This phase II trial studies how well Triplex vaccine works in preventing cytomegalovirus (CMV) infection in patients undergoing a hematopoietic stem cell transplantation. CMV is a virus that may be carried for life and does not cause illness in most healthy individuals. However, in people whose immune systems are lowered (such as those undergoing stem cell transplantation), CMV can reproduce and cause disease and even death. The Triplex vaccine is made up of 3 small pieces of CMV deoxyribonucleic acid (DNA) (the chemical form of genes) placed into a weakened virus called modified vaccinia Ankara (MVA) that may help produce immunity (the ability to recognize and respond to an infection) and reduce the risk of developing complications related to CMV infection.

PRIMARY OBJECTIVE:

I. To determine if CMV-MVA multi-peptide CMV-modified vaccinia Ankara vaccine (Triplex) reduces the frequency of clinically significant CMV reactivation in CMV positive (+) haploidentical hematopoietic cell transplantation (haploHCT) adult recipients from when letermovir (Prevymis) prophylaxis is stopped at day (d)100 until d180 post HCT.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of Triplex in vaccinated, haploHCT recipients by assessing the following: non-relapse mortality (NRM) at d180 post-HCT, severe (grade 3-4) acute graft versus host disease (GVHD), and grade 3-4 adverse events (AEs) (Common Terminology Criteria for Adverse Events [CTCAE] 5.0) probably or definitely related to the vaccination within 2 weeks from each vaccination at d180 post-HCT.

II. To characterize CMV related events in recipients of Triplex compared to placebo, by assessing time-to viremia (number of days from d100 to the date of >= 625 IU/mL), duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (>= 625 IU/mL, > 200 and =< 365 days post-HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative number of CMV specific antiviral treatment days.

III. To evaluate the impact of Triplex on transplant related outcomes up to d365 post-HCT by assessing the incidence of acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, non-relapse mortality, all-cause mortality, infections.

IV. To determine if Triplex increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated, CMV seropositive HCT-recipients.

V. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells.

VI. To compare GVHD biomarkers between the vaccine and placebo groups up to d365 post-HCT.

VII. To determine if immunity to 3 CMV antigens contained in the Triplex vaccine correlates with protection against CMV events, and if T-cell increases reflect vaccine response and exceed placebo immune response levels up to d365 post-HCT.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive letermovir per standard of care (SOC) on days 7-100 and multi-peptide CMV-modified vaccinia Ankara vaccine intramuscularly (IM) on days 100 and 128 post-HCT.

ARM II: Patients receive letermovir per SOC on days 7-100 and placebo IM on days 100 and 128 post-HCT.

After completion of study treatment, patients are followed up to 365 days post-HCT and then for an additional 2 years post-HCT.

Inclusion Criteria:

• All subjects must have the ability to understand and the willingness to sign a written informed consent

• Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT

• Planned peripheral blood stem cell (PBSC) or bone marrow (BM) HCT for the treatment of the following hematologic malignancies:

  • Lymphoma (Hodgkin and non-Hodgkin)

  • Myelodysplastic syndrome

  • Acute lymphoblastic leukemia in first or second remission (for acute lymphoblastic leukemia/lymphoblastic lymphoma, the disease status must be in hematologic remission by bone marrow and peripheral blood. Persistent lymphadenopathy on computed tomography [CT] or CT/positron emission tomography [PET] scan without progression is allowed.)

  • Acute myeloid leukemia in first or second remission

  • Chronic myelogenous leukemia in first chronic or accelerated phase, or in second chronic phase

  • Other hematologic malignancies judged appropriate by the clinical principal investigators (PIs), including chronic lymphocytic leukemia, myeloproliferative disorders and myelofibrosis. Patients with multiple myeloma and those with non-malignant disease such as aplastic anemia are excluded

    • Adult cases of multiple myeloma (MM) are excluded as HCT is not standard of care for MM, and is only performed in very advanced cases with an associated high risk of relapse and NRM. Adults with aplastic anemia are excluded because their standard management includes T cell depletion with agents such as anti-thymocyte globulin (ATG), which is not permissible on this protocol. Patients undergoing a second haploHCT are not eligible (patients who have undergone a previous autologous HCT are eligible)

• Patients receiving myeloablative (MA) or reduced intensity conditioning (RIC) are allowed

• CMV seropositive (recipient)

• Planned related HCT with molecular 3/6 (haploidentical) intermediate/high resolution HLA donor allele matching

• Planned HCT with minimal to no-T cell depletion of graft

• Conditioning and immunosuppressive regimens according to institutional guidelines are permitted

• Negative serum or urine beta human chorionic gonadotropin (HCG) test (female patient of childbearing potential only) within two weeks of registration

• Seronegative for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and active hepatitis B virus (HBV) (surface antigen negative) within 2 months of registration and no history of disseminated cutaneous human papillomavirus (HPV) related disease

• Agreement by females of childbearing potential and sexually active males to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for up to d90 post-HCT. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

Exclusion Criteria:

• Any prior investigational CMV vaccine
• Experimental anti-CMV chemotherapy in the last 6 months
• Live attenuated vaccines (from the time of HCT to d70 post-HCT)
• Medically indicated subunit (Engerix-B for HBV; Gardasil for HPV) or killed vaccines (e.g. influenza, pneumococcal, or allergy treatment with antigen injections) (from the time of HCT to d70 post-HCT)
• Allergy treatment with antigen injections (from the time of HCT to d70 post-HCT)
• Alemtuzumab or any equivalent in vivo T-cell depleting agent (or CD34+ selection) (from the time of HCT to d70 post-HCT)
• Antiviral medications with known therapeutic effects on CMV such as ganciclovir (GCV)/valganciclovir (VAL), foscarnet (FOS), cidofovir, CMX-001, maribavir. Acyclovir has no known therapeutic efficacy against CMV and is allowable as standard of care to prevent herpes simplex virus (HSV) (from the time of HCT to d70 post-HCT)
• Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment EXCEPT Prevymis prophylaxis (prior to d100) (from the time of HCT to d70 post-HCT)
• Conditioning regimens d30 prior to trial participation and up to d180 post-HCT
• Disease-based radiation therapy (not total body irradiation) (from the time of HCT to d70 post-HCT)
• Other investigational product - concurrent enrollment in other clinical trials using any investigational new drugs (IND) with unknown effects on CMV or with unknown toxicity profiles is prohibited (from the time of HCT to d70 post-HCT)
• Other medications that might interfere with the evaluation of the investigational product (from the time of HCT to d70 post-HCT)
• Patients with active autoimmune conditions requiring systemic immunosuppressive therapy within the previous 5 years are not eligible
• Patients considered by PIs/protocol team to have a complicated prior therapy or HCT regimen, or who have a low survival probability (e.g., refractory leukemia and/or undergoing 2nd HCT)
• Poor risk disease/disease status including: chronic myeloid leukemia (CML) in blast crisis, acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) beyond 2nd remission, multiple myeloma, and aplastic anemia
• Pregnant women and women who are lactating. Triplex risks to pregnant women are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the administered vaccine, also breastfeeding should be discontinued if the mother is enrolled on this study
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., social/ psychological issues, etc.
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)