Risk Factors Influencing Humoral Response to COVID 19 Vaccination after Allogeneic Stem Cell Transplantation

Introduction Vaccination against SARS-CoV-2 is approved and strongly recommended in the ongoing pandemic for immunocompromised patients such as patients after allogeneic stem cell transplantation (allo-SCT). EBMT and CDC recommend the vaccination for patients as early as 3 months after allo-SCT in the absence of acute graft versus host disease (GvHD). A humoral response has been demonstrated in 60-95% of healthy adults undergoing vaccination. So far, only few larger cohorts of allogeneic transplanted patients were evaluated for response after vaccination. In most cases patients after allo-SCT were included in larger cohorts of hematological malignancies at high risk for not developing immune reaction after SARS-CoV-2 vaccination. Since infections represent a relevant cause of transplant related mortality and the risk factors impairing the development of an effective humoral response after allo-SCT are not completely defined, we decided to analyze the results of immunization to SARS-CoV-2 vaccination in a multicentric population of allogeneic transplanted patients.

Materials and Methods We retrospectively analyzed data of allo-SCT recipients in two large German transplantation centers for safety and efficacy after two and three (booster) SARS-CoV-2 vaccinations. Patients received mRNA vaccines, like BNT162b2 or mRNA-1273, or the vector-based Vaccines ChAdOx1 and JNJ-78436735. All patients were monitored for antibodies against SARS-CoV2-spike protein (anti-S-IgG) with an IgG ELISA assay or an EIA Assay after two doses of vaccination. Patients who did not develop anti-S-IgG received a third dose and were tested again for anti-S-IgG. Multivariate analysis was calculated using R.

Results Between 03/2021 and 01/2022 a total of 243 allo-SCT patients from two centers in Ulm and Berlin underwent SARS-CoV-2 vaccination. The median age in our cohort was 59 years (range 22-81), 44% of patients were female. Most of the patients had a myeloid disease (75%) and 23% had lymphatic malignancies. The most commonly represented donor type was matched unrelated donor, accounting for 76% of transplantations, followed by matched related donor (22%) and haploidentical donor (2%). Reduced intensity conditioning (RIC) was used in 53% of the cases and a myeloablative conditioning regime (MAC) in 46%. While 83% of patients received two doses of BNT162b2, 10% received ChAdOx1-S and 2% mRNA-1273 respectively. One patient had the JNJ-78436735 vaccine. 5% received a mixed vaccination, mostly ChAdOx1-S followed by a mRNA-vaccine. The two vaccine doses were well tolerated with only 3% patients developing a reactivation of GvHD. No relevant grade 3 or 4 toxicities were observed. Overall, 72% of patients showed a humoral response after two vaccinations. In the multivariate analysis age at time of transplantation (odds ratio [OR] = 0.96, p=0.0065), ongoing immunosuppressive therapy (OR = 0.45, p= 0.029) and lack of immune reconstitution (CD4-T-cell counts <200/µl), (OR = 0.23, p< 0.001) were associated with no response after two vaccine doses, with the latter being the strongest factor for no response. Sex, intensity of conditioning and the use of ATG in the preparing regimen showed no influence on the development of a humoral response after vaccination. We also analyzed the role of the interval between allo-SCT and vaccination, considering different time points (+6, + 12 and + 18 months). No strong association between the time after allo-SCT and the probability to get a specific immune response against SARS-CoV-2 were detected after adjustment for prognostic factors as described above.

Finally, 44 out of 69 patients that did not respond after the second dose received a booster. The interval between the second and third dose was 173 days (median, range 14-285 days) and 56% (25 patients out of 44) showed a seroconversion.

Discussion Patients after allo-SCT represent one of the most vulnerable populations in the current COVID 19- pandemic. Here we report on a large cohort undergoing SARS-CoV-2 vaccination after allo-SCT from two German transplantation centers. We demonstrated that a humoral response could be achieved after the regular approved schedule, especially for those patients who underwent immune reconstitution and were free from immunosuppressive drugs. In over 50% of the initial non-responders after basic vaccination, a seroconversion could be achieved by boostering with a third dose.

Hütter-Krönke:Grifols: Honoraria. Bullinger:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Oncology: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner:AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Syndax: Consultancy, Honoraria; Kronos Bio: Research Funding; Servier: Other: Travel, Accommodations, Expenses; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Sala:Jazz Pharmaceutical: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria; Kite Gilead: Consultancy, Honoraria, Other: Travel Support; Novartis: Honoraria; Takeda: Consultancy.