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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: 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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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: In 2020, France reported 2.7 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making it the second most affected European country by the COVID-19 pandemic after the United Kingdom. However, dynamics of SARS-CoV-2 transmissions within France or between France and other countries remains partially characterized. We propose an analysis of these dynamics on multiple scales, from the continents to the French administrative regions. Methods: We produced 736 SARS-CoV-2 sequences from Ile-de-France (Paris area, France) and analyzed them concomitantly with GISAID deposited sequences to elucidate the origins and spread of the virus from January 2020 to December 2020. A total of 4,571 worldwide sequences, including 1,652 French sequences, constituted the final dataset. All sequences were selected to be representative of each country temporal distribution of SARS-CoV-2 to the week resolution. We used a maximum likelihood phylogenetic framework to estimate the most probable temporal and geographic spread of SARS-CoV-2 within France and worldwide. Depending on the geographical focus (France, Europe or worldwide), we pruned the tree accordingly in 1,000 independent replicates. Results: Phylogenetic analysis revealed that, during the 1st French epidemic wave (from March to May), the majority of viruses introduced to France came from North America (USA) and Europe (Spain, Italy, ?). France regularly transmitted to neighboring European countries: Belgium, Germany, Italy and United Kingdom. Contrary to the 1st wave, inter-country transmission events were limited to neighboring countries and intercontinental transmission were almost absent during the French 2nd wave (from September to November). At the French regions-scale, we observed that Ile-de-France (IDF) was the main source of infections for all other French regions during the 1st epidemic wave, with a minor participation of Provence-Alpes-Côte d'Azur (PACA). For the 2nd epidemic wave, PACA was the main source of infections for all other French regions, with a lower participation of IDF and other regions. Conclusion: Overall, our findings allow a more comprehensive representation of SARS-CoV-2 transmission chains related to and within France and the global temporal distribution of those events, in link with control measures applied during the whole 2020 period. IDF and PACA were the main hubs of transmissions in France for the 1st and the 2nd epidemic waves, respectively.