Serologic response and safety of COVID-19 vaccination in HSCT or CAR T-cell recipients: a systematic review and meta-analysis

Experimental Hematology & Oncology
Chenghao Ge1, Kelei Du2, Mingjie Luo2, Kaini Shen3, Yangzhong Zhou4, Ke Guo2, Yang Liu1, Cong Yin1, Yang Li1, Guanqiao Li5, Xiaoyuan Chen6
1Tsinghua Clinical Research Institute, School of Medicine, Tsinghua University, Beijing, China
2School of Medicine, Tsinghua University, Beijing, China
3Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
4Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
5Vanke School of Public Health, Tsinghua University, Beijing, China
6Office of Clinical Trial Institute, Beijing Tsinghua Changgung Hospital, Beijing, China

Tóm tắt

Abstract Background Patients receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR T-cell) therapy are immunocompromised and at high risk of viral infection, including SAR2-CoV-2 infection. However, the effectiveness and safety of COVID-19 vaccines in these recipients is not well characterized. The present meta-analysis evaluated the serologic response and safety of COVID-19 vaccines in these population. Methods Literature databases (MEDLINE, EMBASE, Web of Science, MedRvix and BioRvix) were searched for original studies with serologic response post COVID-19 vaccination in HSCT or CAR T-cell recipients published until July 14, 2022. The analysis included 27 observational studies with a total of 2899 patients receiving allogeneic HSCT (2506), autologous HSCT (286) or CAR T-cell therapy (107), and 683 healthy participants with serologic response data. Random effects models were used to pool the rate of serologic response to COVID-19 vaccination in HSCT or CAR T-cell recipients and odds ratio comparing with healthy controls. Results The pooled seropositivity rates in HSCT and CAR T-cell recipients were 0.624 [0.506–0.729] for one dose, 0.745 [0.712–0.776] for two doses. The rates were significantly lower than those in healthy controls (nearly 100%). In subgroup analysis, CAR T-cell recipients exhibited an even lower seroconversion rate (one dose: 0.204 [0.094–0.386]; two doses: 0.277 [0.190–0.386]) than HSCT counterparts (one dose: 0.779 [0.666–0.862]; two doses: 0.793 [0.762–0.821]). The rates were comparable between autologous and allogeneic HSCT recipients. Other possible impact factors related to seropositivity were time interval between therapy and vaccination, use of immunosuppressive drugs and immune cell counts. Most vaccine-related adverse effects were mild and resolvable, comparable to general population. Conclusions This analysis revealed a diminished response to COVID-19 vaccines in HSCT or CAR T-cell recipients. Our findings may inform regular COVID-19 vaccination at appropriate intervals after HSCT or CAR T-cell therapy.

Từ khóa


Tài liệu tham khảo

World Health Organization. 2022. https://covid19.who.int/. Accessed 15 July 2022.

Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med. 2021;384(15):1412–23. https://doi.org/10.1056/NEJMoa2101765.

CDC Expands Eligibility for COVID-19 Booster Shots to All Adults. https://www.cdc.gov/media/releases/2021/s1119-booster-shots.html. Accessed 01 Apr 2022.

Lopez Bernal J, Andrews N, Gower C, Robertson C, Stowe J, Tessier E, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ (Clinical research ed). 2021;373: n1088. https://doi.org/10.1136/bmj.n1088.

Haas EJ, Angulo FJ, McLaughlin JM, Anis E, Singer SR, Khan F, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet (London, England). 2021;397(10287):1819–29. https://doi.org/10.1016/s0140-6736(21)00947-8.

Voysey M, Costa Clemens SA, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet (London, England). 2021;397(10277):881–91. https://doi.org/10.1016/s0140-6736(21)00432-3.

LABEL: PFIZER-BIONTECH COVID-19 VACCINE- bnt162b2 injection, suspension. https://www.dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=908ecbe7-2f1b-42dd-94bf-f917ec3c5af8 Accessed 01 Apr 2022.

Holstein SA, Lunning MA. CAR T-cell therapy in hematologic malignancies: a voyage in progress. Clin Pharmacol Ther. 2020;107(1):112–22. https://doi.org/10.1002/cpt.1674.

Larson RC, Maus MV. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 2021;21(3):145–61. https://doi.org/10.1038/s41568-020-00323-z.

Eaves CJ. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood. 2015;125(17):2605–13. https://doi.org/10.1182/blood-2014-12-570200.

Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D, et al. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020;55(2):283–306. https://doi.org/10.1038/s41409-019-0684-0.

Barriga F, Ramírez P, Wietstruck A, Rojas N. Hematopoietic stem cell transplantation: clinical use and perspectives. Biol Res. 2012;45(3):307–16. https://doi.org/10.4067/s0716-97602012000300012.

Gyurkocza B, Lazarus HM, Giralt S. Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy. Bone Marrow Transplant. 2017;52(8):1083–90. https://doi.org/10.1038/bmt.2017.8.

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. https://doi.org/10.1126/scitranslmed.3005930.

Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–37. https://doi.org/10.1056/NEJMoa1817226.

Bupha-Intr O, Haeusler G, Chee L, Thursky K, Slavin M, Teh B. CAR-T cell therapy and infection: a review. Expert Rev Anti Infect Ther. 2021;19(6):749–58. https://doi.org/10.1080/14787210.2021.1855143.

Peinemann F, Smith LA, Kromp M, Bartel C, Kröger N, Kulig M. Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas. Cochrane database Syst Rev. 2013. https://doi.org/10.1002/14651858.CD008216.pub3.

Sharma A, Bhatt NS, St Martin A, Abid MB, Bloomquist J, Chemaly RF, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185–93. https://doi.org/10.1016/s2352-3026(20)30429-4.

Spanjaart AM, Ljungman P, de La Camara R, Tridello G, Ortiz-Maldonado V, Urbano-Ispizua A, et al. Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell malignancies: results of a multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group. Leukemia. 2021;35(12):3585–8. https://doi.org/10.1038/s41375-021-01466-0.

Borek AJ, Maitland K, McLeod M, Campbell A, Hayhoe B, Butler CC, et al. Impact of the COVID-19 pandemic on community antibiotic prescribing and stewardship: a qualitative interview study with general practitioners in England. medRxiv. 2021. https://doi.org/10.1101/2021.11.19.21266529.

EBMT: COVID-19 vaccines. Version 8. https://www.ebmt.org/covid-19-and-bmt Accessed 01 Mar 2022.

Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355: i4919. https://doi.org/10.1136/bmj.i4919.

Matkowska-Kocjan A, Owoc-Lempach J, Chruszcz J, Kuźnik E, Szenborn F, Jurczenko L, et al. The COVID-19 mRNA BNT163b2 vaccine was well tolerated and highly immunogenic in young adults in long follow-up after haematopoietic stem cell transplantation. Vaccines. 2021. https://doi.org/10.3390/vaccines9101209.

Pabst C, Benning L, Liebers N, Janssen M, Caille L, Speer C, et al. Humoral responses and chronic GVHD exacerbation after COVID-19 vaccination post allogeneic stem cell transplantation. Vaccines. 2022. https://doi.org/10.3390/vaccines10020330.

Piñana JL, López-Corral L, Martino R, Montoro J, Vazquez L, Pérez A, et al. SARS-CoV-2-reactive antibody detection after SARS-CoV-2 vaccination in hematopoietic stem cell transplant recipients: prospective survey from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group. Am J Hematol. 2022;97(1):30–42. https://doi.org/10.1002/ajh.26385.

Canti L, Humblet-Baron S, Desombere I, Neumann J, Pannus P, Heyndrickx L, et al. Predictors of neutralizing antibody response to BNT162b2 vaccination in allogeneic hematopoietic stem cell transplant recipients. J Hematol Oncol. 2021;14(1):174. https://doi.org/10.1186/s13045-021-01190-3.

Chiarucci M, Paolasini S, Isidori A, Guiducci B, Loscocco F, Capalbo M, et al. Immunological response against SARS-COV-2 After BNT162b2 vaccine administration is impaired in allogeneic but not in autologous stem cell transplant recipients. Front Oncol. 2021;11: 737300. https://doi.org/10.3389/fonc.2021.737300.

Watanabe M, Yakushijin K, Funakoshi Y, Ohji G, Hojo W, Sakai H, et al. The safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in Japanese patients after allogeneic stem cell transplantation. Vaccines. 2022. https://doi.org/10.3390/vaccines10020158.

Majcherek M, Matkowska-Kocjan A, Szymczak D, Karasek M, Szeremet A, Kiraga A, et al. Two doses of BNT162b2 mRNA vaccine in patients after hematopoietic stem cell transplantation: humoral response and serological conversion predictors. Cancers. 2022. https://doi.org/10.3390/cancers14020325.

Lindemann M, Klisanin V, Thümmler L, Fisenkci N, Tsachakis-Mück N, Ditschkowski M, et al. Humoral and cellular vaccination responses against SARS-CoV-2 in hematopoietic stem cell transplant recipients. Vaccines. 2021. https://doi.org/10.3390/vaccines9101075.

Shem-Tov N, Yerushalmi R, Danylesko I, Litachevsky V, Levy I, Olmer L, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in haematopoietic stem cell transplantation recipients. Br J Haematol. 2022;196(4):884–91. https://doi.org/10.1111/bjh.17918.

Chevallier P, Coste-Burel M, Le Bourgeois A, Peterlin P, Garnier A, Béné MC, et al. Safety and immunogenicity of a first dose of SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem-cells recipients. EJHaem. 2021. https://doi.org/10.1002/jha2.242.

Tamari R, Politikos I, Knorr DA, Vardhana SA, Young JC, Marcello LT, et al. Predictors of humoral response to SARS-CoV-2 vaccination after hematopoietic cell transplantation and CAR T-cell therapy. Blood Cancer Discov. 2021;2(6):577–85. https://doi.org/10.1158/2643-3230.Bcd-21-0142.

Easdale S, Shea R, Ellis L, Bazin J, Davis K, Dallas F, et al. Serologic responses following a single dose of SARS-Cov-2 vaccination in allogeneic stem cell transplantation recipients. Transplant Cell Ther. 2021;27(10):880.e1-e4. https://doi.org/10.1016/j.jtct.2021.07.011.

Healy K, Pin E, Chen P, Söderdahl G, Nowak P, Mielke S, et al. Salivary IgG to SARS-CoV-2 indicates seroconversion and correlates to serum neutralization in mRNA-vaccinated immunocompromised individuals. Med (New York, NY). 2022;3(2):137-53.e3. https://doi.org/10.1016/j.medj.2022.01.001.

Ram R, Hagin D, Kikozashvilli N, Freund T, Amit O, Bar-On Y, et al. Safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients after allogeneic HCT or CD19-based CART therapy-a single-center prospective cohort study. Transplant Cell Ther. 2021;27(9):788–94. https://doi.org/10.1016/j.jtct.2021.06.024.

Redjoul R, Le Bouter A, Beckerich F, Fourati S, Maury S. Antibody response after second BNT162b2 dose in allogeneic HSCT recipients. Lancet (London, England). 2021;398(10297):298–9. https://doi.org/10.1016/s0140-6736(21)01594-4.

Gastinne T, Le Bourgeois A, Coste-Burel M, Guillaume T, Peterlin P, Garnier A, et al. Safety and antibody response after one and/or two doses of BNT162b2 Anti-SARS-CoV-2 mRNA vaccine in patients treated by CAR T cells therapy. Br J Haematol. 2022;196(2):360–2. https://doi.org/10.1111/bjh.17818.

Canti L, Ariën KK, Desombere I, Humblet-Baron S, Pannus P, Heyndrickx L, et al. Antibody response against SARS-CoV-2 Delta and Omicron variants after third-dose BNT162b2 vaccination in allo-HCT recipients. Cancer Cell. 2022. https://doi.org/10.1016/j.ccell.2022.02.005.

Dahiya S, Luetkens T, Lutfi F, Avila S, Iraguha T, Margiotta P, et al. Impaired immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CAR T-cell therapy. Blood Adv. 2022;6(2):686–9. https://doi.org/10.1182/bloodadvances.2021006112.

Parvathaneni K, Toress-Rodriguez K, Meng W, Knox J, Xu X, Weiskopf D, et al. Adoptive immune responses to Sars-Cov2 vaccination in CART19 treated patients. Blood. 2021;138:1757. https://doi.org/10.1182/blood-2021-153730.

Fox TA, Kirkwood AA, Enfield L, O’Reilly M, Arulogun S, D’Sa S, et al. Low seropositivity and suboptimal neutralisation rates in patients fully vaccinated against COVID-19 with B-cell malignancies. Br J Haematol. 2021;195(5):706–9. https://doi.org/10.1111/bjh.17836.

Mamez AC, Pradier A, Giannotti F, Petitpas A, Fabra Urdiola M, Vu-Cantero D, et al. Antibody responses to SARS-CoV2 vaccination in a high proportion of allogeneic hematopoietic stem cell transplant recipients. Swiss Med Wkly. 2021;151(SUPPL 255):28S.

Le Bourgeois A, Coste-Burel M, Guillaume T, Peterlin P, Garnier A, Imbert BM, et al. Interest of a third dose of BNT162b2 anti-SARS-CoV-2 messenger RNA vaccine after allotransplant. Br J Haematol. 2022;196(5):e38–40. https://doi.org/10.1111/bjh.17911.

Maillard A, Redjoul R, Klemencie M, Labussière Wallet H, Le Bourgeois A, D’Aveni M, et al. Antibody response after 2 and 3 doses of SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic cell transplant recipients. Blood. 2022;139(1):134–7. https://doi.org/10.1182/blood.2021014232.

Le Bourgeois A, Coste-Burel M, Guillaume T, Peterlin P, Garnier A, Béné MC, et al. Safety and Antibody response after 1 and 2 doses of BNT162b2 mRNA vaccine in recipients of allogeneic hematopoietic stem cell transplant. JAMA Netw Open. 2021;4(9): e2126344. https://doi.org/10.1001/jamanetworkopen.2021.26344.

Dhakal B, Abedin S, Fenske T, Chhabra S, Ledeboer N, Hari P, et al. Response to SARS-CoV-2 vaccination in patients after hematopoietic cell transplantation and CAR T-cell therapy. Blood. 2021;138(14):1278–81. https://doi.org/10.1182/blood.2021012769.

Abid MB, Rubin M, Ledeboer N, Szabo A, Longo W, Mohan M, et al. Efficacy of a third SARS-CoV-2 mRNA vaccine dose among hematopoietic cell transplantation, CAR T cell, and BiTE recipients. Cancer Cell. 2022;40(4):340–2.

Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Chen P, et al. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. medRxiv. 2021. https://doi.org/10.1101/2021.09.07.21263206.

Busca A, Salmanton-García J, Corradini P, Marchesi F, Cabirta A, Di Blasi R, et al. COVID-19 and CAR-T cells: current challenges and future directions-a report from the EPICOVIDEHA survey by EHA-IDWP. Blood Adv. 2021. https://doi.org/10.1182/bloodadvances.2021005616.

Talic S, Shah S, Wild H, Gasevic D, Maharaj A, Ademi Z, et al. Effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality: systematic review and meta-analysis. BMJ (Clinical research ed). 2021;375: e068302. https://doi.org/10.1136/bmj-2021-068302.

Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44. https://doi.org/10.1056/NEJMoa1707447.

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48. https://doi.org/10.1056/NEJMoa1709866.

Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569–75. https://doi.org/10.1038/s41591-020-1081-3.

Walti CS, Krantz EM, Maalouf J, Boonyaratanakornkit J, Keane-Candib J, Joncas-Schronce L, et al. Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies. JCI Insight. 2021. https://doi.org/10.1172/jci.insight.146743.

Mori A, Onozawa M, Tsukamoto S, Ishio T, Yokoyama E, Izumiyama K, et al. Humoral response to mRNA-based COVID-19 vaccine in patients with myeloid malignancies. Br J Haematol. 2022. https://doi.org/10.1111/bjh.18138.

Herishanu Y, Avivi I, Aharon A, Shefer G, Levi S, Bronstein Y, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165–73. https://doi.org/10.1182/blood.2021011568.

Perry C, Luttwak E, Balaban R, Shefer G, Morales MM, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma. Blood Adv. 2021;5(16):3053–61. https://doi.org/10.1182/bloodadvances.2021005094.

Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-100. https://doi.org/10.1093/cid/cit684.

Cordonnier C, Einarsdottir S, Cesaro S, Di Blasi R, Mikulska M, Rieger C, et al. Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(6):e200–12. https://doi.org/10.1016/s1473-3099(18)30600-5.

Sakuraba A, Luna A, Micic D. Serologic response to coronavirus disease 2019 (COVID-19) vaccination in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis. Gastroenterology. 2022;162(1):88-108.e9. https://doi.org/10.1053/j.gastro.2021.09.055.

Centers for disease control, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/reactogenicity.html. Accessed 01 Apr 2022.

Gilbert PB, Montefiori DC, McDermott AB, Fong Y, Benkeser D, Deng W, et al. Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial. Science (New York, NY). 2022;375(6576):43–50. https://doi.org/10.1126/science.abm3425.

Thông tin
Thông tin xuất bản

Experimental Hematology & Oncology

Thông tin tác giả