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Preprint in English | EMBASE | ID: ppcovidwho-326972


The mutational landscape of SARS-CoV-2 varies at both the dominant viral genome sequence and minor genomic variant population. An early change associated with transmissibility was the D614G substitution in the spike protein. This appeared to be accompanied by a P323L substitution in the viral polymerase (NSP12), but this latter change was not under strong selective pressure. Investigation of P323L/D614G changes in the human population showed rapid emergence during the containment phase and early surge phase of wave 1 in the UK. This rapid substitution was from minor genomic variants to become part of the dominant viral genome sequence. A rapid emergence of 323L but not 614G was observed in a non-human primate model of COVID-19 using a starting virus with P323 and D614 in the dominant genome sequence and 323L and 614G in the minor variant population. In cell culture, a recombinant virus with 323L in NSP12 had a larger plaque size than the same recombinant virus with P323. These data suggest that it may be possible to predict the emergence of a new variant based on tracking the distribution and frequency of minor variant genomes at a population level, rather than just focusing on providing information on the dominant viral genome sequence e.g., consensus level reporting. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Preprint in English | MEDLINE | ID: ppcovidwho-326575


COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNgamma based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

Annals of Oncology ; 31:S992, 2020.
Article in English | EMBASE | ID: covidwho-805759


Background: The SARS-CoV-2 pandemic in the UK triggered a national characterisation protocol and information on co-morbidities including malignant neoplasm is recorded. A lack of prospective data regarding cancer patients with COVID-19 hampers the development of an evidence based approach in this population. The Clinical Characterisation Protocol-CANCER-UK is a UK multi-disciplinary project aimed at characterising the presentation and course of COVID-19 in cancer patients with the aim of informing practice. Methods: The international Severe Acute Respiratory and emerging Infections Consortium (ISARIC)-4C COVID-19 Clinical Information Network (CO-CIN) collects data on hospital inpatients with proven/high likelihood of COVID-19. Data was collected in 166 UK sites using a questionnaire adopted by the WHO. Data on patients with malignant neoplasm was extracted from the main dataset. We chose a priori to restrict any analysis of outcome to patients who were admitted more than 14 days before data extraction (13th May 2020). Results: As of 13th May 2020 1797 of 16160 participants had malignant neoplasm (8.6% of all cases). Age<50 62 (3.5%), 50-60 378 (21%), 70-79 558 (31%), 80+ 1002 (42%). Male 1147 (64%);Female 645 (36%). Commonest comorbidities chromic pulmonary disease (22%), chronic kidney disease (21%), uncomplicated diabetes (19%) and dementia (14%). Outcomes 35% discharged alive, 30% care ongoing & 35% died. Admiited to ICU: 150 cases (25% discharged alive,31% care ongoing & 45% died). Receiving invasive ventiation: 67 cases (18% discharged alive, 25% care ongoing:25% & 57% died). HR mortality for malignancy (adjusted for age, sex, other comorbidity): 1.13 (1.02-1.24, p=0.017). Data on presentation will be presented. Conclusions: Europe’s largest prospective COVID-19 dataset demonstrates that cancer is independently associated with mortality in patients admitted with COVID-19. Data collection is on-going and updated data will be presented including a comparison of cancer vs. non-cancer cohort with regard to presentation, comorbidity and otucomes. Clinical trial identification: ISRCTN66726260. Legal entity responsible for the study: and international Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Coronavirus Clinical Characterisation Consortium (ISARIC4C). Funding: UK Research and Innovation, Medical Research Council and Department for Health and Social Care. Disclosure: All authors have declared no conflicts of interest.