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1.
Meng, B.; Ferreira, I. A. T. M.; Abdullahi, A.; Goonawardane, N.; Saito, A.; Kimura, I.; Yamasoba, D.; Gerba, P. P.; Fatihi, S.; Rathore, S.; Zepeda, S. K.; Papa, G.; Kemp, S. A.; Ikeda, T.; Toyoda, M.; Tan, T. S.; Kuramochi, J.; Mitsunaga, S.; Ueno, T.; Shirakawa, K.; Takaori-Kondo, A.; Brevini, T.; Mallery, D. L.; Charles, O. J.; Bowen, J. E.; Joshi, A.; Walls, A. C.; Jackson, L.; Cele, S.; Martin, D.; Smith, K. G. C.; Bradley, J.; Briggs, J. A. G.; Choi, J.; Madissoon, E.; Meyer, K.; Mlcochova, P.; Ceron-Gutierrez, L.; Doffinger, R.; Teichmann, S.; Pizzuto, M.; de Marco, A.; Corti, D.; Sigal, A.; James, L.; Veesler, D.; Hosmillo, M.; Lee, J. H.; Sampaziotis, F.; Goodfellow, I. G.; Matheson, N. J.; Thukral, L.; Sato, K.; Gupta, R. K.; Kawabata, R.; Morizako, N.; Sadamasu, K.; Asakura, H.; Nagashima, M.; Yoshimura, K.; Ito, J.; Kimura, I.; Uriu, K.; Kosugi, Y.; Suganami, M.; Oide, A.; Yokoyama, M.; Chiba, M.; Saito, A.; Butlertanaka, E. P.; Tanaka, Y. L.; Ikeda, T.; Motozono, C.; Nasser, H.; Shimizu, R.; Yuan, Y.; Kitazato, K.; Hasebe, H.; Nakagawa, S.; Wu, J.; Takahashi, M.; Fukuhara, T.; Shimizu, K.; Tsushima, K.; Kubo, H.; Kazuma, Y.; Nomura, R.; Horisawa, Y.; Nagata, K.; Kawai, Y.; Yanagida, Y.; Tashiro, Y.; Tokunaga, K.; Ozono, S.; Baker, S.; Dougan, G.; Hess, C.; Kingston, N.; Lehner, P. J.; Lyons, P. A.; Matheson, N. J.; Owehand, W. H.; Saunders, C.; Summers, C.; Thaventhiran, J. E. D.; Toshner, M.; Weekes, M. P.; Maxwell, P.; Shaw, A.; Bucke, A.; Calder, J.; Canna, L.; Domingo, J.; Elmer, A.; Fuller, S.; Harris, J.; Hewitt, S.; Kennet, J.; Jose, S.; Kourampa, J.; Meadows, A.; O’Brien, C.; Price, J.; Publico, C.; Rastall, R.; Ribeiro, C.; Rowlands, J.; Ruffolo, V.; Tordesillas, H.; Bullman, B.; Dunmore, B. J.; Fawke, S.; Gräf, S.; Hodgson, J.; Huang, C.; Hunter, K.; Jones, E.; Legchenko, E.; Matara, C.; Martin, J.; Mescia, F.; O’Donnell, C.; Pointon, L.; Pond, N.; Shih, J.; Sutcliffe, R.; Tilly, T.; Treacy, C.; Tong, Z.; Wood, J.; Wylot, M.; Bergamaschi, L.; Betancourt, A.; Bower, G.; Cossetti, C.; de Sa, A.; Epping, M.; Fawke, S.; Gleadall, N.; Grenfell, R.; Hinch, A.; Huhn, O.; Jackson, S.; Jarvis, I.; Krishna, B.; Lewis, D.; Marsden, J.; Nice, F.; Okecha, G.; Omarjee, O.; Perera, M.; Potts, M.; Richoz, N.; Romashova, V.; Yarkoni, N. S.; Sharma, R.; Stefanucci, L.; Stephens, J.; Strezlecki, M.; Turner, L.; de Bie, E. M. D. D.; Bunclark, K.; Josipovic, M.; Mackay, M.; Mescia, F.; Michael, A.; Rossi, S.; Selvan, M.; Spencer, S.; Yong, C.; Allison, J.; Butcher, H.; Caputo, D.; Clapham-Riley, D.; Dewhurst, E.; Furlong, A.; Graves, B.; Gray, J.; Ivers, T.; Kasanicki, M.; Le Gresley, E.; Linger, R.; Meloy, S.; Muldoon, F.; Ovington, N.; Papadia, S.; Phelan, I.; Stark, H.; Stirrups, K. E.; Townsend, P.; Walker, N.; Webster, J.; Scholtes, I.; Hein, S.; King, R.; Márquez, S.; Prado-Vivar, B.; Becerra-Wong, M.; Caravajal, M.; Trueba, G.; Rojas-Silva, P.; Grunauer, M.; Gutierrez, B.; Guadalupe, J. J.; Fernández-Cadena, J. C.; Andrade-Molina, D.; Baldeon, M.; Pinos, A..
Web of Science; 2021.
Preprint in English | Web of Science | ID: ppcovidwho-331154

ABSTRACT

The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.

2.
Heart ; 107(SUPPL 1):A91, 2021.
Article in English | EMBASE | ID: covidwho-1325144

ABSTRACT

Background Limitation of activity and restriction of movement have been widely, and effectively, enforced to reduce COVID- 19 transmission. Physical activity is however a critical measure in the prevention of cardiovascular disease. Pulmonary arterial hypertension (PAH) is a devastating, disease driven by small vessel vascular remodeling, leading to right heart failure. Exercise capacity relates to clinical outcomes and exercise training improves key indicators of cardiopulmonary function. Here, we describe the temporal effects of UK government restriction measures on daily activity, heart rate and quality-of-life (QoL) in patients with PAH. Methods From November 2019 to March 2020 patients were enrolled into the arrhythmia sub-study of The UK National Cohort Study of Idiopathic and Heritable PAH (REC:13/EE/ 0203) and implanted with insertable cardiac monitors. Daily heart rate, heart rate variability and activity were transmitted remotely. Standard questionnaires were administered remotely to assess QoL (EmPHasis-10), anxiety (GAD-7) and depression (PHQ-9). Results Median age of the 26 patients implanted with insertable cardiac monitors was 49 years, 23(88%) were female and 5(19%) had heritable PAH with mutations in BMPR2. At enrolment 10(38.5%) patients were low risk (<5% 1-year mortality), 10(38.5%) were intermediate risk (5-10%) and 6 (23%) were high risk (>10%). The mean duration from insertion to census date was 21.1weeks±5.7. No complications were reported. Completeness of remote monitoring data was 100%. Following lockdown, mean activity was reduced (3.16vrs 2.68hours, -0.48 hours, 95%CI -0.27-0.69, 16%, p<0.0001). During the period April 14th to 23rd QoL was reduced (26(18-38)vrs 32 (17-47), p<0.01) and anxiety (1(0- 9)vrs 10 (5-18), p<0.001) and depression scores increased (3 (1-16)vrs 11 (3-17), p<0.001) compared to pre-lockdown levels. The observed increase in depression scores persisted to the census date (3(1-16)vrs 11(8-17), p<0.01). No change in day or night heart rate, or heart rate variability, was observed and no patients developed COVID-19. Conclusion In this cohort of patients with idiopathic and heritable PAH, UK protective health measures were effective in preventing COVID-19 in patients thought to be vulnerable. However, these protective measures resulted in reduced daily activity and QoL and were associated increased anxiety and depression indicators. Patients may decondition through periods of reduced activity. This may have implications for riskassessment and endpoint adjudication in clinical studies, both of which use measures of exercise capacity.

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