Triplex, a modified version of the recombinant attenuated poxvirus vaccine engineered to induce a virus-specific T-cell response to control cytomegalovirus (CMV) in recipients of allogeneic hematopoietic stem cell transplant (HSCT), was safe and well tolerated with no significant difference in adverse events between the vaccine and placebo groups, according to study results published in the Annals of Internal Medicine.1

In this prospective, double-blind, first-in-patient phase 2 trial (ClinicalTrials.gov identifier: NCT02506933) conducted at 3 cancer centers in the United States that specialize in allogeneic HSCT, researchers randomly assigned CMV-seropositive HSCT receipts at high risk for CMV reactivation in a 1:1 ratio to the Triplex or placebo group. Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HSCT. Patients were clinically and immunologically monitored for roughly 1 year after HSCT.

The primary efficacy outcome was CMV events to day 100, defined as CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease. The 3 primary safety outcomes were nonrelapse mortality by day 100, severe (grade 3 or 4) graft-vs-host disease (GVHD), and grade 3 or 4 adverse events within 2 weeks after vaccination that were probably or definitely attributable to injection.

The study was designed to have 90% power to detect a reduction in CMV events in the vaccine group at a 1-sided significance level of 0.10, deemed appropriate for an initial phase 2 study.

Of the 102 patients in the study cohort, 46 of the 51 patients assigned to the Triplex group (90%) and 45 of those in the placebo group (88%) received the second injection on day 56. The primary outcome occurred in 5 patients in the Triplex group (9.8%) and 10 in the placebo group (19.6%). The hazard ratio for CMV events by day 100 after HSCT was 0.46 (95% CI, 0.16-1.4; 1-sided P =.075).

No patient in the Triplex group died of nonrelapse causes during the first 100 days. Results also demonstrated that the risk for a CMV-related event in the first 100 days post-transplantation was halved in patients who received the Triplex vaccine. Incidence of severe GVHD after injection was similar between groups (hazard ratio, 1.1; 95% CI, 0.53-2.4; P =.23).

In addition, patients in the Triplex group had no serious adverse events or grade 3 or 4 adverse events that were probably or definitely related to vaccination within 2 weeks after the first or second injection.

Results of the immunogenicity analysis showed immune reconstitution of functionally activated CD137+ CD4+, and CD137+ CD8+ pp65-specific T cells to be significantly enhanced in the Triplex group through day 100, as well as 1 year after HSCT. Levels of CD137+ CD4+ and CD8+ IE1- and IE2-specific T cells did not significantly differ between groups.

A post hoc multivariate analysis of risk factors for CMV events over the full year of follow-up showed significant risk for a CMV event when GVHD occurred and prednisone was administered (hazard ratio, 12; 95% CI, 4.9-31; P <.001).

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The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial. In addition, the viremia threshold (CMV DNA level ≥1250 IU/mL) recommended by the lead institution for preemptive therapy initiation was not uniformly followed by the other sites.

“Triplex is currently the subject of multiple ongoing and planned studies, including one involving vaccination of the donor (followed by the recipient) in higher-risk stem cell transplant patients, potentially introducing CMV immunity sooner and positioning Triplex ahead of prophylactic antivirals in the standard of care,” according to the company website.2

Disclosure: This study was in part funded by Helocyte. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

References

1. Aldoss I, La Rosa C, Baden LR, et al; TRIPLEX VACCINE Study Group. Poxvirus vectored cytomegalovirus vaccine to prevent cytomegalovirus viremia in transplant recipients: a phase 2, randomized clinical trial [published online February 11, 2020]. Ann Intern Med. doi:10.7326/M19-2511

2. Triplex. Helocyte. http://helocyte.com/development-pipeline/triplex/ Accessed February 18, 2020.