Inflammatory markers and auto-Abs to type I IFNs in COVID-19 convalescent plasma cohort study.

BACKGROUND: COVID-19 convalescent plasma (CCP) contains neutralising anti-SARS-CoV-2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. METHODS: CCP (n = 766) was compared to non-convalescent control plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralising auto-Abs to type I IFNs and reported adverse events in the recipients. FINDINGS: CCP exhibited a statistically significant increase in IL-6 and TNF-alpha levels (0.531 ± 0.04 vs 0.271 ± 0.04; (95% confidence interval [CI], 0.07371-0.4446; p = 0.0061) and 0.900 ± 0.07 vs 0.283 ± 0.07 pg/mL; (95% [CI], 0.3097-0.9202; p = 0.0000829) and lower IL-10 (0.731 ± 0.07 vs 1.22 ± 0.19 pg/mL; (95% [CI], -0.8180 to -0.1633; p = 0.0034) levels than control plasma. Neutralising auto-Abs against type I IFNs were detected in 14/766 (1.8%) CCPs and were not associated with reported adverse events when transfused. Inflammatory markers and bioactivity in CCP with or without auto-Abs, or in CCP whether or not linked to adverse events in transfused patients, did not differ to a statistically significant extent. INTERPRETATION: Overall, CCP exhibited moderately increased inflammatory markers compared to the control plasma with no discernible differences in ex-vivo bioactivity. Auto-Abs to type I IFNs detected in a small fraction of CCP were not associated with reported adverse events or differences in inflammatory markers. Additional studies, including careful clinical evaluation of patients treated with CCP, are required in order to further define the clinical relevance of these findings. FUNDING: French National Blood Service-EFS, the Association "Les Amis de Rémi" Savigneux, France, the "Fondation pour la Recherche Médicale (Medical Research Foundation)-REACTing 2020".

Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant.

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.

Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis.

Patients with hematological malignancy and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatments impair humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears as a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2. We report the effect of CCP in a cohort of 112 patients with hematological malignancy and COVID-19 and a propensity score analysis on subgroups of patients with B-cell lymphoid disease treated (n = 81) or not (n = 120) with CCP between May 1, 2020 and April 1, 2021. The overall survival of the whole cohort was 65% (95% CI = 56-74.9) and 77.5% (95% CI = 68.5-87.7) for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibody therapy was associated with better overall survival, whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome. After an inverse probability of treatment weighting approach, we observed in anti-CD20-exposed patients with B-cell lymphoid disease a decreased mortality of 63% (95% CI = 31-80) in the CCP-treated group compared to the CCP-untreated subgroup, confirmed in the other sensitivity analyses. Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response.

La diversité du répertoire des cellules B mémoires fait face aux variants du SRAS-CoV2 après la vaccination par ARNm chez les individus naïfs et guéris

L'émergence de variants portant des mutations dans des épitopes clés a fait craindre que l'évolution virale n'érode l'immunité acquise. Caractérisé la dynamique et la fonctionnalité de la réponse B mémoire naturelle et acquise après administration d'un vaccin à ARNm. Nous avons analysé, au cours du temps, 33 sujets avec un antécédent de la COVID-19 et 23 individus naïfs avant et après vaccination par ARNm. Nous avons combiné différentes approches, l'analyse transcriptomique en cellule unique, le séquençage du VH, le phénotypages cellulaire par cytométrie en flux multi-paramétriques ainsi que la mesure du pouvoir neutralisant des anticorps et leur affinité. La mémoire B anti-SARS-Cov-2 porte une empreinte d'un passage par le centre germinatif et parait stable chez la majorité des patients, et ce un an après l'infection initiale. Le rappel vaccinal mobilise les B mémoires sans entraîner de réduction de leur diversité. Chez les patients guéris, les B mémoires spécifiques du RBD montrent des preuves évidentes de sélection par affinité, un processus toujours en cours chez les individus naïfs, deux mois après leur deuxième dose. Seule une faible proportion de clones B mémoires spécifiques du domaine RBD n'a pas réussi à reconnaître le variant B.1.351. Néanmoins, de puissantes B mémoires neutralisant le B.1.351 pourraient toujours être détectés chez tous les individus naïfs et guéris de la Covid-19. En raison de sa diversité et de son affinité, le répertoire B mémoires anti la protéine RBDwt, sélectionné lors de l'infection ou la vaccination contient des clones capables de faire face à l'évolution virale. (French) [ABSTRACT FROM AUTHOR] Copyright of Transfusion Clinique et Biologique is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Protocole d'usage thérapeutique du plasma de convalescent de COVID-19–Suivi

L'ANSM a autorisé dans une décision du 29.04.2020, la collecte, la préparation, la conservation, la distribution et la délivrance du plasma de convalescent COVID-19 (PCC), celle-ci étant réalisée dans le cadre d'un protocole d'utilisation thérapeutique (PUT) pour les patients ayant une infection sévère à SARS-CoV-2 selon divers critères d'éligibilité. L'anonymisation de la demande est effectuée si l'indication a été validée en réunion de concertation pluridisciplinaire et que le patient a donné son consentement à la transfusion. Le nombre de demandes hebdomadaires de PCC fluctue beaucoup, avec un pic à 54 fin avril-début mai 2021. Au 13,07.2021, plus de 1000 demandes ont été reçues. Parmi les patients ayant reçu au moins un PCC, environ 2/3 sont des hommes et la quasi-totalité ont une comorbidité. Les patients sont âgés de quelques mois à 93 ans, 14 étant des enfants (6 de 0–9 ans, 8 de 10–19 ans). La distribution des groupes sanguins est similaire à celle de la population générale. À la demande de l'ANSM, un suivi avec le détail des transfusions, la survenue éventuelle d'un effet indésirable receveur ainsi que l'évolution du patient jusqu'à un bilan final est demandé et a été reçu pour une partie des patients. Certains ont bénéficié de plusieurs épisodes transfusionnels : deux pour 38 patients, et trois pour 6 patients avec une demande de suivi par séquençage viral à la recherche de sélection de variant. Les données des patients seront rétrospectivement incluses dans une cohorte nationale, dont le promoteur est l'IMEA et l'EFS un collaborateur scientifique, cohorte dans laquelle les patients recevant du PCC dans le cadre du PUT seront inclus prospectivement. (French) [ABSTRACT FROM AUTHOR] Copyright of Transfusion Clinique et Biologique is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Emerging RNA-Dependent RNA Polymerase Mutation in a Remdesivir-Treated B-cell Immunodeficient Patient With Protracted Coronavirus Disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered virus for which remdesivir is the only antiviral available. We report the occurrence of a mutation in RdRP (D484Y) following treatment with remdesivir in a 76-year-old female with post-rituximab B-cell immunodeficiency and persistent SARS-CoV-2 viremia. A cure was achieved after supplementation with convalescent plasma.

mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants.

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.

ABO blood group and COVID-19: a review on behalf of the ISBT COVID-19 Working Group.

Growing evidence suggests that ABO blood group may play a role in the immunopathogenesis of SARS-CoV-2 infection, with group O individuals less likely to test positive and group A conferring a higher susceptibility to infection and propensity to severe disease. The level of evidence supporting an association between ABO type and SARS-CoV-2/COVID-19 ranges from small observational studies, to genome-wide-association-analyses and country-level meta-regression analyses. ABO blood group antigens are oligosaccharides expressed on red cells and other tissues (notably endothelium). There are several hypotheses to explain the differences in SARS-CoV-2 infection by ABO type. For example, anti-A and/or anti-B antibodies (e.g. present in group O individuals) could bind to corresponding antigens on the viral envelope and contribute to viral neutralization, thereby preventing target cell infection. The SARS-CoV-2 virus and SARS-CoV spike (S) proteins may be bound by anti-A isoagglutinins (e.g. present in group O and group B individuals), which may block interactions between virus and angiotensin-converting-enzyme-2-receptor, thereby preventing entry into lung epithelial cells. ABO type-associated variations in angiotensin-converting enzyme-1 activity and levels of von Willebrand factor (VWF) and factor VIII could also influence adverse outcomes, notably in group A individuals who express high VWF levels. In conclusion, group O may be associated with a lower risk of SARS-CoV-2 infection and group A may be associated with a higher risk of SARS-CoV-2 infection along with severe disease. However, prospective and mechanistic studies are needed to verify several of the proposed associations. Based on the strength of available studies, there are insufficient data for guiding policy in this regard.

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

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has 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 pre-existing 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.

Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.