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1.
biorxiv; 2022.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2022.10.14.512216

ABSTRACT

The worldwide pandemic caused by SARS-CoV-2 has remained a human medical threat due to the continued evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants for therapeutic and prophylactic use. A stabilized autologous SARS-CoV-2 spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants of concern, with COVA309-35 being the most potent against the autologous virus, as well as against Omicron BA.1 and BA.2. When combining the COVA309 mAbs as cocktails or bispecific antibody formats, the breadth and potency was significantly improved against all tested variants. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.

2.
medrxiv; 2022.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2022.04.08.22273602

ABSTRACT

ImportanceIn patients with hematologic malignancies, the immunogenicity of the standard 2-dose mRNA-1273 coronavirus disease 19 (COVID-19) vaccination schedule is often insufficient due to underlying disease and current or recent therapy. ObjectiveTo determine whether a 3rd mRNA-1273 vaccination raises antibody concentrations in immunocompromised hematology patients to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. DesignProspective observational cohort study. SettingFour academic hospitals in the Netherlands. Participants584 evaluable immunocompromised hematology patients, all grouped in predefined cohorts spanning the spectrum of hematologic malignancies. ExposureOne additional vaccination with mRNA-1273 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and MeasuresSerum IgG antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after each vaccination, and pseudovirus neutralization of wildtype, delta and omicron variants in a subgroup of patients. ResultsIn immunocompromised hematology patients, a 3rd mRNA-1273 vaccination led to 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 3rd 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 malignancies 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 on or shortly after rituximab therapy, CD19-directed chimeric antigen receptor T cell therapy recipients, and chronic lymphocytic leukemia patients on ibrutinib were less or unresponsive to the 3rd vaccination. In the 27 patients who received cell therapy between the 2nd and 3rd vaccination, S1 antibodies were preserved, but a 3rd mRNA-1273 vaccination did not significantly enhance S1 IgG concentrations except for multiple myeloma patients receiving autologous HCT. A 3rd vaccination significantly improved neutralization capacity per antibody. Conclusions and RelevanceThe primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial RegistrationEudraCT 2021-001072-41 Key pointsO_ST_ABSQuestionC_ST_ABSCan a 3rd mRNA-1273 vaccination improve COVID-19 antibody concentrations in immunocompromised hematology patients to levels similar to healthy adults after the standard 2-dose mRNA-1273 schedule? FindingsIn this prospective observational cohort study that included 584 immunocompromised hematology patients, a 3rd mRNA-1273 vaccination significantly improved SARS-CoV-2 antibody concentrations to levels not significantly different from those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Pseudovirus neutralization capacity per antibody of wild type virus and variants of concern also significantly improved. MeaningThe primary COVID-19 vaccination schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination.


Subject(s)
Lymphoma, B-Cell , Hematologic Neoplasms , Immunologic Deficiency Syndromes , Coronavirus Infections , COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Multiple Myeloma
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