Adoptive transfer of functional SARS‐COV‐2‐specific immunity from donor graft to hematopoietic stem cell transplant recipients

Abstract

Immunocompromised recipients of allogeneic hematopoietic stem cell transplant (HCT) are at increased risk of severe COVID-19. 1 During the first year of a successful HCT, circulating T-cells arise from donor CD34 + cells and can react to antigens exposed to the donor through natural infection or vaccination before transplantation. Therefore, donor pathogen exposure or vaccination pre-graft can be beneficial to the recipient when mounting cellular and humoral response to augment immune reconstitution and control post-HCT natural infection or increase vaccination responses. 2 Here, we present evidence of transfer and expansion of SARS-CoV-2-specific adaptive immunity from three matched unrelated donors (MUDs), vaccinated with licensed COVID-19 vaccines to unvaccinated and vaccinated recipients. The 10/10 matched (with permissive HLA-DPB1 locus mismatch) MUDs and their recipients did not have COVID-19 history nor developed active infection through study completion (d + 180). All three recipients engrafted and achieved full donor chimerism (>95%) 3 by d + 30.The patient from MUD/R1 pair (Table 1S) was a 29-year-old Hispanic male, with body mass index of 40.07 kg/m 2 , hypertension, diabetes, diagnosed with Philadelphia like B-cell acute lymphoblastic leukemia, with cytokine receptor-like factor 2 rearrangement. The mRNA-1273 vaccinated MUD donor was a 33-year-old male. The recipient underwent a myeloablative HCT soon after CD-19 CAR T-cell therapy, while in second complete remission (CR2) with negative measurable residual disease (MRD), using fractionated total body irradiation with etoposide. He received GVHD prophylaxis of tacrolimus and sirolimus (tacro/siro). He developed grade 1 skin GVHD around d + 24, which resolved with topical therapy. He did not receive a COVID-19 vaccine because prior to HCT, the patient was unstable and not ambulatory.Patient from MUD/R2 pair was a 74-year-old Caucasian male with history of hypertension, diagnosed with acute myeloid leukemia with deletion Y and SRSF2 mutation, who was in CR1 with negative MRD after receiving hypomethylating agent and venetoclax. The BNT162b2 mRNA vaccinated MUD donor was a 30-year-old female.The recipient underwent reduced intensity HCT using fludarabine and melphalan conditioning (FM), with tacro/siro GVHD prophylaxis in combination with itacitinib JAK-1 inhibitor (NCT04339101). He devel-

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

“…Hence, the robust levels of CMV‐specific T cells observed at day +28 during the engraftment period were likely expanded in the donor by Triplex vaccination and transferred with the stem cell graft in the recipients. The concomitant finding of significantly enhanced levels of MVA viral vector‐specific T cells at day +28 in Triplex vaccinated MRD recipients, compared to unvaccinated MRD recipients further supports that T cells, induced in donors by Triplex vaccination could be transferred into the recipients at infusion 29,42 . Studies on durability of immunity after smallpox vaccination showed that vaccinia‐specific antibodies may persist up to 75 years post‐vaccination, whereas T‐cell responses have a half‐life of 8–15 years 55 .…”

“…Emphasis is usually placed on post‐transplant vaccination, but there are data on the efficacy of pretransplant vaccinations, and trials have shown promising results if both recipients and donors receive vaccinations before transplantation 40,41 . Recent evidence supports that immunization of donors and recipients before HCT can significantly enhance immunogenic T and B cell responses and increase response to vaccination post‐HCT 29,42 . However, there is limited availability of long‐term safety data on using vaccination in donors and recommendation for donor vaccination still faces logistical and ethical challenges 43–45 …”

“…40,41 Recent evidence supports that immunization of donors and recipients before HCT can significantly enhance immunogenic T and B cell responses and increase response to vaccination post-HCT. 29,42 However, there is limited availability of long-term safety data on using vaccination in donors and recommendation for donor vaccination still faces logistical and ethical challenges. [43][44][45] In our study population consisting of HCT donors, who were matched siblings or related to the recipients, adherence to the protocol was high, which was essential to ensure the overall success and feasibility of the trial.…”

Allogeneic hematopoietic stem cell transplantation in the COVID-19 era

“…Similar results were reported by Jullien et al (122), with a higher humoral response in the vaccinated-donor group (representing 9 of 17 patients studied). In their study, La Rosa et al (123), reported the transfer of passive cellular and humoral immunity from the donor to the recipient. After a selection of three vaccinated donors (with two of them who probably had asymptomatic COVID-19 based on the presence of anti-N antibodies), they analyzed the transfer of immunity in three recipients, one of whom was not vaccinated prior to transplant.…”

Functional SARS-CoV-2-specific T cells of donor origin in allogeneic stem cell transplant recipients of a T-cell-replete infusion: A prospective observational study

“…It has been shown by us and others that donor B-and T-cell immunity from pathogen exposure or vaccination pre-graft collection can be transferred to the recipient, expanding during immune reconstitution and improving vaccination responses and/ or controlling post-HCT infections (16,17). In recipients with a successful HCT outcome, circulating T cells arise from donor CD34 + cells during the first year post-HCT and can react to antigens exposed to the donor through natural infection or vaccination before transplantation (18,19).…”