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Background: The COVID-19 pandemic has been striking for three years and, despite the regular arise of new variants, populations are now widely immune and protected from severe symptoms. However, immunocompromised patients still have worse clinical outcomes, higher mortality and rarely develop effective immunity through vaccination or infection. Here, we studied the temporal distribution of infections, viral loads (VL) as well as the viral genetic diversity among an immunocompromised patient cohort, between January 2021 and September 2022. Method(s): Overall, 478 immunocompromised patients (solid organ transplant, HIV positive, cancer, autoimmune disease) and 234 controls (healthcare workers) from Pitie-Salpetriere and Bichat Claude-Bernard University hospitals (Paris, FRANCE) were diagnosed with SARS-CoV-2 infection by RT-qPCR. Whole genome sequencing was performed according to ARTIC protocol on Oxford Nanopore platform. All 712 full viral genomes were used to determine lineages and mapped to Wuhan-Hu-1 reference to produce a maximum likelihood phylogenetic tree (IQTree, 1000 bootstraps). Differences in temporal distributions of infections and VL were assessed using nonparametric statistical tests. Result(s): According to phylogenetic analysis, genomes from SARS-CoV- 2 infecting immunocompromised patients and those infecting healthy individuals are distributed in a similar way. No significant genetic differences can be observed between viral genomes from patients and controls within the different lineages. Temporal distribution of COVID-19 infections were also similar between immunocompromised patients and controls, with the exception of BA.2 variant for which controls were infected earlier (p< 0.001). VL were significantly lower in immunocompromised patients infected with Omicron variants (p=0.04). No differences in VL were observed for Alpha and Delta variants. Conclusion(s): At diagnosis, no intrinsic genetic divergence was observed in virus infecting immunocompromised patients compared to those circulating in the general population. Similarities in temporal distribution of infections between controls and patients suggest that these different groups become infected concomitantly. VL appeared to be lower for Omicron variants in immunocompromised patients. An earlier VL peak of Omicron and a testing of immunocompromised patients hospitalized once severe symptoms have appeared could indicate a delayed testing in these patients, once the replicative phase over. (Figure Presented).
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Background: At the end of 2021, concomitantly with the beginning of Omicron variant circulation, pre-exposure prophylaxis with the dual monoclonal long-acting monoclonal antibodies tixagevimab/cilgavimab became available in France to protect patients non-responding or non-eligible to SARS-CoV-2 vaccination at risk of severe COVID-19. Method(s): This study included patients who received tixagevimab/cilgavimab for pre-exposure prophylaxis independently of vaccination status or previous SARS-CoV-2 infection. This prophylaxis strategy was implemented at the Bichat-Claude Bernard University Hospital, Paris since December 2021 Last date of follow-up was November 1st, 2022. Incident SARS-CoV-2 infections were detected based on positive RT-PCR result and/or anti-nucleocapsid antibodies seroconversion. Severe COVID-19 was defined as an infection leading to an hospitalization requiring oxygenotherapy and/or high dose corticotherapy. Result(s): Among the 275 patients who received a tixagevimab/cilgavimab preexposure prophylaxis, 55% (n=153) were solid organ transplant recipients (50% lung, 46% kidney, 4% heart transplants), 42% (n=116) had an autoimmune disease, and 3% (n=6) had other indications. 51% (n=141) of all patients received rituximab. No severe adverse event of tixagevimab/cilgavimab was observed. Incident SARS-CoV-2 infection was diagnosed in 67 patients (24%). Among them, 59% (n=40) were solid organ transplant recipients, 36% (n=24) had an autoimmune disease and overall 52% had received rituximab. For the 56 patients whose infection date was available, the median delay between the last infusion of tixagevimab/cilgavimab and SARS-CoV-2 infection was 62 days (IQR=[30-97]). During the study period, 57% of incident infections occurred between December 17th, 2021 and May 31st, 2022, when BA.1 and BA.2 were the major Omicron sublineages in France, and 43% between June 1st, 2022 and November 2022 1st, a period during which BA.4 and BA.5 were predominant in France. Severe COVID-19 occurred in 6 patients out of 67 (9%);5 were solid organ transplant recipients and 3 received rituximab. No death due to COVID-19 was reported. Conclusion(s): Overall, 76% of patients receiving pre-exposure prophylaxis with tixagevimab/cilgavimab had no incident SARS-CoV-2 infection during the study period. Severe COVID-19 was observed in 9% of infected patients. These results suggest a potential protective effect in-vivo of tixagevimab/cilgavimab during the study period despite the circulation of different Omicron sublineages.
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Background: Immunocompromised hosts with prolonged SARS-CoV-2 infections have been associated with the emergence of novel mutations, especially in the Spike protein, a key target for vaccines and therapeutics. Here, we conducted a case-control study to measure the genetic diversity of SARSCoV- 2 and to search for immunocompromised-specific minority variants. Method(s): SARS-CoV-2-positive patients with lung/cardiac/kidney transplant, HIV-positive, or treated with high doses of corticosteroids for auto-immune diseases were considered as immunocompromised hosts. SARS-CoV-2-positive healthcare workers with no auto-immune disease were used as controls. Samples were analyzed by RT-qPCR at Pitie-Salpetriere and Bichat Claude-Bernard university hospitals (Paris, France). Samples with Cycle threshold < 30 were selected for SARSCoV- 2 whole-genome sequencing using Oxford Nanopore protocol. Raw sequence data were mapped onto the Wuhan-Hu-1 reference genome, and consensus sequences were produced to determine the lineage. Only sequences covering at least 95% at >=50X depth of the Spike gene were investigated. In-house algorithms were developed to identify all majority and minority mutations in Spike. We defined a minority variant when it was present in >=6% and < 50% of the reads;and a majority variant when it was present in >50%. Result(s): We sequenced SARS-CoV-2 genome from 478 COVID-19- positive immunocompromised patients and 234 controls. More minority non-synonymous mutations in Spike were detected in viruses from immunocompromised hosts, compared to viral genomes from controls, in both Delta (p=0.001) and Omicron (p< 0.001) lineages, but not in Alpha (p=0.66) (Figure 1). Interestingly, among the 52 patients infected with the Delta variant, we concomitantly detected at low frequencies the mutations H655Y, N764K, D796Y, in three patients (associated with different auto-immune disease), that are part of Omicron variants signature mutations. Similarly, some patients (n=7) infected by Omicron BA.1 lineage had R346T at low-frequency, later fixed in Omicron BA.4.6 and BQ.1.1 lineages. None of these mutations were observed in the viral genomes from controls. Conclusion(s): Here, we report a higher genetic diversity in Spike gene among SARS-CoV-2 sequences from immunocompromised hosts for Delta and Omicron lineages. These results suggest that immunocompromised patients are more likely to allow viral genetic diversification and are associated with a risk of emergence of novel SARS-CoV-2 variants. (Figure Presented).
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Alors que la vaccination anti-SARS-CoV-2 est devenue un enjeu important de la prise en charge des patients atteints de maladies auto-immunes systémiques telles que le lupus érythémateux systémique (LES), nous manquons de données sur l'impact de la vaccination par ARN messager sur l'auto-immunité. Notre objectif était de décrire l'impact de la vaccination par ARNm sur la production d'interféron alpha et l'auto-immunité cellulaire au cours du lupus. Nous avons réalisé une étude prospective, observationnelle, monocentrique au cours de laquelle nous avons inclus des patients atteints de LES, éligibles à la vaccination anti-SARS-CoV-2 par le vaccin BNT162b2 selon les recommandations françaises alors en vigueur. Nous avons secondairement exclu les patients non-naïfs vis-à-vis de l'infection par le SARS-CoV-2 à T0 et les patients sous mycophénolate, azathioprine ou rituximab. Les patients étaient évalués juste avant la première dose, puis à 1 mois (M1), à 3 mois (M3) et à 6 mois (M6) de leur première dose. En plus du suivi clinicobiologique habituel de la maladie, nous avons évalué la production d'IFN-alpha par les cellules dendritiques plasmacytoïdes (pDCs) en cytométrie de flux. Nous avons également quantifié l'auto-immunité T en mesurant la proportion de cellules T activées (CD154+ CD69+) après stimulation des cellules sanguines mononucléées périphériques (PBMCs) par des antigènes nucléaires (U1-RNP, histones, SS-A, SS-B). Trente-six patients lupiques et 11 contrôles sains ont été inclus. Les patients lupiques étaient majoritairement des femmes (31/36, 81 %) d'un âge médian de 44 [36–50] ans. Nous avons observé une augmentation significative de la proportion de pDCs produisant spontanément de l'IFN-alpha à M1 (1,27 % [0,6–2,6]) et M3 (1,25 % [0,87–1,83]) comparativement à T0 (0,64 [0,27–1,09] %, respectivement p < 0,001 et p < 0,01) chez les lupiques. Nous avons observé une augmentation similaire dans le groupe contrôle, mais uniquement à M1 (1,46 [0,95–2,12] %) comparativement à T0 (0,25 [0,12–0,47] %, p < 0,02). Par ailleurs, les pDCs des patients lupiques exprimaient à leur surface plus de marqueurs d'activation CD86 et HLA-DR à M3 que à T0. Concernant la proportion de cellules T auto-réactives des patients lupiques, nous avons observé, qu'après une hausse non significative entre T0 et M1, les cellules auto-réactives diminuaient significativement dans le temps (coefficient β d l'effet fixe associé au temps dans le modèle linéaire à effet mixte = −0,00067, p = 0,015). Nous n'avons pas observé une telle tendance chez les contrôles. Au cours du suivi, nous avons observé 2 poussées cliniques de la maladie. À l'exception de ces patients, nous n'avons pas constaté de modification significative du SLEDAI, du taux d'anti-dsDNA, de C3 ou de C4 dans la cohorte. Chez les patients lupiques, la vaccination anti-SARS-CoV-2 par ARNm entraîne (1) une augmentation modeste infra-clinique de la production spontanée d'IFN-alpha par les pDCs et (2) une diminution des cellules T auto-réactives spécifiques des antigènes nucléaires. (French) [ FROM AUTHOR]
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Background: An emergency use authorization was issued in March 2021 for two combinations of monoclonal antibodies (MAbs) for SARS-CoV-2 infected patients at high risk of severe COVID-19. We performed a cohort study of patients receiving early treatment with Bamlanivimab/Etesevimab (B/E) or Casirivimab/Imdevimab (C/I) in a Paris university hospital. Methods: All patients receiving a MAbs therapy from March to July 2021 were included. Prescriptions were systematically advised by a multidisciplinary team. Both MAbs dual therapies were used up to May 12th, then only C/I due to local emergence of Delta variant. Nasopharyngeal swabs (NPS) were performed at diagnosis and 7 days after infusion. Additional NPS were collected for hospitalized patients at day 3 and during follow-up until negative RT-PCR or patients discharge. Viral sequencing was carried out and viral mutations were retained if present at more than 20% of viral subpopulations. Results: Overall, 66 patients (19 ambulatory) received a MAbs dual therapy for a documented SARS-CoV-2 asymptomatic infection or within 5 days after symptoms onset. Patients had a median age of 67 years [IQR=41-75], 53% were male, 30 (45%) were receiving immunosuppressive treatment (17 being solid organ recipients), 8 (12%) had chronic respiratory insufficiency, and 6 (9%) were receiving chemotherapy. Regarding variants, 82% were Alpha, 5% Delta and 13% other variants. 8 patients (12%) died (6 treated with B/E and two with C/I). Five deaths were related to COVID-19 worsening and three were unrelated. Among the surviving patients, 42 (64%) did not require any oxygen and 16 (24%) required low-flow oxygen. No severe adverse event related to MAbs occurred. A slower viral decay was observed among patients receiving B/E than C/I, with 17/29 and 5/13 having <30 Ct at day 7 post-infusion (p=0.3), respectively, and 9/14 and 1/8 at day 14 (p=0.03). Different Spike mutations emergence were observed including Q493R in 7 patients and E484K in 2 patients, all infected with an Alpha variant, and detected from 6 to 18 days after MAbs infusion. Among the 9 mutations, 8 occurred after B/E infusion and one Q493R occurred after C/I infusions. Conclusion: We described safety and efficacy of early MAbs therapies administration in a cohort of 66 patients at risk of severe COVID-19. Emergence of mutations were observed under both therapies, with increased frequency under B/E. Further studies including patients infected by Delta variant and receiving C/I infusion are ongoing.
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Background: Recent studies reported poor to moderate humoral response after two vaccine doses in heart transplant recipients (HTR). Currently, French healthcare authorities recommend 2 and 3 vaccine injections for transplant recipients with and without prior SARS-CoV-2 infection, respectively. This study aimed to evaluate level and durability of humoral immunity with this vaccination strategy. Methods: This single-center cohort study included HTR followed at Paris Bichat hospital between January 2020 and September 2021. Analyses were performed using automated immunoassays (Abbot) to quantify anti-spike IgG (cut-off ≥ 7.1 BAU/mL) and anti-nucleocapsid IgG (cut-off index > 0.49), respectively. Categorical variables were described as number (%) and continuous variables with median (IQR). Results: A total of 181 HTR (75.7% males, age 58 y [47-66]) transplanted between June 1990 and June 2021, with cardiomyopathy (n=95), coronary artery disease (n=61), valvular cardiomyopathy (n=19) or other transplant indications were included. Median time from transplantation to first vaccine dose was 4.2 y [1.8-6.6]. 143 HTR (79%) had no SARS-CoV-2 infection history (HTRn) and 38 (21%) contracted the infection (HTRi) (56% before and 42% after vaccination initiation). After 2 vaccine injections, anti-S IgG seroconversion was observed for only 16% (n=12/76) of HTRn. Overall, anti-S IgG titers were lower in HTRn than in HTRi (0.5 [0.2-2.6] vs 578 [1.4-4449] BAU/mL, respectively, p=0.0001). The 3rd vaccine dose enabled to obtain 42% (n=33/72) of seroconversion among HTRn with median anti-S titers of 3.2 BAU/mL [0.4-35.0]. Only half seroconverters HTRn reached the 260 BAU/mL cut-off chosen by French authorities to define vaccination efficacy. Interestingly, these patients seem to have a sustained humoral response 4 months after the 3rd dose. Conclusion: This study gives new insights on the effect of the 3rd vaccine dose in HTR with low rate of seroconversion and low titers of anti-S IgG but sustained humoral response when seroconversion occurs. Studies on vaccine efficacy against SARS-CoV-2 variants and cell-mediated immune response in this cohort are ongoing.