Primary exposure to SARS-CoV-2 variants elicits convergent epitope specificities, immunoglobulin V gene usage and public B cell clones.

An important consequence of infection with a SARS-CoV-2 variant is protective humoral immunity against other variants. However, the basis for such cross-protection at the molecular level is incompletely understood. Here, we characterized the repertoire and epitope specificity of antibodies elicited by infection with the Beta, Gamma and WA1 ancestral variants and assessed their cross-reactivity to these and the more recent Delta and Omicron variants. We developed a method to obtain immunoglobulin sequences with concurrent rapid production and functional assessment of monoclonal antibodies from hundreds of single B cells sorted by flow cytometry. Infection with any variant elicited similar cross-binding antibody responses exhibiting a conserved hierarchy of epitope immunodominance. Furthermore, convergent V gene usage and similar public B cell clones were elicited regardless of infecting variant. These convergent responses despite antigenic variation may account for the continued efficacy of vaccines based on a single ancestral variant.

Boosting corrects a memory B cell defect in SARS-CoV-2 mRNA-vaccinated patients with inflammatory bowel disease.

Immunosuppressed patients with inflammatory bowel disease (IBD) generate lower amounts of SARS-CoV-2 spike antibodies after mRNA vaccination than healthy controls. We assessed SARS-CoV-2 spike S1 receptor binding domain-specific (S1-RBD-specific) B lymphocytes to identify the underlying cellular defects. Patients with IBD produced fewer anti-S1-RBD antibody-secreting B cells than controls after the first mRNA vaccination and lower amounts of total and neutralizing antibodies after the second. S1-RBD-specific memory B cells were generated to the same degree in IBD and control groups and were numerically stable for 5 months. However, the memory B cells in patients with IBD had a lower S1-RBD-binding capacity than those in controls, which is indicative of a defect in antibody affinity maturation. Administration of a third shot to patients with IBD elevated serum antibodies and generated memory B cells with a normal antigen-binding capacity. These results show that patients with IBD have defects in the formation of antibody-secreting B cells and affinity-matured memory B cells that are corrected by a third vaccination.

Implementation of an Anticoagulation Practice Guideline for COVID-19 via a Clinical Decision Support System in a Large Academic Health System and Its Evaluation: Observational Study.

BACKGROUND: Studies evaluating strategies for the rapid development, implementation, and evaluation of clinical decision support (CDS) systems supporting guidelines for diseases with a poor knowledge base, such as COVID-19, are limited. OBJECTIVE: We developed an anticoagulation clinical practice guideline (CPG) for COVID-19, which was delivered and scaled via CDS across a 12-hospital Midwest health care system. This study represents a preplanned 6-month postimplementation evaluation guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. METHODS: The implementation outcomes evaluated were reach, adoption, implementation, and maintenance. To evaluate effectiveness, the association of CPG adherence on hospital admission with clinical outcomes was assessed via multivariable logistic regression and nearest neighbor propensity score matching. A time-to-event analysis was conducted. Sensitivity analyses were also conducted to evaluate the competing risk of death prior to intensive care unit (ICU) admission. The models were risk adjusted to account for age, gender, race/ethnicity, non-English speaking status, area deprivation index, month of admission, remdesivir treatment, tocilizumab treatment, steroid treatment, BMI, Elixhauser comorbidity index, oxygen saturation/fraction of inspired oxygen ratio, systolic blood pressure, respiratory rate, treating hospital, and source of admission. A preplanned subgroup analysis was also conducted in patients who had laboratory values (D-dimer, C-reactive protein, creatinine, and absolute neutrophil to absolute lymphocyte ratio) present. The primary effectiveness endpoint was the need for ICU admission within 48 hours of hospital admission. RESULTS: A total of 2503 patients were included in this study. CDS reach approached 95% during implementation. Adherence achieved a peak of 72% during implementation. Variation was noted in adoption across sites and nursing units. Adoption was the highest at hospitals that were specifically transformed to only provide care to patients with COVID-19 (COVID-19 cohorted hospitals; 74%-82%) and the lowest in academic settings (47%-55%). CPG delivery via the CDS system was associated with improved adherence (odds ratio [OR] 1.43, 95% CI 1.2-1.7; P<.001). Adherence with the anticoagulation CPG was associated with a significant reduction in the need for ICU admission within 48 hours (OR 0.39, 95% CI 0.30-0.51; P<.001) on multivariable logistic regression analysis. Similar findings were noted following 1:1 propensity score matching for patients who received adherent versus nonadherent care (21.5% vs 34.3% incidence of ICU admission within 48 hours; log-rank test P<.001). CONCLUSIONS: Our institutional experience demonstrated that adherence with the institutional CPG delivered via the CDS system resulted in improved clinical outcomes for patients with COVID-19. CDS systems are an effective means to rapidly scale a CPG across a heterogeneous health care system. Further research is needed to investigate factors associated with adherence at low and high adopting sites and nursing units.

High-affinity memory B cells induced by SARS-CoV-2 infection produce more plasmablasts and atypical memory B cells than those primed by mRNA vaccines.

Although both infections and vaccines induce memory B cell (MBC) populations that participate in secondary immune responses, the MBCs generated in each case can differ. Here, we compare SARS-CoV-2 spike receptor binding domain (S1-RBD)-specific primary MBCs that form in response to infection or a single mRNA vaccination. Both primary MBC populations have similar frequencies in the blood and respond to a second S1-RBD exposure by rapidly producing plasmablasts with an abundant immunoglobulin (Ig)A+ subset and secondary MBCs that are mostly IgG+ and cross-react with the B.1.351 variant. However, infection-induced primary MBCs have better antigen-binding capacity and generate more plasmablasts and secondary MBCs of the classical and atypical subsets than do vaccine-induced primary MBCs. Our results suggest that infection-induced primary MBCs have undergone more affinity maturation than vaccine-induced primary MBCs and produce more robust secondary responses.