Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus‐specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis

Abstract

To enhance protective cytomegalovirus (CMV)‐specific T cells in immunosuppressed recipients of an allogeneic hematopoietic cell transplant (HCT), we evaluated post‐HCT impact of vaccinating healthy HCT donors with Triplex. Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non‐replicating poxvirus derived from the vaccinia virus strain Ankara. It demonstrated tolerability and immunogenicity in healthy adults and HCT recipients, in whom it also reduced CMV reactivation. Here, we report feasibility, safety, and immunological outcomes of a pilot phase 1 trial (NCT03560752 at ClinicalTrials.gov) including 17 CMV‐seropositive recipients who received an HCT from a matched related donor (MRD) vaccinated with 5.1 × 108 pfu/ml of Triplex before cell harvest (median 15, range 11–28 days). Donor and recipient pairs who committed to participation in the trial resulted in exceptional adherence to the protocol. Triplex was well‐tolerated with limited adverse events in donors and recipients, who all engrafted with full donor chimerism. On day 28 post‐HCT, levels of functional vaccinia‐ and CMV‐specific CD137+ CD8+ T cells were significantly higher (p < .0001 and p = .0174, respectively) in recipients of Triplex vaccinated MRD than unvaccinated MRD (control cohort). Predominantly, central and effector memory CMV‐specific T‐cell responses continued to steadily expand through 1‐year follow‐up. CMV viremia requiring antivirals developed in three recipients (18%). In summary, this novel approach represents a promising strategy applicable to different HCT settings for limiting the use of antiviral prophylaxis, which can impair and delay CMV‐specific immunity, leading to CMV reactivation requiring treatment.

Primary, Secondary, and Tertiary Prevention of Congenital Cytomegalovirus Infection

“…The outcome measures generally target T-cell responses, and CMV-specific T-cell antigens are usually included in a viral vector vaccine [84]. Recently, in phase I clinical trials, one of these vaccines (CMV-MVA triplex vaccine of the City of Hope Medical Center) have not only demonstrated a safe profile among HSCT participants treated with the vaccine, but also the ability to elicit robust cytotoxic T lymphocyte (CTL) responses through donor vaccination in CMV-positive recipients [85,101]. Indeed, CMV-specific CD137 + CD8 + T cells were significantly higher (p-value < 0.0001 and p-value = 0.0174, respectively) in recipients who received an HCT from a Triplex-vaccinated matched related donor than an unvaccinated donor (control cohort) [101].…”

“…Recently, in phase I clinical trials, one of these vaccines (CMV-MVA triplex vaccine of the City of Hope Medical Center) have not only demonstrated a safe profile among HSCT participants treated with the vaccine, but also the ability to elicit robust cytotoxic T lymphocyte (CTL) responses through donor vaccination in CMV-positive recipients [85,101]. Indeed, CMV-specific CD137 + CD8 + T cells were significantly higher (p-value < 0.0001 and p-value = 0.0174, respectively) in recipients who received an HCT from a Triplex-vaccinated matched related donor than an unvaccinated donor (control cohort) [101]. The promising results of the cellular and humoral responses obtained in phase I have enabled some of these vaccines to enter phase II clinical trials [85,92].…”

Stimulation of Potent Humoral and Cellular Immunity via Synthetic Dual-Antigen MVA-Based COVID-19 Vaccine COH04S1 in Cancer Patients Post Hematopoietic Cell Transplantation and Cellular Therapy

“…However, it is likely that the majority of allo-HCT recipients were transplanted with a non-naïve donor graft, given that these transplants took place at a time when vaccination rates in the US and Europe reached up to 78% [ 36 ]. Multiple studies have shown that donor natural or vaccine-induced immunity can be transferred to the recipient and boosted via vaccination [ 37 , 38 , 39 ]. How COH04S1 compares to Comirnaty ® in stimulating SARS-CoV-2-specific immunity in this heavily treated, likely non-naïve population is being evaluated in the randomized blinded portion of the trial.…”

Cytomegalovirus-specific T cell immunity reconstitution following allogeneic hematopoietic stem cell transplantation: a pilot stduy

“…Over the past decade, signi cant progresses have been made in understanding the immune control system during CMV exposure following allo-HSCT (22)(23)(24)(25). Earlier studies suggested that the reconstitution of CD4 + T cells precedes and subsequently orchestrates CD8 + T cell reconstitution to provide enhanced protection against CMV disease(26, 27).…”