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318 results found
McKay PF, Zhou J, Frise R, et al., 2022, Polymer formulated self-amplifying RNA vaccine is partially protective against influenza virus infection in ferrets, Oxford Open Immunology, Vol: 3, ISSN: 2633-6960
COVID-19 has demonstrated the power of RNA vaccines as part of a pandemic response toolkit. Another virus with pandemic potential is influenza. Further development of RNA vaccines in advance of a future influenza pandemic will save time and lives. As RNA vaccines require formulation to enter cells and induce antigen expression, the aim of this study was to investigate the impact of a recently developed bioreducible cationic polymer, pABOL for the delivery of a self-amplifying RNA (saRNA) vaccine for seasonal influenza virus in mice and ferrets. Mice and ferrets were immunized with pABOL formulated saRNA vaccines expressing either haemagglutinin (HA) from H1N1 or H3N2 influenza virus in a prime boost regime. Antibody responses, both binding and functional were measured in serum after immunization. Animals were then challenged with a matched influenza virus either directly by intranasal inoculation or in a contact transmission model. While highly immunogenic in mice, pABOL-formulated saRNA led to variable responses in ferrets. Animals that responded to the vaccine with higher levels of influenza virus-specific neutralizing antibodies were more protected against influenza virus infection. pABOL-formulated saRNA is immunogenic in ferrets, but further optimization of RNA vaccine formulation and constructs is required to increase the quality and quantity of the antibody response to the vaccine.
Wang F, Sheppard CM, Mistry B, et al., 2022, The C-terminal LCAR of host ANP32 proteins interacts with the influenza A virus nucleoprotein to promote the replication of the viral RNA genome, NUCLEIC ACIDS RESEARCH, Vol: 50, Pages: 5713-5725, ISSN: 0305-1048
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- Citations: 5
Eales O, Wang H, Haw D, et al., 2022, Trends in SARS-CoV-2 infection prevalence during England’s roadmap out of lockdown, January to July 2021
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Following rapidly rising COVID-19 case numbers, England entered a national lockdown on 6 January 2021, with staged relaxations of restrictions from 8 March 2021 onwards.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>We characterise how the lockdown and subsequent easing of restrictions affected trends in SARS-CoV-2 infection prevalence.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>On average, risk of infection is proportional to infection prevalence. The REal-time Assessment of Community Transmission-1 (REACT-1) study is a repeat cross-sectional study of over 98,000 people every round (rounds approximately monthly) that estimates infection prevalence in England. We used Bayesian P-splines to estimate prevalence and the time-varying reproduction number (<jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub>) nationally, regionally and by age group from round 8 (beginning 6 January 2021) to round 13 (ending 12 July 2021) of REACT-1. As a comparator, a separate segmented-exponential model was used to quantify the impact on <jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> of each relaxation of restrictions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Following an initial plateau of 1.54% until mid-January, infection prevalence decreased until 13 May when it reached a minimum of 0.09%, before increasing until the end of the study to 0.76%. Following the first easing of restrictions, which included schools reopening, the reproduction number <jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> incre
Chadeau M, Eales O, Bodinier B, et al., 2022, Breakthrough SARS-CoV-2 infections in double and triple vaccinated adults and single dose vaccine effectiveness among children in Autumn 2021 in England: REACT-1 study, EClinicalMedicine, Vol: 48, Pages: 1-14, ISSN: 2589-5370
Background: Prevalence of SARS-CoV-2 infection with Delta variant was increasing in England in late summer 2021 among children aged 5 to 17 years, and adults who had received two vaccine doses. In September 2021, a third (booster) dose was offered to vaccinated adults aged 50 years and over, vulnerable adults and healthcare/care-home workers, and a single vaccine dose already offered to 16 and 17 year-olds was extended to children aged 12 to 15 years. Methods: SARS-CoV-2 community prevalence in England was available from self-administered throat and nose swabs using reverse transcriptase polymerase chain reaction (RT-PCR) in round 13 (24 June to 12 July 2021, N= 98,233), round 14 (9 to 27 September 2021, N = 100,527) and round 15 (19 October to 5 November 2021, N = 100,112) from the REACT-1 study randomised community surveys. Linking to National Health Service (NHS) vaccination data for consenting participants, we estimated vaccine effectiveness in children aged 12 to 17 years and compared swab-positivity rates in adults who received a third dose with those who received two doses. Findings: Weighted SARS-CoV-2 prevalence was 1.57% (1.48%, 1.66%) in round 15 compared with 0.83% (0.76%, 0.89%) in round 14, and the previously observed link between infections and hospitalisations and deaths had weakened. Vaccine effectiveness against infection in children aged 12 to 17 years was estimated (round 15) at 64.0% (50.9%, 70.6%) and 67.7% (53.8%, 77.5%) for symptomatic infections. Adults who received a third vaccine dose were less likely to test positive compared to those who received two doses, with adjusted odds ratio of 0.36 (0.25, 0.53). Interpretation: Vaccination of children aged 12 to 17 years and third (booster) doses in adults were effective at reducing infection risk. High rates of vaccination, including booster doses, are a key part of the strategy to reduce infection rates in the community.
Subissi L, von Gottberg A, Thukral L, et al., 2022, An early warning system for emerging SARS-CoV-2 variants, NATURE MEDICINE, Vol: 28, Pages: 1110-1115, ISSN: 1078-8956
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- Citations: 22
Cann A, Clarke C, Brown J, et al., 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow assay for antibody prevalence studies following vaccination: a diagnostic accuracy study [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 6, ISSN: 2398-502X
Background: Lateral flow immunoassays (LFIAs) are able to achieve affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Methods: This was a prospective diagnostic accuracy study. Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following two doses of SARS-CoV-2 vaccine, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination and subsequent follow up. During the participants visit, finger-prick blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG was detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. A total of 186 paired samples were collected. The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay Results: The LFIA had an estimated sensitivity of 92.0% (114/124; 95% confidence interval [CI] 85.7% to 96.1%) and specificity of 93.6% (58/62; 95% CI 84.3% to 98.2%) using the Abbott assay as reference standard (using the threshold for positivity of 7.10 BAU/ml) Conclusions: Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveillance but does not meet criteria for individual testing.
Willett BJ, Kurshan A, Thakur N, et al., 2022, Distinct antigenic properties of the SARS-CoV-2 Omicron lineages BA.4 and BA.5
<jats:title>Abstract</jats:title><jats:p>Over the course of the pandemic variants have arisen at a steady rate. The most recent variants to emerge, BA.4 and BA.5, form part of the Omicron lineage and were first found in Southern Africa where they are driving the current wave of infection.</jats:p><jats:p>In this report, we perform an in-depth characterisation of the antigenicity of the BA.4/BA.5 Spike protein by comparing sera collected post-vaccination, post-BA.1 or BA.2 infection, or post breakthrough infection of vaccinated individuals with the Omicron variant. In addition, we assess sensitivity to neutralisation by commonly used therapeutic monoclonal antibodies.</jats:p><jats:p>We find sera collected post-vaccination have a similar ability to neutralise BA.1, BA.2 and BA.4/BA.5. In contrast, in the absence of vaccination, prior infection with BA.2 or, in particular, BA.1 results in an antibody response that neutralises BA.4/BA.5 poorly. Breakthrough infection with Omicron in vaccinees leads to a broad neutralising response against the new variants. The sensitivity of BA.4/BA.5 to neutralisation by therapeutic monoclonal antibodies was similar to that of BA.2.</jats:p><jats:p>These data suggest BA.4/BA.5 are antigenically distinct from BA.1 and, to a lesser extent, BA.2. The enhanced breadth of neutralisation observed following breakthrough infection with Omicron suggests that vaccination with heterologous or multivalent antigens may represent viable strategies for the development of cross-neutralising antibody responses.</jats:p>
Frise R, Baillon L, Zhou J, et al., 2022, A self-amplifying RNA vaccine protects against SARS-CoV-2 (D614G) and Alpha variant of concern (B.1.1.7) in a transmission-challenge hamster model, VACCINE, Vol: 40, Pages: 2848-2855, ISSN: 0264-410X
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- Citations: 2
Elliott P, Eales O, Steyn N, et al., 2022, Twin peaks: the Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England
BACKGROUNDRapid transmission of the SARS-CoV-2 Omicron variant has led to record-breaking incidencerates around the world. Sub-lineages have been detected in many countries with BA.1replacing Delta and BA.2 replacing BA.1.METHODSThe REal-time Assessment of Community Transmission-1 (REACT-1) study has trackedSARS-CoV-2 infection in England using RT-PCR results from self-administered throat and noseswabs from randomly-selected participants aged 5+ years. Rounds of data collection wereapproximately monthly from May 2020 to March 2022.RESULTSIn March 2022, weighted prevalence was 6.37% (N=109,181), more than twice that inFebruary 2022 following an initial Omicron peak in January 2022. Of the lineagesdetermined by viral genome sequencing, 3,382 (99.97%) were Omicron, including 346(10.2%) BA.1, 3035 (89.7%) BA.2 and one (0.03%) BA.3 sub-lineage; the remainder (1, 0.03%)was Delta AY.4. The BA.2 Omicron sub-lineage had a growth rate advantage (compared toBA.1 and sub-lineages) of 0.11 (95% credible interval [CrI], 0.10, 0.11). Prevalence wasincreasing overall (reproduction number R=1.07, 95% CrI, 1.06, 1.09), with the greatestincrease in those aged 55+ years (R=1.12, 95% CrI, 1.09, 1.14) among whom estimatedprevalence on March 31, 2022 was 8.31%, nearly 20-fold the median prevalence since May1, 2020.CONCLUSIONSWe observed unprecedented levels of SARS-CoV-2 infection in England in March 2022 and analmost complete replacement of Omicron BA.1 by BA.2. The high and increasing prevalencein older adults may increase hospitalizations and deaths despite high levels of vaccination.(Funded by the Department of Health and Social Care in England.)
Eales O, de Oliveira Martins L, Page AJ, et al., 2022, The new normal? Dynamics and scale of the SARS-CoV-2 variant Omicron epidemic in England
<jats:title>Summary</jats:title><jats:p>The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants which have led to substantial changes in the epidemiology of the virus. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant was first detected in late November 2021 and exhibited a high degree of immune evasion, leading to increased infection rates in many countries. However, estimates of the magnitude of the Omicron wave have relied mainly on routine testing data, which are prone to several biases. Here we infer the dynamics of the Omicron wave in England using PCR testing and genomic sequencing obtained by the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys testing random samples of the population of England. We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections in England during February-March 2022 as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct genomic variants, intermittent epidemics of similar magnitude as the Omicron wave may become the ‘new normal’.</jats:p>
Närhi F, Moonesinghe SR, Shenkin SD, et al., 2022, Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study., The Lancet Digital Health, Vol: 4, Pages: e220-e234, ISSN: 2589-7500
BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70-0·89], p=0·0001, for 70-79 years; 0·52 [0·46-0·58], p<0·0001, for >80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75-80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant wom
Chadeau-Hyam M, Wang H, Eales O, et al., 2022, SARS-CoV-2 infection and vaccine effectiveness in England (REACT-1): a series of cross-sectional random community surveys, The Lancet Respiratory Medicine, Vol: 10, Pages: 355-366, ISSN: 2213-2600
SummaryBackground England has experienced a third wave of the COVID-19 epidemic since the end of May, 2021, coincidingwith the rapid spread of the delta (B.1.617.2) variant, despite high levels of vaccination among adults. Vaccinationrates (single dose) in England are lower among children aged 16–17 years and 12–15 years, whose vaccination inEngland commenced in August and September, 2021, respectively. We aimed to analyse the underlying dynamicsdriving patterns in SARS-CoV-2 prevalence during September, 2021, in England.Methods The REal-time Assessment of Community Transmission-1 (REACT-1) study, which commenced datacollection in May, 2020, involves a series of random cross-sectional surveys in the general population of Englandaged 5 years and older. Using RT-PCR swab positivity data from 100 527 participants with valid throat and noseswabs in round 14 of REACT-1 (Sept 9–27, 2021), we estimated community-based prevalence of SARS-CoV-2 andvaccine effectiveness against infection by combining round 14 data with data from round 13 (June 24 to July 12, 2021;n=172 862).Findings During September, 2021, we estimated a mean RT-PCR positivity rate of 0·83% (95% CrI 0·76–0·89), with areproduction number (R) overall of 1·03 (95% CrI 0·94–1·14). Among the 475 (62·2%) of 764 sequenced positiveswabs, all were of the delta variant; 22 (4·63%; 95% CI 3·07–6·91) included the Tyr145His mutation in the spikeprotein associated with the AY.4 sublineage, and there was one Glu484Lys mutation. Age, region, key worker status,and household size jointly contributed to the risk of swab positivity. The highest weighted prevalence was observedamong children aged 5–12 years, at 2·32% (95% CrI 1·96–2·73) and those aged 13–17 years, at 2·55% (2·11–3·08).The SARS-CoV-2 epidemic grew in those aged 5–11 years, with an R of 1&m
Killingley B, Mann AJ, Kalinova M, et al., 2022, Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults, Nature Medicine, Vol: 28, Pages: 1031-1041, ISSN: 1078-8956
Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study’s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2–4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative cor
Pinto AL, Rai RK, Brown JC, et al., 2022, Ultrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium, Nature Communications, Vol: 13, Pages: 1-14, ISSN: 2041-1723
Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
Chadeau-Hyam M, Tang D, Eales O, et al., 2022, The Omicron SARS-CoV-2 epidemic in England during February 2022
Background The third wave of COVID-19 in England peaked in January 2022 resulting fromthe rapid transmission of the Omicron variant. However, rates of hospitalisations and deathswere substantially lower than in the first and second wavesMethods In the REal-time Assessment of Community Transmission-1 (REACT-1) study weobtained data from a random sample of 94,950 participants with valid throat and nose swabresults by RT-PCR during round 18 (8 February to 1 March 2022).Findings We estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credibleinterval [CrI] 2.76–3.00), with a within-round reproduction number (R) overall of 0.94 (0·91–0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) andadults aged 18 to 54 years, we observed a level or increasing weighted prevalence amongthose aged 55 years and older with an R of 1.04 (1.00–1.09). Among 1,195 positive sampleswith sublineages determined, only one (0.1% [0.0–0.5]) corresponded to AY.39 Deltasublineage and the remainder were Omicron: N=390, 32.7% (30.0–35.4) were BA.1; N=473,39.6% (36.8–42.5) were BA.1.1; and N=331, 27.7% (25.2–30.4) were BA.2. We estimated anR additive advantage for BA.2 (vs BA.1 or BA.1.1) of 0.40 (0.36–0.43). The highest proportionof BA.2 among positives was found in London.Interpretation In February 2022, infection prevalence in England remained high with levelor increasing rates of infection in older people and an uptick in hospitalisations. Ongoingsurveillance of both survey and hospitalisations data is required.Funding Department of Health and Social Care, England.
Winslow RL, Zhou J, Windle EF, et al., 2022, SARS-CoV-2 environmental contamination from hospitalised patients with COVID-19 receiving aerosol-generating procedures, THORAX, Vol: 77, Pages: 259-267, ISSN: 0040-6376
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- Citations: 27
Spencer AJ, Morris S, Ulaszewska M, et al., 2022, The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 beta (B.1.351) and other variants of concern in preclinical studies, EBIOMEDICINE, Vol: 77, ISSN: 2352-3964
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- Citations: 7
Zhang Z, Penn R, Barclay WS, et al., 2022, Naïve human macrophages are refractory to SARS-CoV-2 infection and exhibit a modest inflammatory response early in infection, Viruses, Vol: 14, Pages: 1-10, ISSN: 1999-4915
Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN- and/or infected with either live or UV-inactivated SARS-CoV- 2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the E viral gene for SARS- CoV-2 or M gene for influenza and TCID50 or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 exposed MDM with notable absence of IFN-β induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN-α enhanced proinflammatory cytokine expression upon exposure to virus. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.
Ward H, Whittaker M, Flower B, et al., 2022, Population antibody responses following COVID-19 vaccination in 212,102 individuals, Nature Communications, Vol: 13, ISSN: 2041-1723
Population antibody surveillance helps track immune responses to COVID-19 vaccinations at scale, and identify host factors that may affect antibody production. We analyse data from 212,102 vaccinated individuals within the REACT-2 programme in England, which uses self-administered lateral flow antibody tests in sequential cross-sectional community samples; 71,923 (33.9%) received at least one dose of BNT162b2 vaccine and 139,067 (65.6%) received ChAdOx1. For both vaccines, antibody positivity peaks 4-5 weeks after first dose and then declines. At least 21 days after second dose of BNT162b2, close to 100% of respondents test positive, while for ChAdOx1, this is significantly reduced, particularly in the oldest age groups (72.7% [70.9–74.4] at ages 75 years and above). For both vaccines, antibody positivity decreases with age, and is higher in females and those with previous infection. Antibody positivity is lower in transplant recipients, obese individuals, smokers and those with specific comorbidities. These groups will benefit from additional vaccine doses.
Elliott P, Bodinier B, Eales O, et al., 2022, Rapid increase in Omicron infections in England during December 2021: REACT-1 study., Science, Vol: 375, Pages: eabn8347-eabn8347, ISSN: 0036-8075
The unprecedented rise in SARS-CoV-2 infections during December 2021 was concurrent with rapid spread of the Omicron variant in England and globally. We analyzed prevalence of SARS-CoV-2 and its dynamics in England from end November to mid-December 2021 among almost 100,000 participants from the REACT-1 study. Prevalence was high with rapid growth nationally and particularly in London during December 2021, and an increasing proportion of infections due to Omicron. We observed large falls in swab positivity among mostly vaccinated older children (12-17 years) compared with unvaccinated younger children (5-11 years), and in adults who received a third (booster) vaccine dose vs. two doses. Our results reinforce the importance of vaccination and booster campaigns, although additional measures have been needed to control the rapid growth of the Omicron variant.
Zhou J, Peacock TP, Brown JC, et al., 2022, Mutations that adapt SARS-CoV-2 to mink or ferret do not increase fitness in the human airway, CELL REPORTS, Vol: 38, ISSN: 2211-1247
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Eales O, Ainslie KEC, Walters CE, et al., 2022, Appropriately smoothing prevalence data to inform estimates of growth rate and reproduction number
<jats:title>Abstract</jats:title><jats:p>The time-varying reproduction number (<jats:bold><jats:italic>R</jats:italic></jats:bold><jats:sub><jats:bold><jats:italic>t</jats:italic></jats:bold></jats:sub>) can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of <jats:bold><jats:italic>R</jats:italic></jats:bold><jats:sub><jats:bold><jats:italic>t</jats:italic></jats:bold></jats:sub> from case data. However, these are not easily adapted to point prevalence data nor can they infer <jats:bold><jats:italic>R</jats:italic></jats:bold><jats:sub><jats:bold><jats:italic>t</jats:italic></jats:bold></jats:sub> across periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020 – December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of <jats:bold><jats:italic>R</jats:italic></jats:bold><jats:sub><jats:bold><jats:italic>t</jats:italic></jats:bold></jats:sub> over the period of two subsequent rounds (6-8 weeks) and single rounds (2-3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in <jats:bold><jats:italic>R</jats:italic></jats:bold><jats:sub><jats
Zhang Z, Penn R, Barclay WS, et al., 2022, Primary macrophages exhibit a modest inflammatory response early in SARS-CoV-2 infection
<jats:title>Abstract</jats:title><jats:p>Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN-α and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the<jats:italic>E</jats:italic>viral gene for SARS-CoV-2 or<jats:italic>M</jats:italic>gene for influenza and TCID<jats:sub>50</jats:sub>or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 infected MDM with notable absence of IFN-β induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN-α enhanced proinflammatory cytokine expression upon infection. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.</jats:p>
Dejnirattisai W, Huo J, Zhou D, et al., 2022, SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses, Cell, Vol: 185, Pages: 467-484.e15, ISSN: 0092-8674
On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.
Gray-Rodriguez S, Jensen MP, Otero-Jimenez M, et al., 2022, Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes, Journal of Pathology, Vol: 257, ISSN: 0022-3417
SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS-CoV-2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS-CoV-2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 post-mortem cases and 16 biopsies with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 status from the peaks of the pandemic in 2020 and four pre-COVID post-mortem controls. SARS-CoV-2 anti-NP staining in the post-mortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained post-mortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE-2 expression, the entry receptor for SARS-CoV-2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS-CoV-2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms to the organ tropism of
Pollock KM, Cheeseman HM, Szubert AJ, et al., 2022, Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial, EClinicalMedicine, Vol: 44, ISSN: 2589-5370
Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received. Interpretation: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimis
Killingley B, Mann A, Kalinova M, et al., 2022, Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge
<jats:title>Abstract</jats:title> <jats:p>To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID<jats:sub>50</jats:sub> of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log<jats:sub>10</jats:sub> copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.</jats:p>
Singanayagam A, Hakki S, Dunning J, et al., 2022, Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study., The Lancet. Infectious diseases, Vol: 22, Pages: 183-195, ISSN: 1473-3099
<h4>Background</h4>The SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community.<h4>Methods</h4>Between Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases' vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status.<h4>Findings</h4>The SAR in household contacts exposed to the delta variant was 25% (95% CI 18-33) for fully vaccinated individuals compared with 38% (24-53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (medi
Elliott P, Eales O, Bodinier B, et al., 2022, Post-peak dynamics of a national Omicron SARS-CoV-2 epidemic during January 2022
Background: Rapid transmission of the SARS-CoV-2 Omicron variant has led to the highestever recorded case incidence levels in many countries around the world.Methods: The REal-time Assessment of Community Transmission-1 (REACT-1) study hasbeen characterising the transmission of the SARS-CoV-2 virus using RT-PCR test results fromself-administered throat and nose swabs from randomly-selected participants in England atages 5 years and over, approximately monthly since May 2020. Round 17 data were collectedbetween 5 and 20 January 2022 and provide data on the temporal, socio-demographic andgeographical spread of the virus, viral loads and viral genome sequence data for positiveswabs.Results: From 102,174 valid tests in round 17, weighted prevalence of swab positivity was4.41% (95% credible interval [CrI], 4.25% to 4.56%), which is over three-fold higher than inDecember 2021 in England. Of 3,028 sequenced positive swabs, 2,393 lineages weredetermined and 2,374 (99.2%) were Omicron including 19 (0.80% of all Omicron lineages)cases of BA.2 sub-lineage and one BA.3 (0.04% of all Omicron) detected on 17 January 2022,and only 19 (0.79%) were Delta. The growth of the BA.2 Omicron sub-lineage against BA.1and its sub-lineage BA.1.1 indicated a daily growth rate advantage of 0.14 (95% CrI, 0.03,0.28) for BA.2, which corresponds to an additive R advantage of 0.46 (95% CrI, 0.10, 0.92).Within round 17, prevalence was decreasing overall (R=0.95, 95% CrI, 0.93, 0.97) butincreasing in children aged 5 to 17 years (R=1.13, 95% CrI, 1.09, 1.18). Those 75 years andolder had a swab-positivity prevalence of 2.46% (95% CI, 2.16%, 2.80%) reflecting a highlevel of infection among a highly vulnerable group. Among the 3,613 swab-positiveindividuals reporting whether or not they had had previous infection, 2,334 (64.6%)reported previous confirmed COVID-19. Of these, 64.4% reported a positive test from 1 to30 days before their swab date. Risks of infection were increased among essential/keyworkers
Keeling MJ, Dyson L, Guyver-Fletcher G, et al., 2022, Fitting to the UK COVID-19 outbreak, short-term forecasts and estimating the reproductive number, Statistical Methods in Medical Research, ISSN: 0962-2802
The COVID-19 pandemic has brought to the fore the need for policy makers to receive timely and ongoing scientific guidance in response to this recently emerged human infectious disease. Fitting mathematical models of infectious disease transmission to the available epidemiological data provide a key statistical tool for understanding the many quantities of interest that are not explicit in the underlying epidemiological data streams. Of these, the effective reproduction number, R, has taken on special significance in terms of the general understanding of whether the epidemic is under control (R<1). Unfortunately, none of the epidemiological data streams are designed for modelling, hence assimilating information from multiple (often changing) sources of data is a major challenge that is particularly stark in novel disease outbreaks. Here, focusing on the dynamics of the first wave (March–June 2020), we present in some detail the inference scheme employed for calibrating the Warwick COVID-19 model to the available public health data streams, which span hospitalisations, critical care occupancy, mortality and serological testing. We then perform computational simulations, making use of the acquired parameter posterior distributions, to assess how the accuracy of short-term predictions varied over the time course of the outbreak. To conclude, we compare how refinements to data streams and model structure impact estimates of epidemiological measures, including the estimated growth rate and daily incidence.
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