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... Show moreBackground 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 wildtype (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. Show less
Haggenburg, S.; Hofsink, Q.; Lissenberg-Witte, B.I.; Broers, A.E.C.; Doesum, J.A. van; Binnendijk, R.S. van; ... ; Cobra Kai Study Team 2022
IMPORTANCE: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. OBJECTIVE: To... Show moreIMPORTANCE: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. OBJECTIVE: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities. EXPOSURES: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. MAIN OUTCOMES AND MEASURES: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients. RESULTS: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiplemyeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody. CONCLUSIONS AND RELEVANCE: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Show less
Background: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great... Show moreBackground: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.Objectives: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI.Methods: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination.Results: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response.Conclusions: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations. Show less
Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit... Show moreVaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dosemRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG >= 300 binding antibody units (BAUs)/mLwas considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >= 50% of patients obtained S1 IgG >= 300 BAUs/mL after 2-dosemRNA-1273. All patients with sickle cell disease or chronicmyeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG >= 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses inmyeloidmalignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <= 2months formultiplemyeloma, 8months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer-cell number, and number of immunosuppressants predicted S1 IgG >= 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded fromvaccination. Show less
