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Rapid vaccine-induced population immunity is a key global strategy to control COVID-19. Vaccination programmes must maximise early impact, particularly with accelerated spread of new variants.1 Most vaccine platforms use a two-dose prime-boost approach to generate an immune response against the virus S1 spike protein, the titres of which correlate with functional virus neutralisation and increase with boosting.2,3 To enable larger numbers of people to receive the first dose, delayed administration of the second dose has been advocated and implemented by some.1 The impact of previous SARS-CoV-2 infection on the need for boosting is not known. To test this, we undertook a nested case-control analysis of 51 participants of COVIDsortium,4,5 an ongoing longitudinal observational study of health-care workers (HCWs) in London who underwent weekly PCR and quantitative serology testing from the day of the first UK lockdown on March 23, 2020, and for 16 weeks onwards. 24 of 51 HCWs had a previous laboratory-confirmed mild or asymptomatic SARS-CoV-2 infection, as confirmed by positive detection of antibodies against the SARS-CoV-2 nucleocapsid (Elecsys Anti-SARS-CoV-2 N ECLIA, Roche Diagnostics, Burgess Hill, UK) or the receptor binding domain of the SARS-CoV-2 S1 subunit of the spike protein (anti-S; Elecsys anti-SARS-CoV-2 spike ECLIA, Roche Diagnostics), whereas 27 HCWs remained seronegative.

Throughout the Ebola virus disease (EVD) epidemic in West Africa, field laboratory testing for EVD has relied on complex, multi-step real-time reverse transcription PCR (RT-PCR) assays; an accurate sample-to-answer RT-PCR test would reduce time to results and potentially increase access to testing. We evaluated the performance of the Cepheid GeneXpert Ebola assay on clinical venipuncture whole blood (WB) and buccal swab (BS) specimens submitted to a field biocontainment laboratory in Sierra Leone for routine EVD testing by RT-PCR (\"Trombley assay\"). This study was conducted in the Public Health England EVD diagnostic laboratory in Port Loko, Sierra Leone, using residual diagnostic specimens remaining after clinical testing. EDTA-WB specimens (n = 218) were collected from suspected or confirmed EVD patients between April 1 and July 20, 2015. BS specimens (n = 71) were collected as part of a national postmortem screening program between March 7 and July 20, 2015. EDTA-WB and BS specimens were tested with Xpert (targets: glycoprotein [GP] and nucleoprotein [NP] genes) and Trombley (target: NP gene) assays in parallel. All WB specimens were fresh; 84/218 were tested in duplicate on Xpert to compare WB sampling methods (pipette versus swab); 43/71 BS specimens had been previously frozen. In all, 7/218 (3.2%) WB and 7/71 (9.9%) BS samples had Xpert results that were reported as \"invalid\" or \"error\" and were excluded, leaving 211 WB and 64 BS samples with valid Trombley and Xpert results. For WB, 22/22 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 84.6%-100%), and 181/189 Trombley-negative samples were Xpert-negative (specificity 95.8%, 95% confidence interval (CI) 91.8%-98.2%). Seven of the eight Trombley-negative, Xpert-positive (Xpert cycle threshold [Ct] range 37.7-43.4) WB samples were confirmed to be follow-up submissions from previously Trombley-positive EVD patients, suggesting a revised Xpert specificity of 99.5% (95% CI 97.0%-100%). For Xpert-positive WB samples (n = 22), Xpert NP Ct values were consistently lower than GP Ct values (mean difference -4.06, 95% limits of agreement -6.09, -2.03); Trombley (NP) Ct values closely matched Xpert NP Ct values (mean difference -0.04, 95% limits of agreement -2.93, 2.84). Xpert results (positive/negative) for WB sampled by pipette versus swab were concordant for 78/79 (98.7%) WB samples, with comparable Ct values for positive results. For BS specimens, 20/20 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 83.2%-100%), and 44/44 Trombley-negative samples were Xpert-negative (specificity 100%, 95% CI 92.0%-100%). This study was limited to testing residual diagnostic samples, some of which had been frozen before use; it was not possible to test the performance of the Xpert Ebola assay at point of care. The Xpert Ebola assay had excellent performance compared to an established RT-PCR benchmark on WB and BS samples in a field laboratory setting. Future studies should evaluate feasibility and performance outside of a biocontainment laboratory setting to facilitate expanded access to testing.

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314). Authors utilise a cohort of healthcare workers, infected during the first wave of the SARS-CoV-2 pandemic, to assess symptom persistence and humoral and cellular immunity.

At present, diagnosis of Ebola virus disease requires transport of venepuncture blood to field biocontainment laboratories for testing by real-time RT-PCR, resulting in delays that complicate patient care and infection control efforts. Therefore, an urgent need exists for a point-of-care rapid diagnostic test for this disease. In this Article, we report the results of a field validation of the Corgenix ReEBOV Antigen Rapid Test kit. We performed the rapid diagnostic test on fingerstick blood samples from 106 individuals with suspected Ebola virus disease presenting at two clinical centres in Sierra Leone. Adults and children who were able to provide verbal consent or assent were included; we excluded patients with haemodynamic instability and those who were unable to cooperate with fingerstick or venous blood draw. Two independent readers scored each rapid diagnostic test, with any disagreements resolved by a third. We compared point-of-care rapid diagnostic test results with clinical real-time RT-PCR results (RealStar Filovirus Screen RT-PCR kit 1·0; altona Diagnostics GmbH, Hamburg, Germany) for venepuncture plasma samples tested in a Public Health England field reference laboratory (Port Loko, Sierra Leone). Separately, we performed the rapid diagnostic test (on whole blood) and real-time RT-PCR (on plasma) on 284 specimens in the reference laboratory, which were submitted to the laboratory for testing from many clinical sites in Sierra Leone, including our two clinical centres. In point-of-care testing, all 28 patients who tested positive for Ebola virus disease by RT-PCR were also positive by fingerstick rapid diagnostic test (sensitivity 100% [95% CI 87·7–100]), and 71 of 77 patients who tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92·2% [95% CI 83·8–97·1]). In laboratory testing, all 45 specimens that tested positive by RT-PCR were also positive by the rapid diagnostic test (sensitivity 100% [95% CI 92·1–100]), and 214 of 232 specimens that tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92·2% [88·0–95·3]). The two independent readers agreed about 95·2% of point-of-care and 98·6% of reference laboratory rapid diagnostic test results. Cycle threshold values ranged from 15·9 to 26·3 (mean 22·6 [SD 2·6]) for the PCR-positive point-of-care cohort and from 17·5 to 26·3 (mean 21·5 [2·7]) for the reference laboratory cohort. Six of 16 banked plasma samples from rapid diagnostic test-positive and altona-negative patients were positive by an alternative real-time RT-PCR assay (the Trombley assay); three (17%) of 18 samples from individuals who were negative by both the rapid diagnostic test and altona test were also positive by Trombley. The ReEBOV rapid diagnostic test had 100% sensitivity and 92% specificity in both point-of-care and reference laboratory testing in this population (maximum cycle threshold 26·3). With two independent readers, the test detected all patients who were positive for Ebola virus by altona real-time RT-PCR; however, this benchmark itself had imperfect sensitivity. Abundance Foundation.

ObjectiveLyme disease is a tick-borne disease of increasing incidence and public concern across the Northern Hemisphere. However, the socio-demographics and geographic distribution of the population affected in England and Wales are poorly understood. Therefore, the proposed study was designed to describe the demographics and distribution of laboratory-confirmed cases of Lyme disease from a national testing laboratory.DesignAn ecological study of routinely collected laboratory surveillance data.SettingPublic Health England’s national Lyme disease testing laboratory.Participants3986 laboratory-confirmed cases of Lyme disease between 2013 and 2016.ResultsIn England and Wales, the incidence of laboratory-confirmed Lyme disease rose significantly over the study period from 1.62 cases per 100 000 in 2013 to 1.95 cases per 100 000 in 2016. There was a bimodal age distribution (with peaks at 6–10 and 61–65 years age bands) with a predominance of male patients. A significant clustering of areas with high Lyme disease incidence was located in southern England. An association was found between disease incidence and socioeconomic status, based on the patient’s resident postcode, with more cases found in less deprived areas. Cases were disproportionately found in rural areas compared with the national population distribution.ConclusionsThese results suggest that Lyme disease patients originate from areas with higher socioeconomic status and disproportionately in rural areas. Identification of the Lyme disease hotspots in southern England, alongside the socio-demographics described, will enable a targeted approach to public health interventions and messages.

Without an effective vaccine, as was the case early in the 2014-2016 Ebola Outbreak in West Africa, disease control depends entirely on interrupting transmission through early disease detection and prompt patient isolation. Lateral Flow Immunoassays (LFI) are a potential supplement to centralized reference laboratory testing for the early diagnosis of Ebola Virus Disease (EVD). The goal of this study was to assess the performance of commercially available simple and rapid antigen detection LFIs, submitted for review to the WHO via the Emergency Use Assessment and Listing procedure. The study was performed in an Ebola Treatment Centre laboratory involved in EVD testing in Sierra Leone. In light of the current Ebola outbreak in May 2018 in the Democratic Republic of Congo, which highlights the lack of clarity in the global health community about appropriate Ebola diagnostics, our findings are increasingly critical. A cross-sectional study was conducted to assess comparative performance of four LFIs for detecting EVD. LFIs were assessed against the same 328 plasma samples and 100 whole EDTA blood samples, using the altona RealStar Filovirus Screen real-time RT-PCR as the bench mark assay. The performance of the Public Health England (PHE) in-house Zaire ebolavirus-specific real time RT-PCR Trombley assay was concurrently assessed. Statistical analysis using generalized estimating equations was conducted to compare LFI performance. Sensitivity and specificity varied between the LFIs, with specificity found to be significantly higher for whole EDTA blood samples compared to plasma samples in at least 2 LFIs (P≤0.003). Using the altona RT-PCR assay as the bench mark, sensitivities on plasma samples ranged from 79.53% (101/127, 95% CI: 71.46-86.17%) for the DEDIATEST EBOLA (SD Biosensor) to 98.43% (125/127, 95% CI: 94.43-99.81%) for the One step Ebola test (Intec). Specificities ranged from 80.20% (158/197, 95% CI: 74.07-88.60%) for plasma samples using the ReEBOV Antigen test Kit (Corgenix) to 100.00% (98/98, 95% CI: 96.31-100.00%) for whole blood samples using the DEDIATEST EBOLA (SD Biosensor) and SD Ebola Zaire Ag (SD Biosensor). Results also showed the Trombley RT-PCR assay had a lower limit of detection than the altona assay, with some LFIs having higher sensitivity than the altona assay when the Trombley assay was the bench mark. All of the tested EVD LFIs may be considered suitable for use in an outbreak situation (i.e. rule out testing in communities), although they had variable performance characteristics, with none possessing both high sensitivity and specificity. The non-commercial Trombley Zaire ebolavirus RT-PCR assay warrants further investigation, as it appeared more sensitive than the current gold standard, the altona Filovirus Screen RT-PCR assay.

Abstract Background Every year, many thousands of travellers return to the United Kingdom (UK) from visits to other countries and some will become unwell due to infections acquired abroad. Many imported infections have similar clinical presentations, such as fever and myalgia, so diagnostic testing is an important tool to improve patient management and outcomes. The aim of this study was to examine the demographics, travel history, presenting symptoms and diagnostic outcomes of referrals to the UK’s specialist diagnostic Rare & Imported Pathogens Laboratory (RIPL) for the period 2015–2020. Methods Anonymised clinical and laboratory data were extracted from RIPL’s Laboratory Information Management System and cleaned prior to descriptive analysis of the data. Travel history data were mapped to one of eight world regions, whereas symptom data were categorised into presenting syndromes. Diagnostic data were categorised as either positive, equivocal or negative. Results During the period 2015–2020, RIPL received 73 951 samples from 53 432 patients suspected of having infections that are rare in the UK. The most common age group for unwell returning travellers was 30–39 years and the most commonly reported travel destination was Southern and SE Asia. Dengue virus was the most diagnosed infection overall, followed by chikungunya, Zika, leptospirosis and spotted fever group Rickettsia. Dengue virus was among the top three most frequent diagnoses for all world regions except Europe and represented 62.5% of all confirmed/probable diagnoses. Conclusions None of the top five infections diagnosed by RIPL in travellers are vaccine-preventable, therefore understanding traveller demographics, destination-specific risk factors and encouraging preventative behaviours is the best available strategy to reduce the number of returning travellers who become infected. Prompt referral of acute samples with a detailed travel history, including purpose of travel and activities undertaken as well as dates and destinations can be a valuable tool in designing public health interventions and diagnostic algorithms.

Crimean–Congo haemorrhagic fever (CCHF) is a widely distributed and potentially fatal tick-borne viral disease with no licensed specific treatments or vaccines. In 2019, WHO published an advanced draft of a research and development roadmap for CCHF that prioritised the development and deployment of the medical countermeasures most needed by CCHF-affected countries. This Personal View presents updated CCHF research and development priorities and is the product of broad consultation with a working group of 20 leading experts in 2023–24. The strategic goals, milestones, and timelines have been revised and expanded to reflect scientific advances since 2019, including the identification of antibodies with therapeutic potential and the progression of four vaccine candidates through phase 1 clinical trials. This update emphasises the need for a One Health approach to manage CCHF, from integrated cross-sectoral surveillance to novel interventions that target ticks and their vertebrate hosts to reduce CCHF virus transmission to humans. The overarching vision for rapid diagnostics and specific therapeutics by 2028, followed by options to limit CCHF virus transmission and control disease by 2030, is deliberately ambitious and will only be achieved through coordinated international action from affected countries, funders, scientists, product developers, manufacturers, regulators, national authorities, and policy makers.

Precision monitoring of antibody responses during the COVID-19 pandemic is increasingly important during large scale vaccine rollout and rise in prevalence of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) variants of concern (VOC). Equally important is defining Correlates of Protection (CoP) for SARS-CoV-2 infection and COVID-19 disease. Data from epidemiological studies and vaccine trials identified virus neutralising antibodies (Nab) and SARS-CoV-2 antigen-specific (notably RBD and S) binding antibodies as candidate CoP. In this study, we used the World Health Organisation (WHO) international standard to benchmark neutralising antibody responses and a large panel of binding antibody assays to compare convalescent sera obtained from: a) COVID-19 patients; b) SARS-CoV-2 seropositive healthcare workers (HCW) and c) seronegative HCW. The ultimate aim of this study is to identify biomarkers of humoral immunity that could be used to differentiate severe from mild or asymptomatic SARS-CoV-2 infections. Some of these biomarkers could be used to define CoP in further serological studies using samples from vaccination breakthrough and/or re-infection cases. Whenever suitable, the antibody levels of the samples studied were expressed in International Units (IU) for virus neutralisation assays or in Binding Antibody Units (BAU) for ELISA tests. In this work we used commercial and non-commercial antibody binding assays; a lateral flow test for detection of SARS-CoV-2-specific IgG/IgM; a high throughput multiplexed particle flow cytometry assay for SARS-CoV-2 Spike (S), Nucleocapsid (N) and Receptor Binding Domain (RBD) proteins); a multiplex antigen semi-automated immuno-blotting assay measuring IgM, IgA and IgG; a pseudotyped microneutralisation test (pMN) and an electroporation-dependent neutralisation assay (EDNA). Our results indicate that overall, severe COVID-19 patients showed statistically significantly higher levels of SARS-CoV-2-specific neutralising antibodies (average 1029 IU/ml) than those observed in seropositive HCW with mild or asymptomatic infections (379 IU/ml) and that clinical severity scoring, based on WHO guidelines was tightly correlated with neutralisation and RBD/S antibodies. In addition, there was a positive correlation between severity, N-antibody assays and intracellular virus neutralisation.

Undifferentiated febrile illness (UFI) is one of the most common reasons for people seeking healthcare in low-income countries. While illness and death due to specific infections such as malaria are often well-quantified, others are frequently uncounted and their impact underappreciated. A number of high consequence infectious diseases, including Ebola virus, are endemic or epidemic in the Federal Republic of Sudan which has experienced at least 12 UFI outbreaks, frequently associated with haemorrhage and high case fatality rates (CFR), since 2012. One of these occurred in Darfur in 2015/2016 with 594 cases and 108 deaths (CFR 18.2%). The aetiology of these outbreaks remains unknown. We report a retrospective cohort study of the 2015/2016 Darfur outbreak, using a subset of 65 of 263 outbreak samples received by the National Public Health Laboratory which met selection criteria of sufficient sample volume and epidemiological data. Clinical features included fever (95.8%), bleeding (95.7%), headache (51.6%) and arthralgia (42.2%). No epidemiological patterns indicative of person-to-person transmission or health-worker cases were reported. Samples were tested at the Public Health England Rare and Imported Pathogens Laboratory using a bespoke panel of likely pathogens including haemorrhagic fever viruses, arboviruses and Rickettsia, Leptospira and Borrelia spp. Seven (11%) were positive for Crimean-Congo haemorrhagic fever virus (CCHFV) by real-time reverse transcription PCR. The remaining samples tested negative on all assays. CCHFV is an important cause of fever and haemorrhage in Darfur, but not the sole major source of UFI outbreaks in Sudan. Prospective studies are needed to explore other aetiologies, including novel pathogens. The presence of CCHFV has critical infection, prevention and control as well as clinical implications for future response. Our study reinforces the need to boost surveillance, lab and investigative capacity to underpin effective response, and for local and international health security.