Bivalent COVID-19 vaccines boost the capacity of pre-existing SARS-CoV-2-specific memory B cells to cross-recognize Omicron subvariants (preprint)

Bivalent COVID-19 vaccines comprising ancestral Wuhan-Hu-1 (WH1) and the Omicron BA.1 or BA.5 subvariant elicit enhanced serum antibody responses to emerging Omicron subvariants. We characterized the memory B-cell (Bmem) response following a fourth dose with a BA.1 or BA.5 bivalent vaccine, and compared the immunogenicity with a WH1 monovalent fourth dose. Healthcare workers previously immunized with mRNA or adenoviral vector monovalent vaccines were sampled before and one-month after a monovalent, BA.1 or BA.5 bivalent fourth dose COVID-19 vaccine. RBD-specific Bmem were quantified with an in-depth spectral flow cytometry panel including recombinant RBD proteins of the WH1, BA.1, BA.5, BQ.1.1, and XBB.1.5 variants. All recipients had slightly increased WH1 RBD-specific Bmem numbers. Recognition of Omicron subvariants was not enhanced following monovalent vaccination, while both bivalent vaccines significantly increased WH1 RBD-specific Bmem cross-recognition of all Omicron subvariants tested by flow cytometry. Thus, Omicron-based bivalent vaccines can improve recognition of descendent Omicron subvariants by pre-existing, WH1-specific Bmem, beyond that of a conventional, monovalent vaccine. This provides new insights into the capacity of variant-based mRNA booster vaccines to improve immune memory against emerging SARS-CoV-2 variants.

Distinct COVID-19 vaccine combinations result in divergent immune responses (preprint)

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, BA.2-descendent lineages have become dominant, such as XBB.1.5 or BA.2.86. Here, we assessed how different COVID-19 priming regimens affect the immunogenicity of the recently used bivalent booster vaccinations and breakthrough infections. BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, we highlight important "lessons learned" from the employed COVID-19 vaccination strategies. Our data further support the use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

Three-dose mRNA-1273 vaccination schedule: sufficient antibody response in majority of immunocompromised hematology patients (preprint)

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.

SARS-CoV-2 hyperimmune globulin for severely immunocompromised patients with COVID-19: a randomised, controlled, double-blind, phase 3 trial (preprint)

Background: Severely immunocompromised patients are at risk for severe COVID-19. Benefit from convalescent plasma in these patients is suggested but data from randomised trials are lacking. The aim of this study is to determine efficacy of SARS-CoV-2 hyperimmune globulin (COVIG) in treatment of severely immunocompromised, hospitalised COVID-19 patients. Methods: In this randomised, controlled, double-blind, multicentre, phase 3 trial, severely immunocompromised patients who were hospitalised with symptomatic COVID-19 were randomly assigned (1:1) to receive 15 grams of COVIG or 15 grams of intravenous immunoglobulin without SARS-CoV-2 antibodies (IVIG, control). Patients included were solid organ transplant patients with three drugs from different immunosuppressive classes or patient with disease or treatment severely affecting B-cell function. Patients that required mechanical ventilation or high flow nasal oxygen were excluded. All investigators, research staff, and participants were masked to group allocation. The primary endpoint was occurrence of severe COVID-19 evaluated up until day 28 after treatment, defined as the need for mechanical ventilation, high-flow nasal oxygen, readmission for COVID-19 after hospital discharge or lack of clinical improvement on day seven or later. This trial is registered with Netherlands Trial Register (NL9436). Findings: From April, 2021, to July, 2021, 18 participants were enrolled at three sites in the Netherlands; 18 patients were analysed. Recruitment was halted prematurely when casirivimab/imdevimab became the recommended therapy in the Dutch COVID-19 treatment guideline for seronegative, hospitalised COVID-19 patients. Median age was 58 years and all but two were negative for SARS-CoV-2 spike IgG at baseline. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven of eight (88%) in the IVIG control group (p = 0.015, Fisher's exact test). Interpretation: COVIG reduced the incidence of severe COVID-19 in severely immunocompromised patients, hospitalised with COVID-19. COVIG may be a valuable treatment in this patient group and can be used when no monoclonal antibody therapies are available. Funding: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply Foundation.

Added Value of Chest CT in Suspected COVID-19: An Analysis of 239 Patients (preprint)

Introduction: Clinicians have been struggling with the optimal diagnostic approach of patients with suspected COVID-19. We evaluated the added value of chest CT over RT-PCR alone. Methods: Consecutive adult patients with suspected COVID-19 presenting to the emergency department (Academic Medical Center, Amsterdam University Medical Centers, the Netherlands) from March 16th to April 16th were retrospectively included if they required hospital admission and underwent chest CT and RT-PCR testing for SARS-CoV-2 infection. The CO-RADS classification was used to assess the radiological probability of COVID-19, where a score of 1-2 was considered as negative, 3 as indeterminate, and 4-5 as positive. CT results were stratified by initial RT-PCR results. For patients with a negative RT-PCR but a positive CT, serology or multidisciplinary discussion after clinical follow-up constituted the final diagnosis. Results: 258 patients with suspected COVID-19 were admitted, of which 239 were included because they had both CT and RT-PCR testing upon admission. Overall, 112 patients (46.9%) had a positive initial RT-PCR, and 14 (5.9%) had a positive repeat RT-PCR. Of 127 patients with a negative or indeterminate initial RT-PCR, 38 (29.9% [95%CI 21.3-39.3%]) had a positive CT. Of these, 13 had a positive RT-PCR upon repeat testing, and 5 had positive serology. The remaining 20 patients were assessed in a multidisciplinary consensus meeting, and for 13 it was concluded that COVID-19 was ‘very likely’. Of 112 patients with a positive initial RT-PCR result, CT was positive in 104 (92.9% [95%CI 89.3-97.5%]). Conclusion: In a high-prevalence emergency department setting, chest CT showed high probability of COVID-19 (CO-RADS 4-5) in 29.9% of patients with a negative or indeterminate initial RT-PCR result. As the majority of these patients had proven or ‘very likely’ COVID-19 after follow-up, we believe that CT helps in the identification of patients who should be admitted in isolation.