Omicron BA.1 breakthrough infection drives long-term remodeling of the memory B cell repertoire in vaccinated individuals. (preprint)

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reaction, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.

Immune escape of SARS-CoV-2 Omicron variant from mRNA vaccination-elicited RBD-specific memory B cells. (preprint)

Memory B cells (MBCs) represent a second layer of immune protection against SARS-CoV-2. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant is of major concern. We used bio-layer interferometry to assess the affinity against the receptor-binding-domain (RBD) of Omicron spike of 313 naturally expressed monoclonal IgG that were previously tested for affinity and neutralization against VOC prior to Omicron. We report here that Omicron evades recognition from a larger fraction of these antibodies than any of the previous VOCs. Additionally, whereas 30% of these antibodies retained high affinity against Omicron-RBD, our analysis suggest that Omicron specifically evades antibodies displaying potent neutralizing activity against the D614G and Beta variant viruses. Further studies are warranted to understand the consequences of a lower memory B cell potency on the overall protection associated with current vaccines.

Memory B cells control SARS-CoV-2 variants upon mRNA vaccination of naive and COVID-19 recovered individuals. (preprint)

How a previous SARS-CoV-2 infection may amplify and model the memory B cell (MBC) response elicited by mRNA vaccines was addressed by a comparative longitudinal study of two cohorts, naive individuals and disease-recovered patients, up to 2 months after vaccination. The quality of the memory response was assessed by analysis of the VDJ repertoire, affinity and neutralization against variants of concerns (VOC), using unbiased cultures of 2452 MBCs. Upon boost, the MBC pool of recovered patients selectively expanded, further matured and harbored potent neutralizers against VOC. Maturation of the MBC response in naive individuals was much less pronounced. Nevertheless, and as opposed to their weaker neutralizing serum response, half of their RBD-specific MBCs displayed high affinity towards multiple VOC and one-third retained neutralizing potency against B.1.351. Thus, repeated vaccine challenges could reduce these differences by recall of affinity-matured MBCs and allow naive vaccinees to cope efficiently with VOC.

Maturation and persistence of the anti-SARS-CoV-2 memory B cell response. (preprint)

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role have been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 Spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including preexisting cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late remarkably stable memory B-cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.

Corticosteroids are associated with increased survival in elderly presenting severe SARS-Cov2 infection (preprint)

To assess the effectiveness of corticosteroids among elderly patients with COVID-19 pneumonia requiring oxygen. Design Comparative observational study based on routine care data. Baseline characteristics of patients were balanced using propensity-score inverse probability of treatment weighting. Setting Geriatric and infectious diseases wards from 36 hospitals in France and Luxembourg. Participants Adults [≥] 80 years old PCR confirmed SARS-CoV-2 infection or typical CT-scan images, requiring oxygen [≥] 3L/min and with an inflammatory syndrome (C-reactive protein [≥] 40mg/L). Measurements The primary outcome was overall survival at day 14. The secondary outcome was the proportion of patients discharged from hospital to home/rehabilitation on day 14. Adverse events were abstracted from electronic health records. Results Among the 267 patients included in the analysis, 96 were assigned to the treatment group. Median age was 86, interquartile range 83 to 90 and 95% had a SARS-CoV-2 PCR-confirmed diagnosis. Use of corticosteroids was significantly associated with an increased survival (weighted hazard ratio [wHR] 0.66, 95% CI 0.44 to 0.97). There was no significant difference between the treatment and control groups regarding the proportion of patients discharged to home/rehabilitation at day 14 (wRR 1.11, 95% CI 0.68 to 1.81). Twenty-two (16.7%) patients receiving corticosteroids developed adverse events while only 11 (6.4%) from the control group did. Conclusions Corticosteroids were associated with a significant increase the day-14 overall survival of patients over 80 years old hospitalized for severe COVID-19.

Association between corticosteroids and intubation or death among patients with COVID-19 pneumonia in non-ICU settings: an observational study using of real-world data from 51 hospitals in France and Luxembourg (preprint)

Objective To assess the effectiveness of corticosteroids on outcomes of patients with mild COVID-19 pneumonia. Methods We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) vs standard of care (no-CTC group) among patients [≤] 80 years old with COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death at Day 28. Baseline characteristics of patients were balanced using propensity score inverse probability of treatment weighting. Results Among the 891 patients included in the analysis, 203 were assigned to the CTC group. At day 28, corticosteroids did not reduce the rate of the primary outcome (wHR 0.92, 95% CI 0.61 to 1.39) nor the cumulative death rate (wHR 1.03, 95% CI 0.54 to 1.98). Corticosteroids significantly reduced the rate of the primary outcome for patients requiring oxygen [≥] at 3L/min (wHR 0.50, 95% CI 0.30 to 0.85) or C-Reactive Protein (CRP) [≥] 100mg/L (wHR 0.44, 95%CI 0.23 to 0.85). We found a higher number of hyperglycaemia events among patients who received corticosteroids, but number of infections were similar across the two groups. Conclusions We found no association between the use of corticosteroids and intubation or death in the broad population of patients [≤]80 years old with COVID-19 hospitalized in non-ICU settings. However, the treatment was beneficial for patients with [≥] 3L/min oxygen or CRP [≥] 100mg/L at baseline. These data support the need to confirm the right timing of corticosteroids for patients with mild COVID.

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial (preprint)

Background Treatments are urgently needed to prevent respiratory failure and deaths from coronavirus disease 2019 (COVID-19). Hydroxychloroquine (HCQ) has received worldwide attention because of positive results from small studies. Methods We used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen [≥] 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day. The composite primary endpoint was transfer to intensive care unit (ICU) within 7 days from inclusion and/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47-1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation. Interpretation These results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.