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1.
Nat Immunol ; 23(1): 40-49, 2022 01.
Article in English | MEDLINE | ID: covidwho-1585824

ABSTRACT

SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3-11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens.


Subject(s)
Antibodies, Viral/immunology , Coronavirus 229E, Human/immunology , Coronavirus OC43, Human/immunology , Cross Protection/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adaptive Immunity/immunology , Adult , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Child , Child, Preschool , Cross Reactions/immunology , Humans
2.
PLoS Pathog ; 17(12): e1010022, 2021 12.
Article in English | MEDLINE | ID: covidwho-1546978

ABSTRACT

Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 , Immunization, Secondary , SARS-CoV-2/immunology , /immunology , /immunology , COVID-19/immunology , COVID-19/mortality , COVID-19/prevention & control , HEK293 Cells , Humans
3.
PLoS Pathog ; 17(9): e1009929, 2021 09.
Article in English | MEDLINE | ID: covidwho-1430555

ABSTRACT

Remdesivir (RDV), a broadly acting nucleoside analogue, is the only FDA approved small molecule antiviral for the treatment of COVID-19 patients. To date, there are no reports identifying SARS-CoV-2 RDV resistance in patients, animal models or in vitro. Here, we selected drug-resistant viral populations by serially passaging SARS-CoV-2 in vitro in the presence of RDV. Using high throughput sequencing, we identified a single mutation in RNA-dependent RNA polymerase (NSP12) at a residue conserved among all coronaviruses in two independently evolved populations displaying decreased RDV sensitivity. Introduction of the NSP12 E802D mutation into our SARS-CoV-2 reverse genetics backbone confirmed its role in decreasing RDV sensitivity in vitro. Substitution of E802 did not affect viral replication or activity of an alternate nucleoside analogue (EIDD2801) but did affect virus fitness in a competition assay. Analysis of the globally circulating SARS-CoV-2 variants (>800,000 sequences) showed no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we observed an excess of substitutions in spike at corresponding sites identified in the emerging SARS-CoV-2 variants of concern (i.e., H69, E484, N501, H655) indicating that they can arise in vitro in the absence of immune selection. The identification and characterisation of a drug resistant signature within the SARS-CoV-2 genome has implications for clinical management and virus surveillance.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19 , Coronavirus RNA-Dependent RNA Polymerase/genetics , Drug Resistance, Microbial/genetics , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Animals , Biological Evolution , COVID-19/drug therapy , Chlorocebus aethiops , Humans , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
4.
Vet Rec ; 188(8): e247, 2021 04.
Article in English | MEDLINE | ID: covidwho-1198417

ABSTRACT

OBJECTIVES: The aim of the study was to find evidence of SARS-CoV-2 infection in UK cats. DESIGN: Tissue samples were tested for SARS-CoV-2 antigen using immunofluorescence and for viral RNA by in situ hybridisation. A set of 387 oropharyngeal swabs that had been submitted for routine respiratory pathogen testing was tested for SARS-CoV-2 RNA using reverse transcriptase quantitative PCR. RESULTS: Lung tissue collected post-mortem from cat 1 tested positive for both SARS-CoV-2 nucleocapsid antigen and RNA. SARS-CoV-2 RNA was detected in an oropharyngeal swab collected from cat 2 that presented with rhinitis and conjunctivitis. High throughput sequencing of the viral genome revealed five single nucleotide polymorphisms (SNPs) compared to the nearest UK human SARS-CoV-2 sequence, and this human virus contained eight SNPs compared to the original Wuhan-Hu-1 reference sequence. An analysis of the viral genome of cat 2 together with nine other feline-derived SARS-CoV-2 sequences from around the world revealed no shared cat-specific mutations. CONCLUSIONS: These findings indicate that human-to-cat transmission of SARS-CoV-2 occurred during the COVID-19 pandemic in the UK, with the infected cats developing mild or severe respiratory disease. Given the ability of the new coronavirus to infect different species, it will be important to monitor for human-to-cat, cat-to-cat and cat-to-human transmission.


Subject(s)
COVID-19/veterinary , Cat Diseases/virology , Lung/virology , SARS-CoV-2/isolation & purification , Zoonoses , Animals , COVID-19/epidemiology , COVID-19/transmission , Cats , Female , Humans , RNA, Viral , SARS-CoV-2/genetics , United Kingdom/epidemiology
5.
J Infect Dis ; 223(6): 971-980, 2021 03 29.
Article in English | MEDLINE | ID: covidwho-1155782

ABSTRACT

Identifying drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and quantifying population immunity is crucial to prepare for future epidemics. We performed a serial cross-sectional serosurvey throughout the first pandemic wave among patients from the largest health board in Scotland. Screening of 7480 patient serum samples showed a weekly seroprevalence ranging from 0.10% to 8.23% in primary and 0.21% to 17.44% in secondary care, respectively. Neutralization assays showed that highly neutralizing antibodies developed in about half of individuals who tested positive with enzyme-linked immunosorbent assay, mainly among secondary care patients. We estimated the individual probability of SARS-CoV-2 exposure and quantified associated risk factors. We show that secondary care patients, male patients, and 45-64-year-olds exhibit a higher probability of being seropositive. The identification of risk factors and the differences in virus neutralization activity between patient populations provided insights into the patterns of virus exposure during the first pandemic wave and shed light on what to expect in future waves.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/epidemiology , Cell Line , Cross-Sectional Studies , Delivery of Health Care , Demography , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunity , Male , Middle Aged , Pandemics , Risk Factors , Scotland/epidemiology , Seroepidemiologic Studies , Young Adult
6.
Pept Sci (Hoboken) ; : e24217, 2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1014097

ABSTRACT

COVID-19 is caused by a novel coronavirus called severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Virus cell entry is mediated through a protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2). A series of stapled peptide ACE2 peptidomimetics based on the ACE2 interaction motif were designed to bind the coronavirus S-protein RBD and inhibit binding to the human ACE2 receptor. The peptidomimetics were assessed for antiviral activity in an array of assays including a neutralization pseudovirus assay, immunofluorescence (IF) assay and in-vitro fluorescence polarization (FP) assay. However, none of the peptidomimetics showed activity in these assays, suggesting that an enhanced binding interface is required to outcompete ACE2 for S-protein RBD binding and prevent virus internalization.

7.
J Infect Dis ; 223(6): 971-980, 2021 03 29.
Article in English | MEDLINE | ID: covidwho-998363

ABSTRACT

Identifying drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and quantifying population immunity is crucial to prepare for future epidemics. We performed a serial cross-sectional serosurvey throughout the first pandemic wave among patients from the largest health board in Scotland. Screening of 7480 patient serum samples showed a weekly seroprevalence ranging from 0.10% to 8.23% in primary and 0.21% to 17.44% in secondary care, respectively. Neutralization assays showed that highly neutralizing antibodies developed in about half of individuals who tested positive with enzyme-linked immunosorbent assay, mainly among secondary care patients. We estimated the individual probability of SARS-CoV-2 exposure and quantified associated risk factors. We show that secondary care patients, male patients, and 45-64-year-olds exhibit a higher probability of being seropositive. The identification of risk factors and the differences in virus neutralization activity between patient populations provided insights into the patterns of virus exposure during the first pandemic wave and shed light on what to expect in future waves.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/epidemiology , Cell Line , Cross-Sectional Studies , Delivery of Health Care , Demography , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunity , Male , Middle Aged , Pandemics , Risk Factors , Scotland/epidemiology , Seroepidemiologic Studies , Young Adult
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