Publications

The Pirbright Institute publication directory contains details of selected publications written by our researchers.

There were a total of 2157 results for your search.
Park J-G, Oladunni F S, Rohaim M A, Whittingham-Dowd J, Tollitt J, Assas B M, Alhazmi W, Almilaibary A, Iqbal M, Chang P, Escalona R, Shivanna V, Torrelles J B, Worthington J J, Jackson-Jones L H, Martinez-Sobrido L, Munir M (2021)

Immunogenicity and protective efficacy of an intranasal live-attenuated vaccine against SARS-CoV-2 in preclinical animal models

bioRxiv, 2021.01.08.425974

Abstract

The global deployment of an effective and safe vaccine is currently a public health priority to curtail the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a Newcastle disease virus (NDV)-based intranasal vectored-vaccine in mice and hamsters for its immunogenicity, safety and protective efficacy in challenge studies with SARS-CoV-2. The recombinant (r)NDV-S vaccine expressing spike (S) protein of SARS-CoV-2 administrated via intranasal route in mice induced high levels of SARS-CoV-2-specific neutralizing immunoglobulin A (IgA) and IgG2a antibodies and T cell-mediated immunity. Hamsters vaccinated with two doses of vaccine showed complete protection from clinical disease including lung infection, inflammation, and pathological lesions after SARS-CoV-2 challenge. Importantly, a single or double dose of intranasal rNDV-S vaccine completely blocked SARS-CoV-2 shedding in nasal turbinate and lungs within 4 days of vaccine administration in hamsters. Taken together, intranasal administration of rNDV-S has the potential to control infection at the site of inoculation, which should prevent both the clinical disease and transmission to halt the spread of the COVID-19 pandemic.

Abstract

We have developed a low-cost molecularly imprinted polymer (MIP)-based fluorometric assay to directly quantify myoglobin in a biological sample. The assay uses a previously unreported method for the development of microwave-assisted rapid synthesis of aldehyde functionalized magnetic nanoparticles, in just 20 min. The aldehyde functionalized nanoparticles have an average size of 7.5 nm ± 1.8 and saturation magnetizations of 31.8 emu g-1 with near-closed magnetization loops, confirming their superparamagnetic properties. We have subsequently shown that protein tethering was possible to the aldehyde particles, with 0.25 ± 0.013 mg of myoglobin adsorbed to 20 mg of the nanomaterial. Myoglobin-specific fluorescently tagged MIP (F-MIP) particles were synthesized and used within the assay to capture myoglobin from a test sample. Excess F-MIP was removed from the sample using protein functionalized magnetic nanoparticles (Mb-SPION), with the remaining sample analyzed using fluorescence spectroscopy. The obtained calibration plot of myoglobin showed a linear correlation ranging from 60 pg ml-1 to 6 mg ml-1 with the limit of detection of 60 pg ml-1. This method was successfully used to detect myoglobin in spiked fetal calf serum, with a recovery rate of more than 93%.

Everett H E, van Diemen P M, Aramouni M, Ramsay A, Coward V J, Pavot V, Canini L, Holzer B, Morgan S, Dynamics sLoLa Consortium, Woolhouse M E J, Tchilian E, Brookes S M, Brown I H, Charleston B, Gilbert S (2021)

Vaccines that reduce viral shedding do not prevent transmission of H1N1 pandemic 2009 swine influenza a virus infection to unvaccinated pigs

Journal of Virology 95 (4)

Abstract

Swine influenza A virus (swIAV) infection causes substantial economic loss and disease burden in humans and animals. The 2009 pandemic H1N1 (pH1N1) influenza A virus is now endemic in both populations. In this study we evaluated the efficacy of different vaccines in reducing nasal shedding in pigs following pH1N1 virus challenge. We also assessed transmission from immunized and challenged to naive, directly in-contact pigs. Pigs were immunised with either adjuvanted, whole inactivated virus (WIV) vaccines or viral vectored (ChAdOx1 and MVA) vaccines expressing either the homologous or heterologous influenza A virus hemagglutinin (HA) glycoprotein as well as an influenza viral pseudotype (S-FLU) vaccine expressing heterologous HA. Only two vaccines containing homologous HA, which also induced high hemagglutination inhibitory antibody titers, significantly reduced virus shedding in challenged animals. Nevertheless, virus transmission from challenged to naive, in-contact animals occurred in all groups, although was delayed in groups of vaccinated animals with reduced virus shedding.

IMPORTANCE This study was designed to determine whether vaccination of pigs with conventional, WIV or viral-vectored vaccines reduces pH1N1 swine influenza virus shedding following challenge and can prevent transmission to naive in-contact animals. Even when viral shedding was significantly reduced following challenge, infection was transmissible to susceptible co-housed recipients. This knowledge is important to inform disease surveillance and control strategies, and to determine the vaccine coverage required in a population, thereby defining disease moderation or herd protection. WIV or viral-vectored vaccines homologous to the challenge strain significantly reduced virus shedding from directly infected pigs, but vaccination did not completely prevent transmission to co-housed naive pigs.

Abstract

A vaccine providing both powerful Ab and cross-reactive T cell immune responses against influenza viruses would be beneficial for both humans and pigs. In this study, we evaluated i.m., aerosol (Aer), and simultaneous systemic and respiratory immunization (SIM) by both routes in Babraham pigs, using the single cycle candidate influenza vaccine S-FLU. After prime and boost immunization, pigs were challenged with H1N1pdm09 virus. i.m.-immunized pigs generated a high titer of neutralizing Abs but poor T cell responses, whereas Aer induced powerful respiratory tract T cell responses but a low titer of Abs. SIM pigs combined high Ab titers and strong local T cell responses. SIM showed the most complete suppression of virus shedding and the greatest improvement in pathology. We conclude that SIM regimes for immunization against respiratory pathogens warrant further study.

Chandler-Bostock R, Mata C P, Bingham R J, Dykeman E C, Meng B, Tuthill T J, Rowlands D J, Ranson N A, Twarock R, Stockley P G (2020)

Assembly of infectious enteroviruses depends on multiple, conserved genomic RNA-coat protein contacts

PLoS Pathogens 16 (12), e1009146

Abstract

Picornaviruses are important viral pathogens, but despite extensive study, the assembly process of their infectious virions is still incompletely understood, preventing the development of anti-viral strategies targeting this essential part of the life cycle. We report the identification, via RNA SELEX and bioinformatics, of multiple RNA sites across the genome of a typical enterovirus, enterovirus-E (EV-E), that each have affinity for the cognate viral capsid protein capsomer. Many of these sites are evolutionarily conserved across known EV-E variants, suggesting they play essential functional roles. Cryo-electron microscopy was used to reconstruct the EV-E particle at ~2.2 Å resolution, revealing extensive density for the genomic RNA. Relaxing the imposed symmetry within the reconstructed particles reveals multiple RNA-CP contacts, a first for any picornavirus. Conservative mutagenesis of the individual RNA-contacting amino acid side chains in EV-E, many of which are conserved across the enterovirus family including poliovirus, is lethal but does not interfere with replication or translation. Anti-EV-E and anti-poliovirus aptamers share sequence similarities with sites distributed across the poliovirus genome. These data are consistent with the hypothesis that these RNA-CP contacts are RNA Packaging Signals (PSs) that play vital roles in assembly and suggest that the RNA PSs are evolutionarily conserved between pathogens within the family, augmenting the current protein-only assembly paradigm for this family of viruses.

Abstract

Dengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signaling and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) nonstructural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a three-dimensional (3D) microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue and thus show that pericytes can play a critical role in the etiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue.

IMPORTANCE The World Health Organization considers dengue one of the top 10 global public health problems. There is no specific antiviral therapy to treat dengue virus and no way of predicting which patients will develop potentially fatal severe dengue, typified by vascular leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the vascular leakage-inducing effects of the dengue viral protein NS1 through contact-independent signaling to endothelial cells. While pericytes are known to contribute to noncommunicable vascular leakage, this is the first time these cells have been implicated in the vascular effects of an infectious disease. Our findings could pave the way for new therapies and diagnostics to combat dengue and potentially other infectious vascular leakage syndromes.

Eschbaumer M, Vogtlin A, Paton D J, Barnabei J L, Sanchez-Vazquez M J, Pituco E M, Rivera A M, O'Brien D, Nfon C, Brocchi E, Bakkali Kassimi L, Lefebvre D J, Navarro Lopez R, Maradei E, Duffy S J, Loitsch A, De Clercq K, King D P, Zientara S, Griot C, Beer M (2020)

Non-discriminatory exclusion testing as a tool for the early detection of foot-and-mouth disease incursions

Frontiers in Veterinary Science 7, 552670

Abstract

Endemic circulation of foot-and-mouth disease (FMD) in Africa and Asia poses a continuous risk to countries in Europe, North America, and Oceania which are free from the disease. Introductions of the disease into a free region have dramatic economic impacts, especially if they are not detected at an early stage and controlled rapidly. However, farmers and veterinarians have an obvious disincentive to report clinical signs that are consistent with FMD, due to the severe consequences of raising an official suspicion, such as farm-level quarantine. One way that the risk of late detection can be mitigated is offering non-discriminatory exclusion testing schemes for differential diagnostics, wherein veterinarians can submit samples without the involvement of the competent authority and without sanctions or costs for the farmer. This review considers the benefits and limitations of this approach to improve the early detection of FMD in free countries and gives an overview of the FMD testing schemes currently in use in selected countries in Europe and the Americas as well as in Australia.

Abstract

Marek's disease virus serotype 1 (MDV-1) is an important oncogenic alpha-herpesvirus that induces immunosuppressive and rapid-onset T-cell lymphomatous disease in poultry commonly referred to as Marek's disease (MD). As an excellent biomodel for the study of virally-induced cancers in natural hosts, MDV-1 encoded microRNAs (miRNAs) have been previously demonstrated with the potential roles to act as critical regulators in virus replication, latency, pathogenesis and especially in oncogenesis. Similar to the oncogenic gamma-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), miR-M4-5p, the cellular microRNA-155 (miR-155) ortholog encoded by MDV-1, is also involved in MD oncogenesis. In lymphoblastoid cell lines derived from MDV-induced T-cell lymphomas, miR-M4-5p has been shown to be highly expressed and participate in inducing MD lymphomagenesis by regulating multiple signal pathways. Herein we report the new identification of the host WW domain-containing oxidoreductase (WWOX) as a biological target for miR-M4-5p. Further experiments revealed that as a critical oncomiRNA, miR-M4-5p promotes the proliferations of both chicken embryo fibroblast (CEF) and MSB-1 cells via suppressing cell apoptosis by targeting WWOX, a well-known tumor suppressor. Our data presents a novel insight in elucidating the regulatory mechanisms mediated by the viral analog of miR-155 that potentially contribute to MD tumorigenesis.

Abstract

Chicken astrovirus (CAstV) infection is strongly associated with kidney disease, gout, "white chicks" hatchery disease, and runting and stunting syndrome (RSS). In the present study, 82.5% of 154 clinical samples from different provinces in China were positive for CAstV by RT-PCR. One CAstV isolate, designated as AAstV/Chicken/CHN/2017/NJ01, was successfully isolated from the small intestine of "Yellow" chickens using LMH cells. The genome sequence and structure analyses revealed that NJ1701 had the typical characteristics of avian astroviruses which was genetically distinct from other Avastrovirus. This isolate was classified as Group B subgroup i based on phylogenetic analysis of complete ORF2 (capsid) amino acid sequences. Meanwhile, growth depression and hatchability reduction were observed in the chicken embryo infection experiment. The results in the current study will contribute to our understanding of chicken astrovirus in China.

Vergne T, Gubbins S, Guinat C, Bauzile B, Delpont M, Chakraborty D, Gruson H, Roche B, Andraud M, Paul M, Guerin J-L (2020)

Inferring within-flock transmission dynamics of highly pathogenic avian influenza (H5N8) in France, 2020

bioRxiv, 2020.12.21.423436

Abstract

Following the emergence of highly pathogenic avian influenza (H5N8) in France in early December 2020, we used duck mortality data of the index case to investigate within-flock transmission dynamics. A stochastic epidemic model was adjusted to the daily mortality data and model parameters were estimated using an approximate Bayesian computation sequential Monte Carlo (ABC-SMC) algorithm. Results suggested that the virus was introduced 4 days (95% credible interval: 3; 5) prior to the day suspicion was reported and that the transmission rate was 3.7 day-1 (95%CI: 2.6 - 5.3). On average, ducks started being infectious 3.1 hours (95%CI: 0.4 - 8.0) after infection and remained infectious for 4.4 days (95%CI: 3.1 - 5.6). Model outputs also suggested that the number of infectious ducks was already 3239 (95%CI: 26 - 3706) the day before suspicion, emphasising the substantial latent threat this virus could pose to other poultry farms and to neighbouring wildlife. These estimations can be applied to upcoming outbreaks and made available to veterinary services within few hours. This study illustrates how mechanistic models can provide rapid relevant insights to contribute to the management of infectious disease outbreaks of farmed animals.

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