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At the end of 2022 into early 2023, the UK Health Security Agency reported unusually high levels of scarlet fever and invasive disease caused by Streptococcus pyogenes (StrepA or group A Streptococcus). During this time, we collected and genome-sequenced 341 non-invasive throat and skin S. pyogenes isolates identified during routine clinical diagnostic testing in Sheffield, a large UK city. We compared the data with that obtained from a similar collection of 165 isolates from 2016 to 2017. Numbers of throat-associated isolates collected peaked in early December 2022, reflecting the national scarlet fever upsurge, while skin infections peaked later in December. The most common emm-types in 2022-2023 were emm1 (28.7â%), emm12 (24.9â%) and emm22 (7.7â%) in throat and emm1 (22â%), emm12 (10â%), emm76 (18â%) and emm49 (7â%) in skin. While all emm1 isolates were the M1UK lineage, the comparison with 2016-2017 revealed diverse lineages in other emm-types, including emm12, and emergent lineages within other types including a new acapsular emm75 lineage, demonstrating that the upsurge was not completely driven by a single genotype. The analysis of the capsule locus predicted that only 51â% of throat isolates would produce capsule compared with 78% of skin isolates. Ninety per cent of throat isolates were also predicted to have high NADase and streptolysin O (SLO) expression, based on the promoter sequence, compared with only 56% of skin isolates. Our study has highlighted the value in analysis of non-invasive isolates to characterize tissue tropisms, as well as changing strain diversity and emerging genomic features which may have implications for spillover into invasive disease and future S. pyogenes upsurges.
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Infecções Estreptocócicas , Streptococcus pyogenes , Streptococcus pyogenes/genética , Streptococcus pyogenes/classificação , Streptococcus pyogenes/isolamento & purificação , Humanos , Reino Unido , Infecções Estreptocócicas/microbiologia , Proteínas da Membrana Bacteriana Externa/genética , Antígenos de Bactérias/genética , Faringe/microbiologia , Escarlatina/microbiologia , Escarlatina/epidemiologia , Proteínas de Transporte/genética , Estreptolisinas/genética , Sequenciamento Completo do Genoma/métodos , Proteínas de Bactérias/genética , Filogenia , Criança , Adulto , NAD+ Nucleosidase/genética , NAD+ Nucleosidase/metabolismo , Pele/microbiologia , Pré-Escolar , MasculinoRESUMO
BACKGROUND: Streptococcus pyogenes-related skin infections are increasingly implicated in the development of rheumatic heart disease (RHD) in lower-resourced settings, where they are often associated with scabies. The true prevalence of S. pyogenes-related pyoderma may be underestimated by bacterial culture. METHODS: A multiplex qPCR for S. pyogenes, Staphylococcus aureus and Sarcoptes scabiei was applied to 250 pyoderma swabs from a cross-sectional study of children <5 years in The Gambia. Direct PCR-based emm-typing was used to supplement previous whole genome sequencing (WGS) of cultured isolates. RESULTS: Pyoderma lesions with S. pyogenes increased from 51% (127/250) using culture to 80% (199/250) with qPCR. Compared to qPCR, the sensitivity of culture was 95.4% for S. pyogenes (95% CI 77.2-99.9) in samples with S. pyogenes alone (22/250, 9%), but 59.9% (95% CI 52.3-67.2) for samples with S. aureus co-infection (177/250, 71%). Direct PCR-based emm-typing was successful in 50% (46/92) of cases, identifying 27 emm-types, including six not identified by WGS (total 52 emm-types). CONCLUSIONS: Bacterial culture significantly underestimates the burden of S. pyogenes in pyoderma, particularly when co-infected with S. aureus. Molecular methods should be used to enhance the detection of S. pyogenes in surveillance studies and clinical trials of preventative measures in RHD-endemic settings.
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The fundamental biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (Ncap), its use in diagnostic assays and its potential application as a vaccine component have received considerable attention since the outbreak of the Covid19 pandemic in late 2019. Here we report the scalable expression and purification of soluble, immunologically active, SARS-CoV-2 Ncap in Escherichia coli. Codon-optimised synthetic genes encoding the original Ncap sequence and four common variants with an N-terminal 6His affinity tag (sequence MHHHHHHG) were cloned into an inducible expression vector carrying a regulated bacteriophage T5 synthetic promoter controlled by lac operator binding sites. The constructs were used to express Ncap proteins and protocols developed which allow efficient production of purified Ncap with yields of over 200â mg per litre of culture media. These proteins were deployed in ELISA assays to allow comparison of their responses to human sera. Our results suggest that there was no detectable difference between the 6His-tagged and untagged original Ncap proteins but there may be a slight loss of sensitivity of sera to other Ncap isolates.
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COVID-19 , Proteínas do Nucleocapsídeo de Coronavírus , Escherichia coli , SARS-CoV-2 , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/biossíntese , Proteínas do Nucleocapsídeo de Coronavírus/isolamento & purificação , Proteínas do Nucleocapsídeo de Coronavírus/química , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Humanos , COVID-19/virologia , Fosfoproteínas/genética , Fosfoproteínas/isolamento & purificação , Fosfoproteínas/metabolismoRESUMO
Little is known about SARS-CoV-2 infection risk in African countries with high levels of infection-driven immunity and low vaccine coverage. We conducted a prospective cohort study of 349 participants from 52 households in The Gambia between March 2021 and June 2022, with routine weekly SARS-CoV-2 RT-PCR and 6-monthly SARS-CoV-2 serology. Attack rates of 45% and 57% were seen during Delta and Omicron BA.1 waves respectively. Eighty-four percent of RT-PCR-positive infections were asymptomatic. Children under 5-years had a lower incidence of infection than 18-49-year-olds. One prior SARS-CoV-2 infection reduced infection risk during the Delta wave only, with immunity from ≥2 prior infections required to reduce the risk of infection with early Omicron lineage viruses. In an African population with high levels of infection-driven immunity and low vaccine coverage, we find high attack rates during SARS-CoV-2 waves, with a high proportion of asymptomatic infections and young children remaining relatively protected from infection.
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Infecções Assintomáticas , COVID-19 , SARS-CoV-2 , Humanos , Gâmbia/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , COVID-19/imunologia , COVID-19/prevenção & controle , Incidência , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Feminino , Pré-Escolar , Masculino , Adolescente , Criança , Adulto , Infecções Assintomáticas/epidemiologia , Estudos Prospectivos , Pessoa de Meia-Idade , Adulto Jovem , LactenteRESUMO
BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.
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Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , SARS-CoV-2 , Humanos , Feminino , Masculino , COVID-19/prevenção & controle , COVID-19/imunologia , Pessoa de Meia-Idade , Hospedeiro Imunocomprometido/imunologia , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Idoso , Vacina BNT162/imunologia , Vacina BNT162/administração & dosagem , Anticorpos Antivirais/sangue , Estudos Prospectivos , Imunização Secundária , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Adulto , Linfócitos T/imunologia , Reino Unido , ChAdOx1 nCoV-19/imunologiaRESUMO
BACKGROUND: Streptococcus pyogenes causes more than 500 000 deaths per year globally, which occur disproportionately in low-income and middle-income countries. The roles of S pyogenes skin and pharyngeal carriage in transmission are unclear. We aimed to investigate the clinical epidemiology and household transmission dynamics of both S pyogenes asymptomatic carriage and infection in a high-burden setting. METHODS: We did a 1-year prospective, longitudinal, household cohort study, recruiting healthy participants from households in Sukuta, The Gambia. Households were eligible if they comprised at least three members, including one child younger than 18 years, and were excluded if more than half of household members declined to participate. Households were identified by random GPS coordinates derived from census data. At monthly visits, pharyngeal and normal skin swabs were collected for S pyogenes culture, and sociodemographic data were recorded by interview. Incident pharyngitis and pyoderma infections were captured. Cultured isolates underwent emm genotyping. The primary outcome measures were incidence of S pyogenes carriage and disease. Additional outcomes were prevalence of S pyogenes skin and pharyngeal carriage, S pyogenes skin and pharyngeal clearance time, S pyogenes emm type, risk factors for carriage and disease events, household secondary attack rate, and emm-linked household transmission events. The study is registered on ClinicalTrials.gov, NCT05117528. FINDINGS: Between July 27, 2021, and Sept 28, 2022, 442 participants were enrolled from 44 households. The median age was 15 years (IQR 6-28) and 233 (53%) were female. We identified 17 pharyngitis and 99 pyoderma events and 49 pharyngeal and 39 skin S pyogenes carriage acquisition events. Mean monthly prevalence was 1·4% (95% CI 1·1-1·9) for S pyogenes pharyngeal carriage and 1·2% (0·9-1·6) for S pyogenes skin carriage. Incidence was 120 per 1000 person-years (95% CI 87-166) for S pyogenes pharyngeal carriage, 124 per 1000 person-years (90-170) for S pyogenes skin carriage, 51 per 1000 person-years (31-84) for S pyogenes pharyngitis, and 263 per 1000 person-years (212-327) for S pyogenes pyoderma. Pharyngeal carriage risk was higher during the rainy season (HR 5·67, 95% CI 2·19-14·69) and in larger households (per additional person: 1·03, 1·00-1·05), as was pharyngitis risk (rainy season: 3·00, 1·10-8·22; household size: 1·04, 1·02-1·07). Skin carriage risk was not affected by season or household size, but was lower in female than in male participants (0·45, 0·22-0·92) and highest in children younger than 5 years compared with adults (22·69, 3·08-167·21), with similar findings for pyoderma (female sex: 0·34, 0·19-0·61; age <5 years: 7·00, 2·78-17·64). Median clearance time after carriage acquisition was 4·0 days for both skin (IQR 3·5-7·0) and pharynx (3·5-7·3). The mean household secondary attack rate was 4·9 (95% CI 3·5-6·3) for epidemiologically linked S pyogenes events and 0·74 (0·3-1·2) for emm-linked S pyogenes events. Of the 204 carriage and disease events, emm types were available for 179 (88%). Only 18 emm-linked between-visit household transmission events were identified. Pyoderma was the most common source of S pyogenes household transmissions in 11 (61%) of 18 emm-linked transmissions. Both pharynx to skin and skin to pharynx transmission events were observed. INTERPRETATION: S pyogenes carriage and infection are common in The Gambia, particularly in children. Most events are non-household acquisitions, but skin carriage and pyoderma have an important role in S pyogenes household transmission and bidirectional transmission between skin and pharynx occurs. FUNDING: Wellcome Trust, Chadwick Trust, Fonds National de la Recherche Scientifique (Belgium), European Society for Paediatric Infectious Diseases, and Medical Research Council (UK).
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Portador Sadio , Características da Família , Faringe , Infecções Estreptocócicas , Streptococcus pyogenes , Humanos , Streptococcus pyogenes/isolamento & purificação , Gâmbia/epidemiologia , Feminino , Estudos Longitudinais , Masculino , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/transmissão , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Criança , Adulto , Adolescente , Estudos Prospectivos , Adulto Jovem , Pré-Escolar , Faringe/microbiologia , Prevalência , Incidência , Fatores de Risco , Faringite/microbiologia , Faringite/epidemiologia , Pele/microbiologia , Estudos de Coortes , Pioderma/epidemiologia , Pioderma/microbiologia , Pessoa de Meia-Idade , LactenteRESUMO
BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.
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Enzima de Conversão de Angiotensina 2 , Anticorpos Antivirais , COVID-19 , Evasão da Resposta Imune , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Humanos , COVID-19/imunologia , COVID-19/virologia , Anticorpos Antivirais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Relação Estrutura-Atividade , Anticorpos Monoclonais/imunologia , Mutação/genética , Anticorpos Neutralizantes/imunologia , Afinidade de AnticorposRESUMO
Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
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One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.
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Pesquisa Biomédica , COVID-19 , Humanos , Síndrome de COVID-19 Pós-Aguda , Hospitalização , Imunoglobulina GRESUMO
Group A Streptococcus (Strep A) bacteria causes a broad spectrum of diseases. The most common manifestations of Strep A infection are sore throat and pus-producing skin infections such as impetigo. Complications of Strep A infection can lead to inflammation in the bones, muscles, joints, and internal organs causing acute rheumatic fever and rheumatic heart disease (RHD). In The Gambia, the RHD burden is thought to be very high. However, epidemiological data is minimal, and Strep A control programmes do not exist. This study aimed to explore common beliefs and practices related to sore throats among primary caregivers of children, and healthcare providers in a community with a high Strep A disease burden. Four informal conversations with providers and fifteen semi-structured interviews with caregivers were conducted in the peri-urban area of Sukuta, The Gambia. Sampling was purposive and gradual, beginning from households identified to have recently experienced sore throat through a parallel cohort study. Themes explored in qualitative analysis included: sore throat causal attributions and diagnoses, care practises, health-seeking behaviour, and perceived barriers to using the biomedical sector. We found that sore throats were typically perceived to affect one child in a family, disproportionately or exclusively. Sore throats were rarely perceived as life-threatening, and awareness of links between sore throat and ARF or RHD was not reported among caregivers or providers in this study population. Most cases of sore throat were initially managed at home using traditional medicine which delayed resort to antibiotics, though in two instances of severe pain with the presence of exudate, fear that the child's life was at risk prompted care-seeking through the formal health system. Our findings can inform the development of tailored strategies to increase community knowledge of the potential long-term consequences of sore throats and appropriate care-seeking, alongside improvements in the health system, to prevent Strep A sequelae effectively.
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INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.
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Anticorpos Monoclonais Humanizados , Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cladribina/uso terapêutico , Alemtuzumab/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Transplante Autólogo , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
The high burden of disease and the long-lasting sequelae following Streptococcus pyogenes (Strep A) infections make the development of an effective vaccine a global health priority. Streptolysin O (SLO), is a key toxin in the complex pathogenesis of Strep A infection. Antibodies are elicited against SLO after natural exposure and represent a key target for vaccine-induced immunity. Here we present the setup and characterization of a hemolysis assay to measure functionality of anti-SLO antibodies in human sera. Assay specificity, precision, linearity, reproducibility, and repeatability were determined. The assay was demonstrated to be highly sensitive, specific, reproducible, linear and performed well in assessing functionality of anti-SLO antibodies induced by exposed individuals. Moreover, different sources of critical reagents, in particular red- blood cells, have been compared and had minimal impact on assay performance. The assay presented here has throughput suitable for evaluating sera in vaccine clinical trials and sero-epidemiological studies to gain further insights into the functionality of infection- and vaccine-induced antibodies.
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Infecções Estreptocócicas , Vacinas , Humanos , Streptococcus pyogenes , Hemólise , Reprodutibilidade dos Testes , Estreptolisinas/farmacologia , Proteínas de Bactérias , Anticorpos/farmacologia , Infecções Estreptocócicas/diagnósticoRESUMO
Previous studies have associated COVID-19 symptoms severity with levels of physical activity. We therefore investigated longitudinal trajectories of COVID-19 symptoms in a cohort of healthcare workers (HCWs) with non-hospitalised COVID-19 and their real-world physical activity. 121 HCWs with a history of COVID-19 infection who had symptoms monitored through at least two research clinic visits, and via smartphone were examined. HCWs with a compatible smartphone were provided with an Apple Watch Series 4 and were asked to install the MyHeart Counts Study App to collect COVID-19 symptom data and multiple physical activity parameters. Unsupervised classification analysis of symptoms identified two trajectory patterns of long and short symptom duration. The prevalence for longitudinal persistence of any COVID-19 symptom was 36% with fatigue and loss of smell being the two most prevalent individual symptom trajectories (24.8% and 21.5%, respectively). 8 physical activity features obtained via the MyHeart Counts App identified two groups of trajectories for high and low activity. Of these 8 parameters only 'distance moved walking or running' was associated with COVID-19 symptom trajectories. We report a high prevalence of long-term symptoms of COVID-19 in a non-hospitalised cohort of HCWs, a method to identify physical activity trends, and investigate their association. These data highlight the importance of tracking symptoms from onset to recovery even in non-hospitalised COVID-19 individuals. The increasing ease in collecting real-world physical activity data non-invasively from wearable devices provides opportunity to investigate the association of physical activity to symptoms of COVID-19 and other cardio-respiratory diseases.
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Background: Streptococcus pyogenes (StrepA) causes a significant burden of disease globally from superficial infections to invasive disease. It is responsible for over 500,000 deaths each year, predominantly in low- and middle-income countries (LMIC). Superficial StrepA infections of the skin and pharynx can lead to rheumatic heart disease, the largest cause of StrepA-related deaths in LMIC. StrepA can also asymptomatically colonise normal skin and the pharynx (carriage), potentially increasing infection risk. Streptococcus dysgalactiae subsp. equisimilis (SDSE) carriage is also common in LMIC and may interact with StrepA. This study aims to investigate StrepA and SDSE carriage and infection epidemiology, transmission dynamics and naturally acquired immunity within households in The Gambia. Methods: A longitudinal household observational cohort study will be conducted over one year. 45 households will be recruited from the urban area of Sukuta, The Gambia, resulting in approximately 450 participants. Households will be visited monthly, and available participants will undergo oropharyngeal and normal skin swabbing. Incident cases of pharyngitis and pyoderma will be captured via active case reporting, with swabs taken from disease sites. Swabs will be cultured for the presence of group A, C and G beta-haemolytic streptococci. Isolates will undergo whole genome sequencing. At each visit, clinical, socio-demographic and social mixing data will be collected. Blood serum will be collected at baseline and final visit. Oral fluid and dried blood spot samples will be collected at each visit. Mucosal and serum anti-StrepA antibody responses will be measured. Outcome: This study will report StrepA and SDSE clinical epidemiology, risk factors, transmission dynamics, and serological responses to carriage and infection. Detailed social mixing behaviour will be combined with phylogenetic relatedness to model the extent of transmission occurring withing and between households. The study will provide data to help meet global strategic StrepA research goals.
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IMPORTANCE: Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.
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Infecções Irruptivas , Vacinas , Humanos , Estudos de Casos e Controles , Anticorpos , Linfócitos T CD8-Positivos , SARS-CoV-2 , Linfócitos T CD4-Positivos , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that prior SARS-CoV-2 infection is associated with immune dampening. Taking a broad and comprehensive approach, we characterize mucosal and blood immunity to spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without prior SARS-CoV-2 infection. We find that most individuals increase BA.1/BA.2/BA.5-specific neutralizing antibodies following infection, but confirm that the magnitude of increase and post-omicron titres are higher in the infection-naive. In contrast, significant increases in nasal responses, including neutralizing activity against BA.5 spike, are seen regardless of infection history. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are significantly higher in the previously-infected, who display a maximally induced response with a highly cytotoxic CD8+ phenotype following their 3rd mRNA vaccine dose. Responses to non-spike antigens increase significantly regardless of prior infection status. These findings suggest that hybrid immunity induced by omicron breakthrough infections is characterized by significant immune enhancement that can help protect against future omicron variants.
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Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/classificação , Vacinas contra COVID-19/administração & dosagem , Imunidade , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes , Imunoglobulina A , Linfócitos T/imunologia , Imunidade nas Mucosas , Masculino , Feminino , AdultoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml-1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19 , Vacina BNT162 , ChAdOx1 nCoV-19 , Vacinação , Anticorpos AntiviraisRESUMO
The prevalence and strength of serological responses mounted toward SARS-CoV-2 proteins other than nucleocapsid (N) and spike (S), which may be of use as additional serological markers, remains underexplored. Using high-content microscopy to assess antibody responses against full-length StrepTagged SARS-CoV-2 proteins, we found that 85% (166/196) of unvaccinated individuals with RT-PCR confirmed SARS-CoV-2 infections and 74% (31/42) of individuals infected after being vaccinated developed detectable IgG against the structural protein M, which is higher than previous estimates. Compared with N antibodies, M IgG displayed a shallower time-dependent decay and greater specificity. Sensitivity for SARS-CoV-2 seroprevalence was enhanced when N and M IgG detection was combined. These findings indicate that screening for M seroconversion may be a good approach for detecting additional vaccine breakthrough infections and highlight the potential to use HCM as a rapidly deployable method to identify the most immunogenic targets of newly emergent pathogens.
RESUMO
BACKGROUND: Genomic surveillance of SARS-CoV-2 is crucial for monitoring the spread of COVID-19 and guiding public health decisions, but the capacity for SARS-CoV-2 testing and sequencing in Africa is low. We integrated SARS-CoV-2 surveillance into an existing influenza surveillance network with the aim of providing insights into SARS-CoV-2 transmission and genomics in Ghana. METHODS: In this molecular epidemiological analysis, which is part of a wider multifaceted prospective observational study, we collected national SARS-CoV-2 test data from 35 sites across 16 regions in Ghana from Sept 1, 2020, to Nov 30, 2021, via the Ghanaian integrated influenza and SARS-CoV-2 surveillance network. SARS-CoV-2-positive samples collected through this integrated national influenza surveillance network and from international travellers arriving in Accra were sequenced with Oxford Nanopore Technology sequencing and the ARTIC tiled amplicon method. The sequence lineages were typed with pangolin and the phylogenetic analysis was conducted with IQ-Tree2 and TreeTime. FINDINGS: During the study period, 5495 samples were submitted for diagnostic testing through the national influenza surveillance network (2121 [46·1%] of 4021 samples with complete demographic data were from female individuals and 2479 [53·9%] of 4021 samples were from male individuals). We also obtained 2289 samples from travellers who arrived in Accra and had a positive lateral flow test, of whom 1626 (71·0%, 95% CI 69·1-72·9) were confirmed to be SARS-CoV-2 positive. Co-circulation of influenza and SARS-CoV-2 in Ghana was detected, with increased cases of influenza in November, 2020, November, 2021, and January and June, 2021. In 4124 samples from individuals with influenza-like illness, SARS-CoV-2 was identified in 583 (14·1%, 95% CI 13·1-15·2) samples and influenza in 356 (8·6%, 7·8-9·5). Conversely, in 476 samples from individuals with of severe acute respiratory illness, SARS-CoV-2 was detected in 58 (12·2%, 9·5-15·5) samples and influenza in 95 (19·9%, 16·5-23·9). We detected four waves of SARS-CoV-2 infections in Ghana; each wave was driven by a different variant: B.1 and B.1.1 were the most prevalent lineages in wave 1, alpha (B.1.1.7) was responsible for wave 2, delta (B.1.617.2) and its sublineages (closely related to delta genomes from India) were responsible for wave 3, and omicron variants were responsible for wave 4. We detected omicron variants among 47 (32%) of 145 samples from travellers during the start of the omicron spread in Ghana (wave 4). INTERPRETATION: This study shows the value of repurposing existing influenza surveillance platforms to monitor SARS-CoV-2. Influenza continued to circulate in Ghana in 2020 and 2021, and remained a major cause of severe acute respiratory illness. We detected importations of SARS-CoV-2 variants into Ghana, including those that did or did not lead to onward community transmission. Investment in strengthening national influenza surveillance platforms in low-income and middle-income countries has potential for ongoing monitoring of SARS-CoV-2 and future pandemics. FUNDING: The EDCTP2 programme supported by the EU.
Assuntos
COVID-19 , Influenza Humana , Feminino , Masculino , Humanos , SARS-CoV-2/genética , Gana/epidemiologia , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Teste para COVID-19 , Filogenia , COVID-19/diagnóstico , COVID-19/epidemiologia , GenômicaRESUMO
BACKGROUND: This detailed genomic study characterised multi-drug resistant-Gram negative bacilli (MDR-GNB) carriage in neonates < 2 kg and paired mothers at a low-resource African hospital. METHODS: This cross-sectional cohort study was conducted at the neonatal referral unit in The Gambia with weekly neonatal skin and peri-anal sampling and paired maternal recto-vaginal swabs. Prospective bacteriological culture used MacConkey agar with species identification by API20E and API20NE. All GNB isolates underwent whole genome sequencing on Illumina Miseq platform. Multi-Locus Sequence Typing and SNP-distance analysis identified strain type and relatedness. RESULTS: 135 swabs from 34 neonates and 21 paired mothers, yielded 137 GNB isolates, of which 112 are high quality de novo assemblies. Neonatal MDR-GNB carriage prevalence is 41% (14/34) at admission with 85% (11/13) new acquisition by 7d. Multiple MDR and ESBL-GNB species are carried at different timepoints, most frequently K. pneumoniae and E. coli, with heterogeneous strain diversity and no evidence of clonality. 111 distinct antibiotic resistance genes are mostly beta lactamases (Bla-AMPH, Bla-PBP, CTX-M-15, Bla-TEM-105). 76% (16/21) and 62% (13/21) of mothers have recto-vaginal carriage of ≥1 MDR-GNB and ESBL-GNB respectively, mostly MDR-E. coli (76%, 16/21) and MDR-K. pneumoniae (24%, 5/21). Of 21 newborn-mother dyads, only one have genetically identical isolates (E. coli ST131 and K. pneumoniae ST3476). CONCLUSIONS: Gambian hospitalised neonates exhibit high MDR and ESBL-GNB carriage prevalence with acquisition between birth and 7d with limited evidence supporting mother to neonate transmission. Genomic studies in similar settings are required to further understand transmission and inform targeted surveillance and infection prevention policies.
Bacteria that are resistant to multiple antibiotics are an important cause of infection and death of newborns in low-resource countries, especially small or premature babies born in hospital settings. How these resistant bacteria are acquired on the skin and in the gut of newborns is not known, particularly whether they are commonly transferred from mothers. We studied the bacteria present in small Gambian newborns and their mothers to understand the type of bacteria, amount of antibiotic resistance, number of newborns and mothers affected and similarity of these bacteria between newborns and their mothers. We found that despite many newborns carrying these bacteria, they are different from those present in mothers. This suggests that the bacteria are acquired from the hospital environment. Our study highlights the importance of developing strategies to identify and reduce the presence of such bacteria in hospitals to reduce their acquisition by vulnerable hospitalised newborns.