TY - JOUR
T1 - Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI)
T2 - a cohort study
AU - Hofsink, Quincy
AU - Haggenburg, Sabine
AU - Lissenberg-Witte, Birgit I.
AU - Broers, Annoek E. C.
AU - van Doesum, Jaap A.
AU - van Binnendijk, Rob S.
AU - den Hartog, Gerco
AU - Bhoekhan, Michel S.
AU - Haverkate, Nienke J. E.
AU - van Meerloo, Johan
AU - Burger, Judith A.
AU - Bouhuijs, Joey H.
AU - Smits, Gaby P.
AU - Wouters, Dorine
AU - van Leeuwen, Ester M. M.
AU - Bontkes, Hetty J.
AU - Kootstra, Neeltje A.
AU - Vogels-Nooijen, Sandra
AU - Rots, Nynke
AU - van Beek, Josine
AU - Heemskerk, Mirjam H. M.
AU - Groen, Kazimierz
AU - van Meerten, Tom
AU - Mutsaers, Pim G. N. J.
AU - van Gils, Marit J.
AU - Goorhuis, Abraham
AU - Rutten, Caroline E.
AU - Hazenberg, Mette D.
AU - Nijhof, Inger S.
AU - COBRA KAI Study Team
AU - Kant, Iris M. J.
AU - Graas, Thecla
AU - Toussaint, Belle
AU - de Jong, Sterre
AU - Darwesh, Shahan
AU - Mahes, Sandjiv S.
AU - Kamminga, Dora
AU - Koelewijn, Matthijs
AU - Faber, Gino
AU - Beaumont, Guus
AU - Engel, Marije D.
AU - Pierie, R. Cheyenne N.
AU - Janssen, Suzanne R.
AU - van Dijkman, Edith
AU - Heijmans, Jarom
AU - Witte, Yara Y.
AU - Nahui Palomino, Rogers A.
AU - Zweegman, Sonja
AU - Kater, Arnon P.
AU - Cloos, Jacqueline
AU - Roelandse-Koop, Elianne
AU - Omar, Said Z.
AU - de Rooij, Dennis M.
AU - Sanders, Rogier W.
AU - Poniman, Meliawati
AU - Olijhoek, Wouter
AU - van Rijswijk, Jacqueline
AU - Beaumont, Tim
N1 - Funding Information: This work was funded by The Netherlands Organisation for Health Research and Development and Amsterdam UMC . The authors thank the patients who participated in the trial. The authors would also like to thank staff of Amsterdam UMC, Erasmus UMC, UMC Groningen, Dutch National Institute for Public Health and the Environment, and the Netherlands Comprehensive Cancer Organisation for their help with patient inclusion and data collection. Funding Information: The Netherlands Organisation for Health Research and Development and Amsterdam UMC.This work was funded by The Netherlands Organisation for Health Research and Development and Amsterdam UMC. The authors thank the patients who participated in the trial. The authors would also like to thank staff of Amsterdam UMC, Erasmus UMC, UMC Groningen, Dutch National Institute for Public Health and the Environment, and the Netherlands Comprehensive Cancer Organisation for their help with patient inclusion and data collection. COBRA KAI study team, Iris M.J. Kant, Thecla Graas, Belle Toussaint, Sterre de Jong, Shahan Darwesh, Sandjiv S. Mahes, Dora Kamminga, Matthijs Koelewijn, Gino Faber, Guus Beaumont, Marije D. Engel, R. Cheyenne N. Pierie, Suzanne R. Janssen, Gino Faber, Edith van Dijkman, Jarom Heijmans, Yara Y. Witte, Rogers A. Nahui Palomino, Said Z. Omar, Sonja Zweegman, Arnon P. Kater, Caya van den Vegt, Ilonka Arends-Halbesma, Emma de Pater, Margriet J. Dijkstra, Nynke Y. Rots, Esther Siteur-van Rijnstra, Dennis M. de Rooij, Rogier W. Sanders, Meliawati Poniman, Wouter Olijhoek, Jacqueline van Rijswijk, Tim Beaumont, Lusia Çetinel, Louis Schellekens, Yvonne M. den Hartogh, Jacqueline Cloos, Suzanne S. Weijers, Saïda Tonouh-Aajoud, Selime Avci, Elianne Roelandse-Koop, Willem A. Dik. Publisher Copyright: © 2023 The Author(s)
PY - 2023/7/1
Y1 - 2023/7/1
N2 - Background: Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality. Methods: In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41. Findings: Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations. Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution. Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC.
AB - Background: Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality. Methods: In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41. Findings: Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations. Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution. Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC.
KW - Antibody response
KW - Booster vaccination
KW - COVID-19 vaccination
KW - Haematological malignancies
KW - Immunocompromised
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85163716878&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.eclinm.2023.102040
DO - https://doi.org/10.1016/j.eclinm.2023.102040
M3 - Article
C2 - 37337616
SN - 2589-5370
VL - 61
JO - EClinicalMedicine
JF - EClinicalMedicine
M1 - 102040
ER -