Triplex Vaccine in Preventing CMV Infection in Patients Undergoing Hematopoietic Stem Cell Transplantation

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.