Schmallenberg virus: a systematic international literature review (2011-2019) from an Irish perspective

peer-reviewedIn Autumn 2011, nonspecific clinical signs of pyrexia, diarrhoea, and drop in milk yield were observed in dairy cattle near the German town of Schmallenberg at the Dutch/German border. Targeted veterinary diagnostic investigations for classical endemic and emerging viruses could not identify a causal agent. Blood samples were collected from animals with clinical signs and subjected to metagenomic analysis; a novel orthobunyavirus was identified and named Schmallenberg virus (SBV). In late 2011/early 2012, an epidemic of abortions and congenital malformations in calves, lambs and goat kids, characterised by arthrogryposis and hydranencephaly were reported in continental Europe. Subsequently, SBV RNA was confirmed in both aborted and congenitally malformed foetuses and also in Culicoides species biting midges. It soon became evident that SBV was an arthropod-borne teratogenic virus affecting domestic ruminants. SBV rapidly achieved a pan-European distribution with most countries confirming SBV infection within a year or two of the initial emergence. The first Irish case of SBV was confirmed in the south of the country in late 2012 in a bovine foetus. Since SBV was first identified in 2011, a considerable body of scientific research has been conducted internationally describing this novel emerging virus. The aim of this systematic review is to provide a comprehensive synopsis of the most up-to-date scientific literature regarding the origin of SBV and the spread of the Schmallenberg epidemic, in addition to describing the species affected, clinical signs, pathogenesis, transmission, risk factors, impact, diagnostics, surveillance methods and control measures. This review also highlights current knowledge gaps in the scientific literature regarding SBV, most notably the requirement for further research to determine if, and to what extent, SBV circulation occurred in Europe and internationally during 2017 and 2018. Moreover, recommendations are also made regarding future arbovirus surveillance in Europe, specifically the establishment of a European-wide sentinel herd surveillance program, which incorporates bovine serology and Culicoides entomology and virology studies, at national and international level to monitor for the emergence and re-emergence of arboviruses such as SBV, bluetongue virus and other novel Culicoides-borne arboviruses

Culicoides species composition and abundance on Irish cattle farms: implications for arboviral disease transmission

peer-reviewedBackground Following the emergence of Schmallenberg virus (SBV) in Ireland in 2012, a sentinel herd surveillance program was established in the south of Ireland with the primary aim of investigating the species composition and abundance of Culicoides on livestock farms in the region. Methods Ultraviolet-light trapping for Culicoides was carried out on 10 sentinel farms. Each site was sampled fortnightly over 16 weeks (21st July to 5th November 2014). One Onderstepoort Veterinary Institute UV light trap was run overnight at each site and catches were transferred immediately into 70% ethanol. Culicoides were morphologically identified to species level. Collection site habitats were characterised using the Phase 1 habitat survey technique (Joint Nature Conservation Committee). Results A total of 23,929 individual Culicoides from 20 species was identified, including one species identified in Ireland for the first time, Culicoides cameroni. The most abundant species identified were Culicoides obsoletus/Culicoides scoticus (38%), Culicoides dewulfi (36%), Culicoides pulicaris (9%), Culicoides chiopterus (5%) and Culicoides punctatus (5%), comprising 93% of all Culicoides specimens identified. Collection site habitats were dominated by improved grassland and a combination of broadleaf woodland and native woodland species. Conclusions The most abundant species of Culicoides identified were the putative vectors of bluetongue virus (BTV) and SBV in northern Europe. Their presence and abundance demonstrates the potential for future transmission of arboviruses among livestock in this region

Current antimicrobial use in farm animals in the Republic of Ireland

peer-reviewedAbstract Antimicrobial resistance has been recognised as one of the most difficult challenges facing human and animal health in recent decades. The surveillance of antimicrobial use in animal health plays a major role in dealing with the growing issue of resistance. This paper reviews current data available on antimicrobial use in farmed animals in the Republic of Ireland, including each of the major livestock production sectors; pigs, poultry, dairy, beef and sheep. A systematic literature search was conducted to identify relevant published literature, and ongoing research was identified through the network of authors and searches of each of the research databases of the main agriculture funding bodies in Ireland. The varying quantities and quality of data available across each livestock sector underlines the need for harmonisation of data collection methods. This review highlights the progress that has been made regarding data collection in the intensive production sectors such as pigs and poultry, however, it is clear there are significant knowledge gaps in less intensive industries such as dairy, beef and sheep. To comply with European regulations an antimicrobial data collection system is due to be developed for all food-producing animals in the future, however in the short-term surveillance studies have allowed us to build a picture of current use within the Republic of Ireland. Further studies will allow us to fill current knowledge gaps and build a more comprehensive overview of antimicrobial use in farm animals in Ireland

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

SARS-CoV-2 infections were rising during early summer 2021 in many countries associated with the Delta variant. We assessed RT-PCR swab-positivity in the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. We observed sustained exponential growth with average doubling time (June-July 2021) of 25 days driven by complete replacement of Alpha variant by Delta, and by high prevalence at younger less-vaccinated ages. Unvaccinated people were three times more likely than double-vaccinated people to test positive. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement