The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed ...globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.
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•Reduced B.1.351 neutralization by mAbs and sera induced by early SARS-CoV-2 isolates•B.1.351 neutralization titer reduced 8- to 9-fold for Pfizer and AstraZeneca vaccinees•E484K, K417N, and N501Y cause widespread escape from mAbs•NTD deletion in B.1.351 abrogates neutralization by a potent neutralizing human mAb
Structure-function analysis of the SARS-CoV-2 variant B.1.351 using serum samples from convalescent and vaccinated individuals reveals how mutations in the viral spike protein result in tighter binding to the receptor ACE2 and allow escape from monoclonal antibody neutralization.
We address whether T cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, and NVX-CoV2373) cross-recognize early SARS-CoV-2 variants. T cell responses to early ...variants were preserved across vaccine platforms. By contrast, significant overall decreases were observed for memory B cells and neutralizing antibodies. In subjects ∼6 months post-vaccination, 90% (CD4+) and 87% (CD8+) of memory T cell responses were preserved against variants on average by AIM assay, and 84% (CD4+) and 85% (CD8+) preserved against Omicron. Omicron RBD memory B cell recognition was substantially reduced to 42% compared with other variants. T cell epitope repertoire analysis revealed a median of 11 and 10 spike epitopes recognized by CD4+ and CD8+ T cells, with average preservation > 80% for Omicron. Functional preservation of the majority of T cell responses may play an important role as a second-level defense against diverse variants.
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•T cells of vaccinees recognize SARS-CoV-2 variants, including Omicron•RBD memory B cells’ recognition of Omicron is reduced•A median of 11 CD4 and 10 CD8 spike epitopes are recognized in vaccinees•Average preservation > 80% for Omicron at the epitope level
Human memory T cells induced by SARS-CoV-2 vaccines maintain the ability to recognize viral variants, including the Omicron variant.
SARS-CoV-2 lineage B.1.1.7, a variant that was first detected in the UK in September 2020
, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more ...transmissible than pre-existing variants, but have not identified whether it leads to any change in disease severity
. Here we analyse a dataset that links 2,245,263 positive SARS-CoV-2 community tests and 17,452 deaths associated with COVID-19 in England from 1 November 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because mutations in this lineage prevent PCR amplification of the spike (S) gene target (known as S gene target failure (SGTF)
). On the basis of 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% confidence interval, 39-72%) higher than in cases without SGTF after adjustment for age, sex, ethnicity, deprivation, residence in a care home, the local authority of residence and test date. This corresponds to the absolute risk of death for a 55-69-year-old man increasing from 0.6% to 0.9% (95% confidence interval, 0.8-1.0%) within 28 days of a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate that the hazard of death associated with B.1.1.7 is 61% (42-82%) higher than with pre-existing variants. Our analysis suggests that B.1.1.7 is not only more transmissible than pre-existing SARS-CoV-2 variants, but may also cause more severe illness.
Animal experiments have shown that nonhuman primates, cats, ferrets, hamsters, rabbits, and bats can be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, ...SARS-CoV-2 RNA has been detected in felids, mink, and dogs in the field. Here, we describe an in-depth investigation using whole-genome sequencing of outbreaks on 16 mink farms and the humans living or working on these farms. We conclude that the virus was initially introduced by humans and has since evolved, most likely reflecting widespread circulation among mink in the beginning of the infection period, several weeks before detection. Despite enhanced biosecurity, early warning surveillance, and immediate culling of animals in affected farms, transmission occurred between mink farms in three large transmission clusters with unknown modes of transmission. Of the tested mink farm residents, employees, and/or individuals with whom they had been in contact, 68% had evidence of SARS-CoV-2 infection. Individuals for which whole genomes were available were shown to have been infected with strains with an animal sequence signature, providing evidence of animal-to-human transmission of SARS-CoV-2 within mink farms.
The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic ...sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%–50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.
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•The B.1.1.7 is ∼50% more transmissible than other circulating lineages in the US•The proportion of cases caused by B.1.1.7 is increasing at a rate of ∼7.5% per day•Several independent introductions of B.1.1.7 occurred in early December 2020•We estimate that B.1.1.7 will become dominant in many US states by late March 2021
Genomic epidemiology analyses explain the introduction and transmission of the B.1.1.7 variant of SARS-CoV-2 into the US, with projections for it to soon be the dominant strain in the country.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent ...increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.
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•Vaccine/convalescent sera show reduced neutralization of B.1.617.1 and B.1.617.2•Sera from B.1.351and P.1 show markedly reduced neutralization of B.1.617.2•B.1.351, P.1, and B.1.617.2 are antigenically divergent•Vaccines based on B.1.1.7 may protect broadly against current variants
The B.1.617 lineage of SARS-CoV-2, especially the delta strain, which is B.1.617.2, has contributed to the wave of infection in the Indian subcontinent. Structural and serological analyses show some evidence of antibody escape, and individuals infected previously with the B.1.351 (beta) and P.1 (gamma) variants are likely more susceptible to reinfection by the delta strain. Vaccines based on B.1.1.7 (alpha) are likely to provide the broadest protection against current variants.
Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction
during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing ...prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs.
). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain
. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.
The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern
. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant ...in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell-cell fusion
, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.
Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding was observed from the upper respiratory tract of a female immunocompromised individual with chronic lymphocytic ...leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and of genomic and subgenomic RNA up to 105 days, after initial diagnosis. The infection was not cleared after the first treatment with convalescent plasma, suggesting a limited effect on SARS-CoV-2 in the upper respiratory tract of this individual. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised individuals may shed infectious virus longer than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2-positive individuals as a proxy for shedding of infectious virus.
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•Persistent SARS-CoV-2 infection and shedding in immunocompromised individual•Infectious SARS-CoV-2 isolated up to 70 days after diagnosis•Observed within-host genetic variation with continuous turnover of viral variants•SARS-CoV-2 isolates from the individual do not display altered replication
This case study describes a female immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia who became persistently infected with SARS-CoV-2. Although asymptomatic throughout the course of infection, she demonstrated prolonged shedding of infectious SARS-CoV-2 virus and RNA. This study demonstrates that certain individuals may remain infectious for prolonged periods of time and highlights the need for further studies to understand risk factors for prolonged infectious SARS-CoV-2 shedding.
Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express ...inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 inflammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia.
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•SARS-CoV-2 infection activates human NLRP1 inflammasome in epithelial cells•NSP5 protease cleaves NLRP1 at Glutamine 333 and promotes functional degradation•NSP5 inactivates GSDMD by cleaving in its pore-forming domain at Glutamine 193•GSDME triggers alternative epithelial cell death upon GSDMD inactivation
Planès et al. identify human NLRP1 as an immune sensor of SARS-CoV2 3CL protease.
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