Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial

Abstract

Background: Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT).

Objective: To determine the safety and efficacy of Triplex.

Design: First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933).

Setting: 3 U.S. HCT centers.

Participants: 102 CMV-seropositive HCT recipients at high risk for CMV reactivation.

Intervention: Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens.

Measurements: The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection.

Results: A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.

Limitation: The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial.

Conclusion: No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia.

Primary funding source: National Cancer Institute and Helocyte.

Figure 1.. Enrollment and Randomization of Patients.

Details regarding eligibility and exclusion criteria are provided in the Methods. Reasons for patients lost to follow up (boxes after number received 2^nd injection) are detailed in Table S1. COH denotes City of Hope, DFCI The Dana-Farber Cancer Center Institute, MDA The University of Texas MD Anderson Cancer Center, HCT hematopoietic cell transplantation, GVHD graft-versus-host disease.

Figure 2.. Time-to-Event Curves, Acute GVHD (Grade 3-4), Chronic GVHD, and CMV events.

Kaplan-Meier estimates are shown, with censoring times indicated. Note that for severe acute GVHD, half of the events on each arm, hence half of the separation, was for diagnoses made before the first injection on day 28. These events are not included in estimation of the hazard ratio. CI denotes Confidence Interval, GVHD graft-versus-host disease, CMV cytomegalovirus.

Figure 3.

(A) Longitudinal levels of combined pp65-specific CD137⁺CD4⁺ and CD137⁺CD8⁺ T-cells (10⁹/L, logarithms of the concentrations). T-cell concentrations prior to protocol-defined CMV event were used. The band shown was computed using the loess scatterplot smoother providing the marginal geometric mean concentrations through time for each group. A 95% confidence band is shown in gray and individual measurement trajectories are shown for each study subject, up to 7 days prior to reactivation. Logarithmic spacing of both scales is used to aid visualization. (B) Boxplots showing percentages on arcsine scale of pp65-specific CD137⁺CD8⁺ T effector memory re-expressing the RA isoform (TEMRA) post-HCT. Box spans the interquartile range (IQR), the central bar shows median and the whiskers extend to 1.5 times the IQR.