Some COVID-19 patients are unable to clear their infection or are at risk of severe disease, requiring treatment with neutralising monoclonal antibodies (nmAb) and/or antivirals. The rapid roll-out of novel therapeutics means there is limited understanding of the likely genetic barrier to drug resistance. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to the detection of emerging drug resistance. Here we report the accrual of mutations in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the epitopes of the respective nmAbs. For casirivimab+imdevimab these are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.
BackgroundUnderstanding immunological responses to SARS-CoV-2 vaccinations is integral to the management of SARS-CoV-2. We aimed to investigate determinants of antibody response to the BNT162b2 vaccine. MethodsA cross-sectional analysis of anti-spike binding antibodies in serum samples from healthcare workers after one or two doses. Post-vaccination interval was restricted to [≥]21 days after dose 1, [≥]14 days after dose 2. The primary outcome was anti-S titres with explanatory variables dose, previous infection, dosing interval, age, ethnicity, and comorbidities. Multivariable linear regression was also conducted. ResultsParticipants (n=5,871) included 3,989 post-dose 1, 1,882 post-dose 2. In SARS-CoV-2 infection naive, 99.65% seroconverted after dose 1 and >99.9% seroconverted after dose 2. Geometric mean anti-S titre in the naive cohort was 75.48 Binding Antibody Units/ml after dose 1, 7,049 BAU/ml after dose 2. Anti-S titres were higher in those with previous infection (2,111 BAU/ml post-dose 1, 16,052 BAU/ml post-dose 2), and increased with time between infection and vaccination: 3 months 1,970 (1,506-2,579) vs 9 months; 13,759 (8,097-23,379). Longer dosing intervals increased antibody response post-dose 2: 11-fold higher with a longer interval (>10 weeks) than those with shorter intervals, across all age-groups. Younger participants had higher mean titres (>2.2-fold higher). Multivariable regression modelling corroborated the above associations, and also found higher titres associated with being female or from an ethnic minority but lower titres among immunocompromised participants. ConclusionThe number of antigen exposures and timing between vaccinations plays a significant role in the magnitude of the post-vaccination antibody response, with implications for long-term protection and post-booster antibody responses.
ObjectivesTo explore attitudes and intentions towards COVID-19 vaccination, and influences and sources of information about COVID-19 across diverse ethnic groups (EGs) in the UK. DesignRemote qualitative interviews and focus groups (FGs) conducted June-October 2020 before UK COVID-19 vaccine approval. Data were transcribed and analysed through inductive thematic analysis. SettingGeneral public in the community across England and Wales. Participants100 participants from 19 self-identified EGs with spoken English or Punjabi. ResultsMistrust and doubt were common themes across all EGs including white British and minority EGs, but more pronounced amongst Bangladeshi, Pakistani, Black ethnicities and Travellers. Many participants shared concerns about perceived lack of information about COVID-19 vaccine safety, efficacy and potential unknown adverse effects. Across EGs participants stated occupations with public contact, older adults and vulnerable groups should be prioritised for vaccination. Perceived risk, social influences, occupation, age, co-morbidities and engagement with healthcare influenced participants intentions to accept vaccination once available; all Jewish FG participants intended to accept, while all Traveller FG participants indicated they probably would not. Facilitators to COVID-19 vaccine uptake across all EGs included: desire to return to normality and protect health and wellbeing; perceived higher risk of infection; evidence of vaccine safety and efficacy; vaccine availability and accessibility. COVID-19 information sources were influenced by social factors, culture and religion and included: friends, family; media and news outlets; and research literature. Participants across most different EGs were concerned about misinformation or had negative attitudes towards the media. ConclusionsDuring vaccination programme roll-out, including boosters, commissioners and vaccine providers should provide accurate information, authentic community outreach, and use appropriate channels to disseminate information and counter misinformation. Adopting a context-specific approach to vaccine resources, interventions and policies and empowering communities has potential to increase trust in the programme. Article summary: strengths and limitationsO_LIThis is amongst the largest qualitative studies on attitudes to the COVID-19 pandemic in the UK general public across ethnic groups (EGs), ages and religions, adding insights from a broader range of participants. C_LIO_LIQualitative methodology enabled discussion of participants responses around COVID-19 vaccination, probing to collect rich data to inform recommendations across EGs. C_LIO_LIMost data collection was undertaken in English, possibly excluding sectors of the population who may access COVID-19 information through different sources due to language. C_LIO_LIData collection was June-October 2020 before COVID-19 vaccines were licensed. Attitudes are highly responsive to current information around a COVID-19 vaccine, as well as the state of the pandemic and perceived risk. Data were collected prior to much of the intervention work, putting the attitudes and intentions expressed in this study in a context of minimal community engagement and support. This provides a baseline snapshot of attitudes, providing the option to explore and assess the impact of such interventions. C_LIO_LISocioeconomic data and index of multiple deprivation were not collected, limiting the ability to determine a possible accumulative effect of factors such as socioeconomic status, ethnicity and age. C_LI
ObjectivesTo explore public reactions to the COVID-19 pandemic across diverse ethnic groups. DesignRemote qualitative interviews and focus groups in English or Punjabi. Data were transcribed and analysed through inductive thematic analysis. SettingEngland and Wales June-October 2020. Participants100 participants from 19 diverse self-identified ethnic groups. ResultsDismay, frustration and altruism were reported across all ethnic groups during the first six to nine months of the COVID-19 pandemic. Dismay was caused by participants reported individual, family and community risks, and loss of support networks. Frustration was caused by reported lack of recognition of the efforts of minority ethnic groups (MEGs), inaction by government to address COVID-19 and inequalities, rule breaking by government advisors, changing government rules around: border controls, personal protective equipment, social distancing, eating out, and perceived poor communication around COVID-19 and the Public Health England (PHE) COVID-19 disparities report (leading to reported increased racism and social isolation). Altruism was felt by all, in the resilience of NHS staff and their communities and families pulling together. Data, participants suggested actions, and the Behaviour Change Wheel informed suggested interventions and policies to help control COVID-19. ConclusionTo maintain public trust, it is imperative that governmental bodies consider vulnerable groups, producing clear COVID-19 control guidance with contingency, fiscal, service provision and communication policies for the next rise in COVID-19 cases. This needs to be combined with public interventions including information, education, modelling and enablement of infection prevention through local community involvement and persuasion techniques or incentivisation. Government policy needs to review and include town and social planning leading to environmental restructuring that facilitates infection prevention control. This includes easy access to hand-washing facilities in homes, work, all food providers and shopping centres; toilet facilities as our Travellers mentioned, and adequate living accommodation and work environment facilitating IPC for all. Strengths and limitationsO_LIThis is amongst the largest qualitative studies on attitudes to the COVID-19 pandemic in the UK general public across ethnic groups, ages and religions, adding insights to previous smaller qualitative studies, from a broader range of participants. C_LIO_LIThe qualitative methodology allowed us to discuss participants responses around the COVID-19 pandemic, probing their answers to obtain detailed data to inform needs across ethnic groups. C_LIO_LIMost data collection was undertaken in English and therefore excludes non-English speaking sectors of the population who may have experienced the COVID-19 pandemic differently. C_LIO_LIWe did not obtain the views of older members of the population over 70 years, who were most at risk. C_LIO_LIThe data reflect public perceptions six to nine months into the pandemic when some of the social distancing rules had been relaxed in England; as the pandemic progresses attitudes and needs may well change. C_LI
BackgroundSARS-CoV-2 spreads in hospitals, but the contribution of these settings to the overall COVID-19 burden at a national level is unknown. MethodsWe used comprehensive national English datasets and simulation modelling to determine the total burden (identified and unidentified) of symptomatic hospital-acquired infections. Those unidentified would either be 1) discharged before symptom onset ("missed"), or 2) have symptom onset 7 days or fewer from admission ("misclassified"). We estimated the contribution of "misclassified" cases and transmission from "missed" symptomatic infections to the English epidemic before 31st July 2020. FindingsIn our dataset of hospitalised COVID-19 patients in acute English Trusts with a recorded symptom onset date (n = 65,028), 7% were classified as hospital-acquired (with symptom onset 8 or more days after admission and before discharge). We estimated that only 30% (range across weeks and 200 simulations: 20-41%) of symptomatic hospital-acquired infections would be identified. Misclassified cases and onward transmission from missed infections could account for 15% (mean, 95% range over 200 simulations: 14{middle dot}1%-15{middle dot}8%) of cases currently classified as community-acquired COVID-19. From this, we estimated that 26,600 (25,900 to 27,700) individuals acquired a symptomatic SARS-CoV-2 infection in an acute Trust in England before 31st July 2020, resulting in 15,900 (15,200-16,400) or 20.1% (19.2%-20.7%) of all identified hospitalised COVID-19 cases. ConclusionsTransmission of SARS-CoV-2 to hospitalised patients likely caused approximately a fifth of identified cases of hospitalised COVID-19 in the "first wave", but fewer than 1% of all SARS-CoV-2 infections in England. Using symptom onset as a detection method for hospital-acquired SARS-CoV-2 likely misses a substantial proportion (>60%) of hospital-acquired infections. FundingNational Institute for Health Research, UK Medical Research Council, Society for Laboratory Automation and Screening, UKRI, Wellcome Trust, Singapore National Medical Research Council. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with the terms "((national OR country) AND (contribution OR burden OR estimates) AND ("hospital-acquired" OR "hospital-associated" OR "nosocomial")) AND Covid-19" for articles published in English up to July 1st 2021. This identified 42 studies, with no studies that had aimed to produce comprehensive national estimates of the contribution of hospital settings to the COVID-19 pandemic. Most studies focused on estimating seroprevalence or levels of infection in healthcare workers only, which were not our focus. Removing the initial national/country terms identified 120 studies, with no country level estimates. Several single hospital setting estimates exist for England and other countries, but the percentage of hospital-associated infections reported relies on identified cases in the absence of universal testing. Added value of this studyThis study provides the first national-level estimates of all symptomatic hospital-acquired infections with SARS-CoV-2 in England up to the 31st July 2020. Using comprehensive data, we calculate how many infections would be unidentified and hence can generate a total burden, impossible from just notification data. Moreover, our burden estimates for onward transmission suggest the contribution of hospitals to the overall infection burden. Implications of all the available evidenceLarge numbers of patients may become infected with SARS-CoV-2 in hospitals though only a small proportion of such infections are identified. Further work is needed to better understand how interventions can reduce such transmission and to better understand the contributions of hospital transmission to mortality.
COVID-19 poses a major challenge to care homes, as SARS-CoV-2 is readily transmitted and causes disproportionately severe disease in older people. Here, 1,167 residents from 337 care homes were identified from a dataset of 6,600 COVID-19 cases from the East of England. Older age and being a care home resident were associated with increased mortality. SARS-CoV-2 genomes were available for 700 residents from 292 care homes. By integrating genomic and temporal data, 409 viral clusters within the 292 homes were identified, indicating two different patterns - outbreaks among care home residents and independent introductions with limited onward transmission. Approximately 70% of residents in the genomic analysis were admitted to hospital during the study, providing extensive opportunities for transmission between care homes and hospitals. Limiting viral transmission within care homes should be a key target for infection control to reduce COVID-19 mortality in this population. Impact statementSARS-CoV-2 can spread efficiently within care homes causing COVID-19 outbreaks among residents, who are at increased risk of severe disease, emphasising the importance of stringent infection control in this population.
BackgroundSignificant nosocomial transmission of SARS-CoV-2 has been demonstrated. Understanding the prevalence of SARS-CoV-2 carriage amongst HCWs at work is necessary to inform the development of HCW screening programmes to control nosocomial spread. MethodsCross-sectional snapshot survey from April-May 2020; HCWs recruited from six UK hospitals. Participants self-completed a health questionnaire and underwent a combined viral nose and throat swab, tested by Polymerase Chain Reaction (PCR) for SARS-CoV-2 with viral culture on majority of positive samples. FindingsPoint prevalence of SARS-CoV-2 carriage across the sites was 2{middle dot}0% (23/1152 participants), median cycle threshold value 35{middle dot}70 (IQR:32{middle dot}42-37{middle dot}57). 17 were previously symptomatic, two currently symptomatic (isolated anosmia and sore throat); the remainder declared no prior or current symptoms. Symptoms in the past month were associated with threefold increased odds of testing positive (aOR 3{middle dot}46, 95%CI 1{middle dot}38-8{middle dot}67; p=0{middle dot}008). SARS-CoV-2 virus was isolated from only one (5%) of nineteen cultured samples. A large proportion (39%) of participants reported symptoms in the past month. InterpretationThe point-prevalence is similar to previous estimates for HCWs in April 2020, though a magnitude higher than in the general population. Based upon interpretation of symptom history and testing results including viral culture, the majority of those testing positive were unlikely to be infectious at time of sampling. Development of screening programmes must balance the potential to identify additional cases based upon likely prevalence, expanding the symptoms list to encourage HCW testing, with resource implications and risks of excluding those unlikely to be infectious with positive tests. FundingPublic Health England. Word CountO_ST_ABSResearch in contextC_ST_ABSEvidence before this studyA search of PubMed was performed on 29th April 2020 to identify other major works in this field, using the search terms ("novel coronavirus" OR "SARS-CoV-2" OR "COVID-19" OR "coronavirus") AND ("workers" OR "staff") AND ("testing" OR "screening") from 31st December 2019 onwards with no other limits. This search was updated on 10th May 2020, and in addition reference lists were checked and pre-print papers were shared with us through professional networks. We found three papers commenting on prevalence of asymptomatic/pauci-symptomatic SARS-CoV-2 infection in healthcare workers, with prevalence estimates ranging from 1{middle dot}1 to 8%. One of these studies explored previous symptoms in depth, though this was based upon a retrospective questionnaire and thus subject to recall bias. None of these studies explored exposures to the SARS-CoV-2 virus, commented on whether participants had been tested prior to the start of the study, or broke down results by staff role. Only one reported on estimated viral load (as inferred from cycle threshold [Ct] value), and none reported attempting viral culture. Added value of this studyThis is the first published study of which we are aware that has been conducted across multiple sites in England and is therefore potentially more representative of the overall prevalence of SARS-CoV-2 infectivity amongst HCWs in the workplace. We explored symptoms in the preceding month in more depth than previous studies and in addition asked about previous test results and various exposures, also not commented on in other studies. Additionally, we attempted to isolate virus from some PCR-positive samples to look for evidence of infectious virus. Implications of all the available evidenceAuthors of previous studies have proposed that screening asymptomatic HCWs for SARS-CoV-2 RNA may be beneficial, in addition to screening symptomatic HCWs. Our findings suggest that when prevalence of COVID-19 is very low, routine and repeated screening would be unlikely to have significant value, especially given the majority of participants testing positive in this study were unlikely to be infectious. However, in situations where prevalence levels are high in a particular population or setting, for example in a hospital outbreak, widening the case definition, or screening all HCWs irrespective of symptoms, may be of benefit.
