Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment. - 2021
BNT162 Vaccine; COVID-19 Vaccines; Immunity, Humoral; SARS-CoV-2; COVID-19; Oncology; Cancer Research
Abstract :
[en] [en] BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear.
PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster.
RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission.
CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.
Disciplines :
Oncology
Author, co-author :
Peeters, M ✱; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium, Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp and Antwerp University Hospital, Edegem, Belgium. Electronic address: marc.peeters@uza.be
Verbruggen, L ✱; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Teuwen, L; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Vanhoutte, G; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Vande Kerckhove, S; SD Infectious Diseases in Humans, Service Immune response, Sciensano, Brussels, Belgium
Peeters, B; Department of Laboratory Medicine, Antwerp University Hospital, Edegem, Belgium
Raats, S; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Van der Massen, I; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
De Keersmaecker, S; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Debie, Yana ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire ; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Huizing, M; Biobank Antwerp, Edegem, Belgium
Pannus, P; SD Epidemiology and Public Health, Sciensano, Brussels, Belgium
Neven, K; SD Epidemiology and Public Health, Sciensano, Brussels, Belgium
Ariën, K K; Virology Unit, Institute of Tropical Medicine Antwerp, Antwerp, Belgium, Department of Biomedical Sciences, University of Antwerp, Edegem, Belgium
Martens, G A; Department of Laboratory Medicine, AZ Delta General Hospital, Roeselare, Belgium
Van Den Bulcke, M; SD Epidemiology and Public Health, Sciensano, Brussels, Belgium
Roelant, E; Clinical Trial Center (CTC), CRC Antwerp, Antwerp University Hospital, University of Antwerp, Edegem, Belgium, StatUa, Center for Statistics, University of Antwerp, Antwerp, Belgium
Desombere, I; SD Infectious Diseases in Humans, Service Immune response, Sciensano, Brussels, Belgium
Anguille, S; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
Goossens, M; SD Epidemiology and Public Health, Sciensano, Brussels, Belgium
Vandamme, T; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium, Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp and Antwerp University Hospital, Edegem, Belgium
van Dam, P; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium, Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp and Antwerp University Hospital, Edegem, Belgium
The study was approved by the local ethics committee and was executed in accordance with Good Clinical Practice and the Declaration of Helsinki [ICH GCP E6(R2)]. The regulatory sponsor was the Antwerp University Hospital (EudraCT number 2021-000300-38). This work was supported by the Belgian Government through Sciensano [COVID-19_SC004, COVID-19_SC059, COVID-19_SC061].We kindly thank the B-voice patients as well as the participants of the PICOV-VAC study, the nursing staff members at the Day Care Unit of the Antwerp University Hospital, the staff members of the Biobank Antwerpen and all recruiting physicians: Altintas Sevilay, Berneman Zwi, De Bondt Charlotte, Janssens Annelies, Papadimitriou Konstantinos, Prenen Hans, Raskin Jo, Rasschaert Marika, Kirsten Saevels, Specenier Pol, Tjalma Wiebren, Trinh Xuan Bich, Van Berckelaer Christophe, Van den Brande Jan, Van de Velde Ann and Verlinden Anke. We also thank Caroline Rodeghiero, Fabienne Jurion, Elfriede Heerwegh, Antoine Francotte and St?phane De Craeye for their technical and logistical support in the laboratory and acknowledge Marie-No?lle Schmickler MD, PhD and Mathieu Verbrugghe PhD from Mensura Occupational Health Service Belgium to enable institutional support for this study. We are grateful to Antoine Francotte, Caroline Rodeghiero and Fabienne Jurion for performing serological analyses, to Leo Heyndrickx, Johan Michiels and Betty Willems for neutralising antibody testing and to Laure Mortgat and Elza Duysburgh for the coordination of the HCW study that sampled part of the exploratory samples. This work was supported by the Belgian Government through Sciensano [grant numbers COVID-19_SC004, COVID-19_SC059, COVID-19_SC061]. MP declares to have an advisory role within Remedus. All other authors have declared no conflicts of interest. Data are available upon reasonable request.
WHO Coronavirus (COVID-19) Dashboard. Available at https://covid19.who.int/. (Accessed 26 May 2021)
Wang, Y., Zhang, D., Du, G., et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 395 (2020), 1569–1578.
RECOVERY Collaborative Group Horby, P., Lim, W.S., et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 384 (2021), 693–704.
Aschwanden, C., The false promise of herd immunity for COVID-19. Nature 587 (2020), 26–28.
Marra, A., Generali, D., Zagami, P., et al. Seroconversion in patients with cancer and oncology health care workers infected by SARS-CoV-2. Ann Oncol 32 (2021), 113–119.
Abdul-Jawad, S., Bau, L., Alaguthurai, T., et al. Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients. Cancer Cell 39 (2021), 257–275 e6.
van Dam, P.A., Huizing, M., Papadimitriou, K., Prenen, H., Peeters, M., High mortality of cancer patients in times of SARS-CoV-2: do not generalize!. Eur J Cancer 138 (2020), 225–227.
van Dam, P., Huizing, M., Roelant, E., et al. Immunoglobin G/total antibody testing for SARS-CoV-2: a prospective cohort study of ambulatory patients and health care workers in two Belgian oncology units comparing three commercial tests. Eur J Cancer 148 (2021), 328–339.
Johannesen, T.B., Smeland, S., Aaserud, S., et al. COVID-19 in cancer patients, risk factors for disease and adverse outcome, a population-based study from Norway. Front Oncol, 11, 2021, 652535.
Williamson, E.J., Walker, A.J., Bhaskaran, K., et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 584 (2020), 430–436.
Lievre, A., Turpin, A., Ray-Coquard, I., et al. Risk factors for coronavirus disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: a French nationwide cohort study (GCO-002 CACOVID-19). Eur J Cancer 141 (2020), 62–81.
Wang, Q., Berger, N.A., Xu, R., Analyses of risk, racial disparity, and outcomes among US patients with cancer and COVID-19 infection. JAMA Oncol 7 (2021), 220–227.
van Dam, P.A., Huizing, M., Mestach, G., et al. SARS-CoV-2 and cancer: are they really partners in crime?. Cancer Treat Rev, 89, 2020, 102068.
Polack, F.P., Thomas, S.J., Kitchin, N., et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 383 (2020), 2603–2615.
Kotton, C.N., Poznansky, M.C., Vaccination of oncology patients: an effective tool and an opportunity not to be missed. Oncologist 17 (2012), 1–2.
Rieger, C.T., Liss, B., Mellinghoff, S., et al. Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Oncol 29 (2018), 1354–1365.
Tsigrelis, C., Ljungman, P., Vaccinations in patients with hematological malignancies. Blood Rev 30 (2016), 139–147.
Irsara, C., Egger, A.E., Prokop, W., et al. Clinical validation of the Siemens quantitative SARS-CoV-2 spike IgG assay (sCOVG) reveals improved sensitivity and a good correlation with virus neutralization titers. Clin Chem Lab Med 59 (2021), 1453–1462.
Rasschaert, M., Vanclooster, P., Mertens, T., et al. The tele-transition of toxicity management in routine oncology care during the severe acute respiratory syndrome (SARS-CoV-2) pandemic. Br J Cancer 124 (2021), 1366–1372.
Peeters, M., van Dam, P., Rasschaert, M.A., et al. Prescreening for COVID-19 in patients receiving cancer treatment using a patient-reported outcome platform. ESMO Open, 5, 2020, e000817.
Abdel-Razeq, H., Mansour, A., Abdulelah, H., et al. Thromboembolic events in cancer patients on active treatment with cisplatin-based chemotherapy: another look!. Thromb J, 16, 2018, 2.
Mazza, J.J., Yale, S.H., Arrowood, J.R., et al. Efficacy of the influenza vaccine in patients with malignant lymphoma. Clin Med Res 3 (2005), 214–220.
Massarweh, A., Eliakim-Raz, N., Stemmer, A., et al. Evaluation of seropositivity following BNT162b2 messenger RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer. JAMA Oncol 7 (2021), 1133–1140.
Maneikis, K., Šablauskas, K., Ringelevičiūtė, U., et al. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol 8 (2021), e583–e592.
Monin, L., Laing, A.G., Munoz-Ruiz, M., et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Oncol 22 (2021), 765–778.
Addeo, A., Shah, P.K., Bordry, N., et al. Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer. Cancer Cell 39 (2021), 1091–1098.e2.
Pimpinelli, F., Marchesi, F., Piaggio, G., et al. Fifth-week immunogenicity and safety of anti-SARS-CoV-2 BNT162b2 vaccine in patients with multiple myeloma and myeloproliferative malignancies on active treatment: preliminary data from a single institution. J Hematol Oncol, 14, 2021, 81.
Herishanu, Y., Avivi, I., Aharon, A., et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood 137 (2021), 3165–3173.
Bird, S., Panopoulou, A., Shea, R.L., et al. Response to first vaccination against SARS-CoV-2 in patients with multiple myeloma. Lancet Haematol 8 (2021), e389–e392.
Rousseau, B., Loulergue, P., Mir, O., et al. Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study. Ann Oncol 23 (2012), 450–457.
Amir, E., Seruga, B., Niraula, S., Carlsson, L., Ocaña, A., Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 103 (2011), 1299–1309.
Dulek, D.E., Halasa, N.B., Timing isn't everything: influenza vaccination in cancer patients. Cancer 123 (2017), 731–733.
Keam, B., Kim, M.K., Choi, Y., et al. Optimal timing of influenza vaccination during 3-week cytotoxic chemotherapy cycles. Cancer 123 (2017), 841–848.
Choi, W., Kim, J.G., Beom, S.H., et al. Immunogenicity and optimal timing of 13-valent pneumococcal conjugate vaccination during adjuvant chemotherapy in gastric and colorectal cancer: a randomized controlled trial. Cancer Res Treat 52 (2020), 246–253.
Lee, E.K., Konstantinopoulos, P.A., PARP inhibition and immune modulation: scientific rationale and perspectives for the treatment of gynecologic cancers. Ther Adv Med Oncol, 12, 2020 1758835920944116.
Pescovitz, M.D., Torgerson, T.R., Ochs, H.D., et al. Effect of rituximab on human in vivo antibody immune responses. J Allergy Clin Immunol 128 (2011), 1295–1302.e5.
Zhu, L.P., Cupps, T.R., Whalen, G., Fauci, A.S., Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells. J Clin Invest 79 (1987), 1082–1090.
Huyan, X.H., Lin, Y.P., Gao, T., Chen, R.Y., Fan, Y.M., Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice. Int Immunopharmacol 11 (2011), 1293–1297.
Haas, E.J., Angulo, F.J., McLaughlin, J.M., 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) 397 (2021), 1819–1829.
Dagan, N., Barda, N., Kepten, E., et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med 384 (2021), 1412–1423.
Läubli, H., Balmelli, C., Kaufmann, L., et al. Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events. J Immunother Cancer, 6, 2018, 40.
Desage, A.L., Bouleftour, W., Rivoirard, R., et al. Vaccination and immune checkpoint inhibitors: does vaccination increase the risk of immune-related adverse events? A systematic review of literature. Am J Clin Oncol 44 (2021), 109–113.
Waissengrin, B., Agbarya, A., Safadi, E., Padova, H., Wolf, I., Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors. Lancet Oncol 22 (2021), 581–583.
Shen, C., Wang, Z., Zhao, F., et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 323 (2020), 1582–1589.
Kadkhoda, K., COVID-19: are neutralizing antibodies neutralizing enough?. Transfusion (Paris) 60 (2020), 1602–1603.
Khan, S., Nakajima, R., Jain, A., et al. Analysis of serologic cross-reactivity between common human coronaviruses and SARS-CoV-2 using coronavirus antigen microarray. bioRxiv, 2020, 10.1101/2020.03.24.006544 [Preprint]. 2020.03.24.006544.
Desai, A., Gainor, J.F., Hegde, A., et al. COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials. Nat Rev Clin Oncol 18 (2021), 313–319.
Kamar, N., Abravanel, F., Marion, O., Couat, C., Izopet, J., Del Bello, A., Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med 385 (2021), 661–662.
