key: cord-0023495-hpdm0wev authors: Maillard, Alexis; Redjoul, Rabah; Klemencie, Marion; Wallet, Hélène Labussière; Le Bourgeois, Amandine; D’Aveni, Maud; Huynh, Anne; Berceanu, Ana; Marchand, Tony; Sylvain, Chantepie; Garcia, Carmen Botella; Loschi, Michael; Joris, Magalie; Castilla-Llorente, Cristina; Thiebaut-Bertrand, Anne; François, Sylvie; Leclerc, Mathieu; Chevallier, Patrice; Nguyen, Stephanie title: Antibody Response after 2 and 3 doses of SARS-CoV-2 mRNA Vaccine in Allogeneic Hematopoietic Cell Transplant Recipients date: 2021-11-26 journal: Blood DOI: 10.1182/blood.2021014232 sha: 5ea4af5af0c28ce6222872d451e08833ad7b782a doc_id: 23495 cord_uid: hpdm0wev nan To the editor 90 The prognosis of COVID-19 infection is poor in allogeneic hematopoietic stem-cell 91 transplant (HSCT) recipients. 1 Immunocompromised patients have been excluded from initial 92 trials evaluating SARS-CoV-2 mRNA vaccines 2,3 and there is a crucial need to assess vaccine 93 efficacy among these patients. In several reports from solid organ transplant (SOT) 94 recipients 4-6 as well as from patients with hematologic malignancies, 7,8 a high proportion 95 mounted a negative antibody response after 2 doses of mRNA vaccine, and a third booster 96 dose improved the response rate. Table S1 and S2). In France, guidelines 110 from the SFGM-TC recommended the vaccination for all allogeneic HSCT recipients, except 111 for patients within 3 months of transplantation or in case of uncontrolled graft-versus-host 112 disease. 15 We excluded patients with a history of COVID-19 confirmed by serology or 113 polymerase chain reaction. All patients had given written consent before transplant for data 114 collection for future research, in accordance with the Declaration of Helsinki. The SFGM-TC 115 scientific council approved this study. 116 117 Patients were mainly male (59%), with a median age of 59 years-old (interquartile range 118 (IQR) 46 to 66), most transplanted for myeloid (69%) or lymphoid (26%) malignancies 119 (Table S3 ). The median delay between the transplantation and the initiation of vaccination 120 was 27 months (IQR 14 to 56) and was <12 months for 144 patients (21%). Donors were 121 HLA-matched unrelated for 51%, HLA-identical sibling for 29% and haplo-identical for 122 20%. Results for 81 patients from one center have been previously partly published. 13,14 123 124 The first two doses of the vaccine (96% with BNT162b2) were administered one month 125 apart. At a median of 33 days after dose 2 (IQR 27-52), an antibody response was detectable 126 in 538 patients (78%, 95CI 75 to 81%) with a median antibody level of 749 binding antibody 127 units per milliliter 16 (BAU/mL) (IQR 250 to 2500). Detectable antibody responses were 128 classified as "weak" (< 250 BAU/mL) in 118 patients (17%) and as "good" (≥ 250 BAU/mL) 129 in 420 (61%), with a threshold of 250 BAU/mL which has been associated to an estimate 130 close to 90% of mRNA-1273 efficacy in the COVE trial 17 (Table S2 ). The serologic response 131 rate increased with time from HSCT (figure S1): 32% (95CI 15 to 50%) within the 6 months 132 from transplantation, 50% (95CI 42 to 61%) between 6 and 12 months and 87% (95CI 84 to 133 89%) after one year. 134 In the multivariate analysis ( Figure 1, Table S4 ), factors associated with the absence of 135 humoral responses were a time-interval from HSCT < 12 months (adjusted Odds-Ratio (aOR) 136 2.7, 95CI 1.6 to 4.6), an absolute lymphocyte count <1G/L (aOR 3.1, 95CI 1.8 to 5.1), 137 systemic immunosuppressive treatments within 3 months of vaccination (aOR 3.4, 95CI 2.1 138 to 5.6), together with the use of rituximab within 6 months (aOR 13.7, 95CI 4.1 to 45.2). In a 139 subsequent multivariate analysis conducted on a subset of 352 patients with available 140 gammaglobulinemia, B-CD19+ and T-CD4+ lymphocytes counts (Table S4) , only low B-141 lymphocytes count (aOR 5.7, 95CI 2.8 to 11.9), time-interval from HSCT < 12 months (aOR 142 4.7, 95CI 2.5 to 13.9) and ongoing immunosuppressive treatments (aOR 2.8, 95CI 1.4 to 5.5) 143 remained independently associated with the absence of antibody response. These risk factors 144 are largely consistent with studies conducted in SOT recipients as well as patients with 145 hematological malignancies, 5-8 and could be used to stratify the risk of negative response 146 among HSCT recipients ( Figure S2 ). In particular, patients receiving immunosuppressive 147 treatments had a 56% serologic response rate (Table S1 ), consistently with reports from SOT 148 recipients (ranging from 36 to 54% after 2 doses). 4-6 As immunodepression decreases with 149 distance from HSCT, we specifically analyzed patients vaccinated within the first year from 150 transplantation (Table S5 and S6). In this subgroup, absolute lymphocyte count <1G/L, use of 151 rituximab as well as history of GVHD necessitating systemic treatment were found to be 152 independently associated with the absence of antibody response. Specifically, within this 153 subgroup no independent association was found with time-interval from HSCT (< 6 months 154 versus 6 to 12 months) in multivariate analysis, although our study is likely underpowered to 155 assess this point. 156 157 A systematic third dose was not recommended during the study period and remained at the 158 discretion of the attending physician. In this cohort, 181 allogeneic HSCT recipients received 159 a third dose of mRNA vaccine at a median of 54 days after dose 2, with a subsequent semi-160 quantitative anti-spike serological testing (Figure 2, Table S5 ). Among 70 patients with no 161 prior detectable response (Table S6) Alexis Maillard designed and performed the 200 statistical analyses. All authors participated in data collection Nguyen wrote the first draft of the manuscript. All authors revised and approved the final 202 manuscript. The corresponding author attests that all listed authors meet authorship criteria We thank Nicole Raus for her help in data collection and data management COVID-19 and stem cell transplantation; 221 results from an EBMT and GETH multicenter prospective survey Efficacy and Safety of the mRNA-1273 SARS-223 CoV-2 Vaccine Safety and Efficacy of the BNT162b2 mRNA 225 Covid-19 Vaccine Three Doses of an 227 mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients Antibody Response to 2-Dose SARS-CoV-2 230 mRNA Vaccine Series in Solid Organ Transplant Recipients Antibody response to SARS-CoV-2 mRNA vaccine 232 among kidney transplant recipients: a prospective cohort study Immunogenicity of the BNT162b2 235 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological 236 malignancies in Lithuania: a national prospective cohort study Efficacy of the BNT162b2 mRNA COVID-19 239 vaccine in patients with chronic lymphocytic leukemia Efficiency of a boost with a third dose of anti-241 SARS-CoV-2 messenger RNA-based vaccines in solid organ transplant recipients Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients Antibody Response After a Third Dose of the 246 mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal 247 Serologic Response to 2 Doses Precisions sur la vaccination COVID-19 : modalites d'administration 250 des rappels et vaccination des personnes immunodeprimes et de leurs proches Antibody response after second 255 BNT162b2 dose in allogeneic HSCT recipients Antibody response after third 257 BNT162b2 dose in recipients of allogeneic HSCT. The Lancet Haematology 2021 Recommandations de la SFGM-TC Stratégie de 260 vaccination pour les patients recevant une allogreffe de cellules souches hématopoïétiques WHO International Standard for anti-SARS-263 CoV-2 immunoglobulin Immune Correlates Analysis of the 265 mRNA-1273 COVID-19 Vaccine Efficacy Trial Correlates of protection against symptomatic and 267 asymptomatic SARS-CoV-2 infection Immune correlates of protection by mRNA-1273 269 vaccine against SARS-CoV-2 in nonhuman primates Association of SARS-CoV-2 Seropositive 272 Antibody Test With Risk of Future Infection Neutralizing antibody levels are highly 274 predictive of immune protection from symptomatic SARS-CoV-2 infection None of the authors has a relevant conflict of interest.