reference range 17. Aspartate aminotransferase (AST) (\< 1.25 × upper limit of normal (ULN)) based on institutional normal range 18. Alkaline phosphatase (ALP) ≤ 1.1 × ULN based on institutional normal range 19. Serum creatinine ≤ 1.1 × ULN based on institutional normal range 20. Total measured serum calcium level \>8.5 mg/dL. 21. 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) 22. Gamma-glutamyl transferase (GGT) \< 1.1 × ULN based on institutional normal range 23. Negative HIV-1 and -2 blood test 24. Negative hepatitis B surface antigen (HBsAg). 25. Negative anti-hepatitis C virus (HCV) antibodies or negative HCV nucleic acid test if the anti-HCV is positive. 26. 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-1388 transmission to their partner(s) (in the event that shedding occurs). Exclusion Criteria: 1. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires approval. 2. Of pregnancy potential, pregnant, or breastfeeding. 3. 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. 4. 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. 5. Investigational HIV vaccine(s) or CMV-based vaccine received in prior vaccine trials. For volunteers who have received control/placebo in a TB vaccine trial, eligibility will be determined on a case-by-case basis. 6. Investigational vaccine(s) received within the last 1 year in a prior vaccine trial. Exceptions may be considered 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. 7. Receipt of any of the following within 4 weeks prior to enrollment: * Live replicating vaccine * Any mRNA-based vaccine with FDA licensure, FDA Emergency Use Authorization (EUA), or WHO Emergency Use Listing (EUL) * ACAM2000 vaccine \> 28 days prior with a vaccination scab still present 8. Receipt of any vaccines that are not covered in the exclusion criteria #5-7 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. 9. Initiation of antigen-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiated immunotherapy within the previous year requires approval. 10. 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. 11. Autoimmune disease, current or history of (not exclusionary: mild, well controlled psoriasis). 12. 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. Combination inhalers such as LABA + inhaled corticosteroids are considered one medication. Inclusion of anyone on a stable dose of more than 1 medication for maintenance therapy daily for greater than 2 years requires approval. 13. Asplenia or functional asplenia. 14. Active duty and reserve US military personnel. 15. 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, consult for approval), or cancer that, in the clinical judgment of the site investigator, has potential for recurrence (excluding basal cell carcinoma). 16. 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). 17. 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. For other conditions previously treated with systemic anticoagulants for any therapeutic (non-prophylactic) indication, eligibility may be considered on a case-by-case basis. 18. 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. 19. 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. 20. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any related vaccine or component of the study-vaccine regimen (eg, Histidine, Trehalose dihydrate). 21. History of angioedema: Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema. 22. History of generalized urticaria within the past year. 23. 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. In this context, immunocompromised partners are defined as individuals who would have anticipated poor outcomes with a primary CMV infection in the opinion of the site investigator (eg, transplant recipient). 24. Have intimate contact with a pregnant partner or a partner planning to become pregnant during the course of the study. 25. Healthcare provider who routinely comes into unmasked contact with immunosuppressed patients or pregnant women. 26. Person with primary caregiving interactions with children less than 2 years of age, as determined by the site investigator. 27. Childcare worker who routinely provides care to children under the age of 2 years old. 28. A volunteer with a history of a potential immune-mediated medical condition (PIMMC), either active or remote. Specific examples are listed in Appendix F (AESI index). Not exclusionary: (1) remote history of Bell's palsy (\>2 years ago) not associated with other neurologic symptoms; (2) mild psoriasis or other mild, uncomplicated, localized, or dermatologic condition that does not require ongoing systemic treatment; (3) remote history (\>10 years ago) of Kawasaki disease without sequelae; (4) celiac disease well controlled for 6 months with diet only.