Hofsink Quincy, Haggenburg Sabine, Lissenberg-Witte Birgit I, Broers Annoek E C, van Doesum Jaap A, van Binnendijk Rob S, den Hartog Gerco, Bhoekhan Michel S, Haverkate Nienke J E, van Meerloo Johan, Burger Judith A, Bouhuijs Joey H, Smits Gaby P, Wouters Dorine, van Leeuwen Ester M M, Bontkes Hetty J, Kootstra Neeltje A, Vogels-Nooijen Sandra, Rots Nynke, van Beek Josine, Heemskerk Mirjam H M, Groen Kazimierz, van Meerten Tom, Mutsaers Pim G N J, van Gils Marit J, Goorhuis Abraham, Rutten Caroline E, Hazenberg Mette D, Nijhof Inger S
Department of Haematology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.
Amsterdam Institute for Infection and Immunity, Amsterdam UMC, Amsterdam, Netherlands.
EClinicalMedicine. 2023 Jul;61:102040. doi: 10.1016/j.eclinm.2023.102040. Epub 2023 Jun 15.
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.
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.
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.
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.
The Netherlands Organisation for Health Research and Development and Amsterdam UMC.
血液系统恶性肿瘤患者对SARS-CoV-2疫苗的抗体反应受损。我们旨在研究第四剂mRNA新冠疫苗接种是否能提高抗体的数量和质量。
在荷兰的5个地点进行的这项队列研究中，我们比较了初次感染SARS-CoV-2、免疫功能低下的血液系统恶性肿瘤患者在接种4剂mRNA疫苗（3剂基础系列加1剂加强针）后28天的抗体浓度，与年龄匹配、接受了标准2剂基础mRNA疫苗接种方案并随后接种了第1剂加强针mRNA疫苗的健康个体的抗体浓度。在每次接种前和接种后4周，收集外周血样本以及人口统计学参数和病史数据。根据世界卫生组织新冠病毒血清学检测国际标准，以每毫升结合抗体单位（BAU）对结合SARS-CoV-2刺突1（S1）和核衣壳（N）蛋白的抗体浓度进行定量。血清转化定义为S1 IgG浓度>10 BAU/mL，既往SARS-CoV-2感染定义为N IgG>14.3 BAU/mL。使用表达SARS-CoV-2野生型（D614G）、奥密克戎BA.1和奥密克戎BA.4/5变体刺突蛋白的基于慢病毒的假病毒检测抗体中和活性。本研究已在欧洲临床试验数据库（EudraCT）注册，注册号为2021-001072-41。
2021年3月24日至2021年5月4日期间，723例血液系统疾病患者入组，其中414例符合当前分析的纳入标准。尽管第四剂接种后患者的S1 IgG浓度显著提高，但与58例年龄匹配的健康个体在首次加强针（第三剂）接种后的浓度相比，仍显著较低。中和抗体浓度的升高在B细胞亚群恢复的患者中最为显著，尽管在持续免疫缺陷的患者中也观察到了有效的反应。19%的患者尽管接种了4剂疫苗，但从未发生血清转化。在B细胞耗竭时接种前两剂疫苗，在B细胞恢复期间接种第三剂和第四剂疫苗的患者，与前两剂接种时B细胞数量正常的患者表现出相似的抗体诱导动态。然而，这些抗体的中和能力明显优于两剂接种后B细胞数量正常的患者。
第四剂mRNA新冠疫苗接种提高了大多数血液系统恶性肿瘤患者的S1 IgG浓度。在B细胞耗竭期间接种疫苗可能为B细胞重建后更好的抗体反应质量铺平道路。
荷兰卫生研究与发展组织和阿姆斯特丹大学医学中心。
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