Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies

The emergence of novel Omicron lineages, such as BA.5, may impact the therapeutic efficacy of anti-SARS-CoV-2 neutralizing monoclonal antibodies (mAbs). Here, we evaluated the neutralization and ADCC activity of 6 therapeutic mAbs against Delta, BA.2, BA.4 and BA.5 isolates. The Omicron sub-variants escaped most of the antibodies but remained sensitive to Bebtelovimab and Cilgavimab. Consistent with their shared spike sequence, BA.4 and BA.5 displayed identical neutralization profiles. Sotrovimab was the most efficient at eliciting ADCC. We also analyzed 121 sera from 40 immunocompromised individuals up to 6 months after infusion of 1200 mg of Ronapreve (Imdevimab + Casirivimab), and 300 or 600 mg of Evusheld (Cilgavimab + Tixagevimab). Sera from Ronapreve-treated individuals did not neutralize Omicron subvariants. Evusheld-treated individuals neutralized BA.2 and BA.5, but titers were reduced by 41- and 130-fold, respectively, compared to Delta. A longitudinal evaluation of sera from Evusheld-treated patients revealed a slow decay of mAb levels and neutralization. The decline was more rapid against BA.5. Our data shed light on the antiviral activities of therapeutic mAbs and the duration of effectiveness of Evusheld pre-exposure prophylaxis.

Seroneutralization of Omicron BA.1 and BA.2 in patients receiving anti-SARS-CoV-2 monoclonal antibodies.

The SARS-CoV-2 Omicron BA.1 variant has been supplanted in many countries by the BA.2 sub-lineage. BA.2 differs from BA.1 by about 21 mutations in its spike. Human anti-spike monoclonal antibodies (mAbs) are used for prevention or treatment of COVID-19. However, the capacity of therapeutic mAbs to neutralize BA.1 and BA.2 remains poorly characterized. Here, we first compared the sensitivity of BA.1 and BA.2 to neutralization by 9 therapeutic mAbs. In contrast to BA.1, BA.2 was sensitive to Cilgavimab, partly inhibited by Imdevimab and resistant to Adintrevimab and Sotrovimab. Two combinations of mAbs, Ronapreve (Casirivimab + Imdevimab) and Evusheld (Cilgavimab + Tixagevimab), are indicated as a pre-exposure prophylaxis in immunocompromised persons at risk of severe disease. We analyzed sera from 29 such individuals, up to one month after administration of Ronapreve and/or Evusheld. After treatment, all individuals displayed elevated antibody levels in their sera and neutralized Delta with high titers. Ronapreve recipients did not neutralize BA.1 and weakly impaired BA.2. With Evusheld, neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 patients, respectively. As compared to Delta, titers were more severely decreased against BA.1 (344-fold) than BA.2 (9-fold). We further report 4 breakthrough Omicron infections among the 29 participants. Therefore, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron activity of Ronapreve, and to a lesser extent that of Evusheld, is reduced in patients sera, a phenomenon associated with decreased clinical efficacy.

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

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.

Immunogenicity of BNT162b2 vaccine Against the Alpha and Delta Variants in Immunocompromised Patients

BackgroundThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. To what extent Delta evades vaccine-induced immunity in immunocompromised individuals with systemic inflammatory diseases remains unclear. MethodsWe conducted a prospective study in patients with systemic inflammatory diseases (cases) and controls receiving two doses of BNT162b2. Primary end points were anti-spike antibodies levels and cross-neutralization of Alpha and Delta variants after BNT162b2 vaccine. Secondary end points were T-cell responses, breakthrough infections and safety. ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analyzed. Kinetics of anti-spike IgG and IgA after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralizing response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralized Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralizing activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after 2 doses of BNT162b2. ConclusionsRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (Funded by the Fonds IMMUNOV; ClinicalTrials.gov number, NCT04870411).

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

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.

AI-Driven CT-based quantification, staging and short-term outcome prediction of COVID-19 pneumonia

Improving screening, discovering therapies, developing a vaccine and performing staging and prognosis are decisive steps in addressing the COVID-19 pandemic. Staging and prognosis are especially crucial for organizational anticipation (intensive-care bed availability, patient management planning) and accelerating drug development; through rapid, reproducible and quantified response-to-treatment assessment. In this letter, we report on an artificial intelligence solution for performing automatic staging and prognosis based on imaging, clinical, comorbidities and biological data. This approach relies on automatic computed tomography (CT)-based disease quantification using deep learning, robust data-driven identification of physiologically-inspired COVID-19 holistic patient profiling, and strong, reproducible staging/outcome prediction with good generalization properties using an ensemble of consensus methods. Highly promising results on multiple independent external evaluation cohorts along with comparisons with expert human readers demonstrate the potentials of our approach. The developed solution offers perspectives for optimal patient management, given the shortage of intensive care beds and ventilators1, 2, along with means to assess patient response to treatment.

Ureterorenoscopy with holmium-yttrium-aluminum-garnet fragmentation is a safe and efficient technique for stone treatment in patients with a body mass index superior to 30 kg/m2.

PURPOSE: The aim of the study was to analyze results and morbidity after flexible ureterorenoscopy in patients with a body mass index (BMI) >30 kg/m(2) and to compare with results obtained in a large cohort of nonobese patients. PATIENTS AND METHODS: We conducted a retrospective study including all flexible ureterorenoscopy performed for stone retrieval in our institution between January 2004 and December 2008. During the study period, 224 procedures were performed, of which 18 had to be excluded because of missing BMI data. Thus, a total of 206 procedures were included in the final analysis (34 in 29 obese patients, 172 in 149 nonobese patients). Characteristics of the patients (age, BMI, previous treatment), stones (nature, location, number), and procedures (operating time, morbidity, outcome) were analyzed. Success was defined as clear imaging (completely stone free) on renal tomography and ultrasonography at 1, 3, and 6 months follow-up. RESULTS: Mean BMI was 34±0.6 kg/m(2) in obese patients (OP) and 24±0.2 kg/m(2) in nonobese patients (NOP). Mean stone size, location, and composition were not significantly different between groups. Operative time was also similar in OP and NOP (102.5±6.1 min vs 103±3.4 min, P=NS). The rate of minor complications (fever, hematuria, flank pain) was similar in OP (11.8%) and NOP (11.4%). No major complication necessitating prolonged hospital stay or new surgical procedure was observed. The overall stone-free rate was not significantly different between OP (79.4%) and NOP (70%). CONCLUSION: Flexible ureterorenoscopy is an appropriate treatment for use in obese patients and achieves excellent stone-free rates with low morbidity.