Publications by authors named "A C Banyard"

112 Publications

Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus.

Viruses 2021 02 3;13(2). Epub 2021 Feb 3.

School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham LE12 5RD, UK.

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG's antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.
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http://dx.doi.org/10.3390/v13020234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913267PMC
February 2021

High genetic variability of Schmallenberg virus M-segment leads to efficient immune escape from neutralizing antibodies.

PLoS Pathog 2021 Jan 26;17(1):e1009247. Epub 2021 Jan 26.

Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.

Schmallenberg virus (SBV) is the cause of severe fetal malformations when immunologically naïve pregnant ruminants are infected. In those malformed fetuses, a "hot-spot"-region of high genetic variability within the N-terminal region of the viral envelope protein Gc has been observed previously, and this region co-localizes with a known key immunogenic domain. We studied a series of M-segments of those SBV variants from malformed fetuses with point mutations, insertions or large in-frame deletions of up to 612 nucleotides. Furthermore, a unique cell-culture isolate from a malformed fetus with large in-frame deletions within the M-segment was analyzed. Each Gc-protein with amino acid deletions within the "hot spot" of mutations failed to react with any neutralizing anti-SBV monoclonal antibodies or a domain specific antiserum. In addition, in vitro virus replication of the natural deletion variant could not be markedly reduced by neutralizing monoclonal antibodies or antisera from the field. The large-deletion variant of SBV that could be isolated in cell culture was highly attenuated with an impaired in vivo replication following the inoculation of sheep. In conclusion, the observed amino acid sequence mutations within the N-terminal main immunogenic domain of glycoprotein Gc result in an efficient immune evasion from neutralizing antibodies in the special environment of a developing fetus. These SBV-variants were never detected as circulating viruses, and therefore should be considered to be dead-end virus variants, which are not able to spread further. The observations described here may be transferred to other orthobunyaviruses, particularly those of the Simbu serogroup that have been shown to infect fetuses. Importantly, such mutant strains should not be included in attempts to trace the spatial-temporal evolution of orthobunyaviruses in molecular-epidemiolocal approaches during outbreak investigations.
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http://dx.doi.org/10.1371/journal.ppat.1009247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872300PMC
January 2021

Emergence and spread of novel H5N8, H5N5 and H5N1 clade 2.3.4.4 highly pathogenic avian influenza in 2020.

Emerg Microbes Infect 2021 Dec;10(1):148-151

Department of Virology, Animal and Plant Health Agency, OIE/FAO International Reference Laboratory for Avian Influenza, Swine Influenza and Newcastle Disease Virus, Surrey, UK.

Analyses of HPAI H5 viruses from poultry outbreaks across a wide Eurasian region since July 2020 including the Russian Federation, Republics of Iraq and Kazakhstan, and recent detections in migratory waterfowl in the Netherlands, revealed undetected maintenance of H5N8, likely in galliform poultry since 2017/18 and both H5N5 and H5N1. All viruses belong to A/H5 clade 2.3.4.4b with closely related HA genes. Heterogeneity in Eurasian H5Nx HPAI emerging variants threatens poultry production, food security and veterinary public health.
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http://dx.doi.org/10.1080/22221751.2021.1872355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832535PMC
December 2021

Preliminary optimisation of a simplified sample preparation method to permit direct detection of SARS-CoV-2 within saliva samples using reverse-transcription loop-mediated isothermal amplification (RT-LAMP).

J Virol Methods 2021 03 20;289:114048. Epub 2020 Dec 20.

Hampshire Hospitals NHS Foundation Trust, Department of Microbiology, Basingstoke and North Hants Hospital, Basingstoke, UK.

We describe the optimisation of a simplified sample preparation method which permits rapid and direct detection of SARS-CoV-2 RNA within saliva, using reverse-transcription loop-mediated isothermal amplification (RT-LAMP). Treatment of saliva samples prior to RT-LAMP by dilution 1:1 in Mucolyse™, followed by dilution in 10 % (w/v) Chelex© 100 Resin and a 98 °C heat step for 2 min enabled detection of SARS-CoV-2 RNA in positive saliva samples. Using RT-LAMP, SARS-CoV-2 RNA was detected in as little as 05:43 min, with no amplification detected in 3097 real-time reverse transcription PCR (rRT-PCR) negative saliva samples from staff tested within a service evaluation study, or for other respiratory pathogens tested (n = 22). Saliva samples can be collected non-invasively, without the need for skilled staff and can be obtained from both healthcare and home settings. Critically, this approach overcomes the requirement for, and validation of, different swabs and the global bottleneck in obtaining access to extraction robots and reagents to enable molecular testing by rRT-PCR. Such testing opens the possibility of public health approaches for effective intervention during the COVID-19 pandemic through regular SARS-CoV-2 testing at a population scale, combined with isolation and contact tracing.
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http://dx.doi.org/10.1016/j.jviromet.2020.114048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750029PMC
March 2021

Experimental Lagos bat virus infection in straw-colored fruit bats: A suitable model for bat rabies in a natural reservoir species.

PLoS Negl Trop Dis 2020 12 15;14(12):e0008898. Epub 2020 Dec 15.

Institute of Zoology, Zoological Society of London, Regent's Park, London, United Kingdom.

Rabies is a fatal neurologic disease caused by lyssavirus infection. Bats are important natural reservoir hosts of various lyssaviruses that can be transmitted to people. The epidemiology and pathogenesis of rabies in bats are poorly understood, making it difficult to prevent zoonotic transmission. To further our understanding of lyssavirus pathogenesis in a natural bat host, an experimental model using straw-colored fruit bats (Eidolon helvum) and Lagos bat virus, an endemic lyssavirus in this species, was developed. To determine the lowest viral dose resulting in 100% productive infection, bats in five groups (four bats per group) were inoculated intramuscularly with one of five doses, ranging from 100.1 to 104.1 median tissue culture infectious dose (TCID50). More bats died due to the development of rabies after the middle dose (102.1 TCID50, 4/4 bats) than after lower (101.1, 2/4; 101.1, 2/4) or higher (103.1, 2/4; 104.1, 2/4) doses of virus. In the two highest dose groups, 4/8 bats developed rabies. Of those bats that remained healthy 3/4 bats seroconverted, suggesting that high antigen loads can trigger a strong immune response that abrogates a productive infection. In contrast, in the two lowest dose groups, 3/8 bats developed rabies, 1/8 remained healthy and seroconverted and 4/8 bats remained healthy and did not seroconvert, suggesting these doses are too low to reliably induce infection. The main lesion in all clinically affected bats was meningoencephalitis associated with lyssavirus-positive neurons. Lyssavirus antigen was detected in tongue epithelium (5/11 infected bats) rather than in salivary gland epithelium (0/11), suggesting viral excretion via the tongue. Thus, intramuscular inoculation of 102.1 TCID50 of Lagos bat virus into straw-colored fruit bats is a suitable model for lyssavirus associated bat rabies in a natural reservoir host, and can help with the investigation of lyssavirus infection dynamics in bats.
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http://dx.doi.org/10.1371/journal.pntd.0008898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771871PMC
December 2020

Development of immunohistochemistry and in situ hybridisation for the detection of SARS-CoV and SARS-CoV-2 in formalin-fixed paraffin-embedded specimens.

Sci Rep 2020 12 14;10(1):21894. Epub 2020 Dec 14.

Pathology Department, Animal and Plant Health Agency (APHA), Woodham Lane, New Haw, Addlestone, KT15 3NB, UK.

The rapid emergence of SARS-CoV-2, the causative agent of COVID-19, and its dissemination globally has caused an unprecedented strain on public health. Animal models are urgently being developed for SARS-CoV-2 to aid rational design of vaccines and therapeutics. Immunohistochemistry and in situ hybridisation techniques that facilitate reliable and reproducible detection of SARS-CoV and SARS-CoV-2 viral products in formalin-fixed paraffin-embedded (FFPE) specimens would be of great utility. A selection of commercial antibodies generated against SARS-CoV spike protein and nucleoprotein, double stranded RNA, and RNA probe for spike genes were evaluated for the ability to detect FFPE infected cells. We also tested both heat- and enzymatic-mediated virus antigen retrieval methods to determine the optimal virus antigen recovery as well as identifying alternative retrieval methods to enable flexibility of IHC methods. In addition to using native virus infected cells as positive control material, the evaluation of non-infected cells expressing coronavirus (SARS, MERS) spike as a biosecure alternative to assays involving live virus was undertaken. Optimized protocols were successfully applied to experimental animal-derived tissues. The diverse techniques for virus detection and control material generation demonstrated in this study can be applied to investigations of coronavirus pathogenesis and therapeutic research in animal models.
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http://dx.doi.org/10.1038/s41598-020-78949-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736337PMC
December 2020

Large Extracellular Vesicles Can be Characterised by Multiplex Labelling Using Imaging Flow Cytometry.

Int J Mol Sci 2020 Nov 18;21(22). Epub 2020 Nov 18.

Children's Cancer Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, University of Manchester, Oglesby Cancer Research Building, Manchester Academic Health Science Centre, Manchester Cancer Research Centre, Manchester M20 4GJ, UK.

Extracellular vesicles (EVs) are heterogeneous in size (30 nm-10 µm), content (lipid, RNA, DNA, protein), and potential function(s). Many isolation techniques routinely discard the large EVs at the early stages of small EV or exosome isolation protocols. We describe here a standardised method to isolate large EVs from medulloblastoma cells and examine EV marker expression and diameter using imaging flow cytometry. Our approach permits the characterisation of each large EVs as an individual event, decorated with multiple fluorescently conjugated markers with the added advantage of visualising each event to ensure robust gating strategies are applied.

Methods: We describe step-wise isolation and characterisation of a subset of large EVs from the medulloblastoma cell line UW228-2 assessed by fluorescent light microscopy, transmission electron microscopy (TEM) and tunable resistance pulse sensing (TRPS). Viability of parent cells was assessed by Annexin V exposure by flow cytometry. Imaging flow cytometry (Imagestream Mark II) identified EVs by direct fluorescent membrane labelling with Cell Mask Orange (CMO) in conjunction with EV markers. A stringent gating algorithm based on side scatter and fluorescence intensity was applied and expression of EV markers CD63, CD9 and LAMP 1 assessed.

Results: UW228-2 cells prolifically release EVs of up to 6 µm. We show that the Imagestream Mark II imaging flow cytometer allows robust and reproducible analysis of large EVs, including assessment of diameter. We also demonstrate a correlation between increasing EV size and co-expression of markers screened.

Conclusions: We have developed a labelling and stringent gating strategy which is able to explore EV marker expression (CD63, CD9, and LAMP1) on individual EVs within a widely heterogeneous population. Taken together, data presented here strongly support the value of exploring large EVs in clinical samples for potential biomarkers, useful in diagnostic screening and disease monitoring.
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http://dx.doi.org/10.3390/ijms21228723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699300PMC
November 2020

The Emergence of H7N7 Highly Pathogenic Avian Influenza Virus from Low Pathogenicity Avian Influenza Virus Using an Embryo Culture Model.

Viruses 2020 08 21;12(9). Epub 2020 Aug 21.

Virology Department, Animal and Plant Health Agency (APHA-Weybridge), Addlestone, Surrey KT15 3NB, UK.

Outbreaks of highly pathogenic avian influenza virus (HPAIV) often result in the infection of millions of poultry, causing up to 100% mortality. HPAIV has been shown to emerge from low pathogenicity avian influenza virus (LPAIV) in field outbreaks. Direct evidence for the emergence of H7N7 HPAIV from a LPAIV precursor with a rare di-basic cleavage site (DBCS) was identified in the UK in 2008. The DBCS contained an additional basic amino acid compared to commonly circulating LPAIVs that harbor a single-basic amino acid at the cleavage site (SBCS). Using reverse genetics, outbreak HPAIVs were rescued with a DBCS (H7N7), as seen in the LPAIV precursor or an SBCS representative of common H7 LPAIVs (H7N7). Passage of H7N7 in chicken embryo tissues showed spontaneous evolution to a HPAIV. In contrast, deep sequencing of extracts from embryo tissues in which H7N7 was serially passaged showed retention of the LPAIV genotype. Thus, in chicken embryos, an H7N7 virus containing a DBCS appears naturally unstable, enabling rapid evolution to HPAIV. Evaluation in embryo tissue presents a useful approach to study AIV evolution and allows a laboratory-based dissection of molecular mechanisms behind the emergence of HPAIV.
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http://dx.doi.org/10.3390/v12090920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552004PMC
August 2020

Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy.

Nat Cancer 2020 Feb 10;1(2):210-221. Epub 2020 Feb 10.

Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, United Kingdom.

Our understanding of how checkpoint inhibitors (CPI) affect T cell evolution is incomplete, limiting our ability to achieve full clinical benefit from these drugs. Here we analyzed peripheral T cell populations after one cycle of CPI and identified a dynamic awakening of the immune system revealed by T cell evolution in response to treatment. We sequenced T cell receptors (TCR) in plasma cell-free DNA (cfDNA) and peripheral blood mononuclear cells (PBMC) and performed phenotypic analysis of peripheral T cell subsets from metastatic melanoma patients treated with CPI. We found that early peripheral T cell turnover and TCR repertoire dynamics identified which patients would respond to treatment. Additionally, the expansion of a subset of immune-effector peripheral T cells we call T cells correlated with response. These events are prognostic and occur within 3 weeks of starting immunotherapy, raising the potential for monitoring patients responses using minimally invasive liquid biopsies."
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http://dx.doi.org/10.1038/s43018-019-0022-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046489PMC
February 2020

Towards rabies elimination in the Asia-Pacific region: From theory to practice.

Biologicals 2020 Mar 20;64:83-95. Epub 2020 Feb 20.

Friedrich-Loeffler-Institut, Insel Riems, Germany.

Rabies is a major neglected zoonotic disease and causes a substantial burden in the Asian region. Currently, Pacific Oceania is free of rabies but enzootic areas throughout southeast Asia represent a major risk of disease introduction to this region. On September 25-26, 2019, researchers, government officials and related stakeholders met at an IABS conference in Bangkok, Thailand to engage on the topic of human rabies mediated by dogs. The objective of the meeting was focused upon snowballing efforts towards achieving substantial progress in rabies prevention, control and elimination within Asia by 2030, and thereby to safeguard the Pacific region. Individual sessions focused upon domestic animal, wildlife and human vaccination; the production and evaluation of quality, safety and efficacy of existing rabies biologics; and the future development of new products. Participants reviewed the progress to date in eliminating canine rabies by mass vaccination, described supportive methods to parenteral administration by oral vaccine application, considered updated global and local approaches at human prophylaxis and discussed the considerable challenges ahead. Such opportunities provide continuous engagement on disease management among professionals at a trans-disciplinary level and promote new applied research collaborations in a modern One Health context.
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http://dx.doi.org/10.1016/j.biologicals.2020.01.008DOI Listing
March 2020

Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma.

Nat Commun 2020 02 12;11(1):853. Epub 2020 Feb 12.

Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK.

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.
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http://dx.doi.org/10.1038/s41467-020-14632-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015935PMC
February 2020

Between roost contact is essential for maintenance of European bat lyssavirus type-2 in Myotis daubentonii bat reservoir: 'The Swarming Hypothesis'.

Sci Rep 2020 02 3;10(1):1740. Epub 2020 Feb 3.

Animal and Plant Health Agency (Weybridge), Surrey, KT15 3NB, United Kingdom.

Many high-consequence human and animal pathogens persist in wildlife reservoirs. An understanding of the dynamics of these pathogens in their reservoir hosts is crucial to inform the risk of spill-over events, yet our understanding of these dynamics is frequently insufficient. Viral persistence in a wild bat population was investigated by combining empirical data and in-silico analyses to test hypotheses on mechanisms for viral persistence. A fatal zoonotic virus, European Bat lyssavirus type 2 (EBLV-2), in Daubenton's bats (Myotis daubentonii) was used as a model system. A total of 1839 M. daubentonii were sampled for evidence of virus exposure and excretion during a prospective nine year serial cross-sectional survey. Multivariable statistical models demonstrated age-related differences in seroprevalence, with significant variation in seropositivity over time and among roosts. An Approximate Bayesian Computation approach was used to model the infection dynamics incorporating the known host ecology. The results demonstrate that EBLV-2 is endemic in the study population, and suggest that mixing between roosts during seasonal swarming events is necessary to maintain EBLV-2 in the population. These findings contribute to understanding how bat viruses can persist despite low prevalence of infection, and why infection is constrained to certain bat species in multispecies roosts and ecosystems.
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http://dx.doi.org/10.1038/s41598-020-58521-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997190PMC
February 2020

Current Rabies Vaccines Do Not Confer Protective Immunity against Divergent Lyssaviruses Circulating in Europe.

Viruses 2019 09 24;11(10). Epub 2019 Sep 24.

Department of Virology, Animal and Plant Health Agency (APHA), Addlestone, Surrey KT15 3NB, UK.

The use of the rabies vaccine for post-exposure prophylaxis started as early as 1885, revealing a safe and efficient tool to prevent human rabies cases. Preventive vaccination is the basis for the control of canine-mediated rabies, which has already been eliminated from extensive parts of the world, including Europe. Plans to eliminate canine-mediated human rabies by 2030 have been agreed upon by international organisations. However, rabies vaccines are not efficacious against some divergent lyssaviruses. The presence in European indigenous bats of recently described lyssaviruses, which are not neutralised by antibody responses to existing vaccines, as well as the declaration of an imported case of an African lyssavirus, which also escapes vaccine-derived protection, leaves the European health authorities unable to provide efficacious protective vaccines to some potential situations of human exposure. All these circumstances highlight the need for a universal pan-lyssavirus rabies vaccine, able to prevent human rabies in all circumstances.
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http://dx.doi.org/10.3390/v11100892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832729PMC
September 2019

Pan-lyssavirus Real Time RT-PCR for Rabies Diagnosis.

J Vis Exp 2019 07 10(149). Epub 2019 Jul 10.

Wildlife Zoonoses & Vector-Borne Diseases Research Group, Animal and Plant Health Agency; Institute of Infection and Global Health, University of Liverpool.

Molecular assays are rapid, sensitive and specific, and have become central to diagnosing rabies. PCR based assays have been utilized for decades to confirm rabies diagnosis but have only recently been accepted by the OIE (World Organisation for Animal Health) as a primary method to detect rabies infection. Real-time RT-PCR assays provide real-time data, and are closed-tube systems, minimizing the risk of contamination during setup. DNA intercalating fluorochrome real-time RT-PCR assays do not require expensive probes, minimizing the cost per sample, and when the primers are designed in conserved regions, assays that are specific across virus genera rather than specific to just one virus species are possible. Here we describe a pan-lyssavirus SYBR real-time RT-PCR assay that detects lyssaviruses across the Lyssavirus genus, including the most divergent viruses IKOV, WCBV and LLEBV. In conjunction with dissociation curve analysis, this assay is sensitive and specific, with the advantage of detecting all lyssavirus species. The assay has been adopted in many diagnostic laboratories with quality assured environments, enabling robust, rapid, sensitive diagnosis of animal and human rabies cases.
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http://dx.doi.org/10.3791/59709DOI Listing
July 2019

Trying to treat the untreatable: experimental approaches to clear rabies virus infection from the CNS.

J Gen Virol 2019 08 25;100(8):1171-1186. Epub 2019 Jun 25.

Institute for Infection and Immunity, St George's Hospital Medical School, University of London, London, UK.

Rabies virus causes an invariably fatal encephalitis following the onset of clinical disease. Despite the availability of safe and effective vaccines, the clinical stages of rabies encephalitis remain untreatable, with few survivors being documented. A principal obstacle to the treatment of rabies is the neurotropic nature of the virus, with the blood-brain barrier size exclusion limit rendering the delivery of antiviral drugs and molecules to the central nervous system inherently problematic. This review focuses on efforts to try and overcome barriers to molecule delivery to treat clinical rabies and overviews current progress in the development of experimental live rabies virus vaccines that may have future applications in the treatment of clinical rabies, including the attenuation of rabies virus vectors through either the duplication or mutation of existing genes or the incorporation of non-viral elements within the genome. Rabies post-infection treatment (PIT) remains the holy grail of rabies research.
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http://dx.doi.org/10.1099/jgv.0.001269DOI Listing
August 2019

Avoiding preventable deaths: The scourge of counterfeit rabies vaccines.

Vaccine 2019 04 25;37(17):2285-2287. Epub 2019 Mar 25.

Animal and Plant Health Agency, WHO Collaborating Centre for Characterisation of Rabies and Rabies-Related Viruses, OIE Reference Laboratory for Rabies, Weybridge, UK; Institute of Infection & Global Health, University of Liverpool, Liverpool, UK; St. George's Hospital Medical School, Institute for Infection and Immunity, University of London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2019.03.037DOI Listing
April 2019

Quantifying Levels of Peste Des Petits Ruminants (PPR) Virus in Excretions from Experimentally Infected Goats and Its Importance for Nascent PPR Eradication Programme.

Viruses 2019 03 12;11(3). Epub 2019 Mar 12.

The Pirbright Institute, Ash Road, Woking, Surrey GU24 0NF, UK.

Following the successful eradication of rinderpest, the World Organization of Animal Health (OIE) and the Food and Agriculture Organisation (FAO) have set a goal to globally eradicate Peste des petits ruminants (PPR) by 2030. To support the eradication programme we have quantified the levels of PPR virus (PPRV) nucleic acid excreted in body fluids (blood, feces, saliva, nasal and eye swabs) of PPRV-infected goats to ascertain which days post-infection animals are potentially infectious, and hence direct quarantine activities. The data will also indicate optimal sample strategies to assess presence of PPR infection in the naturally infected herd. Peak PPRV nucleic acid detection in different bodily fluids was between 5 and 10 days post-infection. As such, this period must be considered the most infectious period for contact transmission, although high viral load was observed through RNA detection in nasal excretions from two days post-infection until at least two weeks post-infection. Percentage sample positivity was low both in eye swabs and saliva samples during the early stage of infection although RNA was detected as late as two weeks post-infection. From the individual animal data, PPRV was detected later post-infection in fecal material than in other body fluids and the detection was intermittent. The results from this study indicate that nasal swabs are the most appropriate to sample when considering molecular diagnosis of PPRV.
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http://dx.doi.org/10.3390/v11030249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466160PMC
March 2019

Introduction History of rabies control by vaccination.

Rev Sci Tech 2018 Aug;37(2):305-322

Since antiquity, rabies has remained one of the deadliest infectious diseases known to humankind, with a case fatality rate approaching 100% following the onset of clinical disease. It is present on all continents where terrestrial mammals exist, with the majority of animal and human cases being reported in the resourcelimited countries of Africa and Asia, with thousands of human rabies deaths being recorded annually. It is likely, however, that the global figure of approximately 59,000 annual human rabies fatalities is an underestimate. The impact of the disease has been reduced substantially across vast regions of the globe since the development of effective rabies vaccines. The success of different vaccines and vaccination policies in the defined 'at risk' populations has been born out of scientific innovation. Mass vaccination campaigns of animals, using parenteral vaccines to immunise companion animals, and advances in oral vaccines for wildlife, have allowed the elimination of rabies in terrestrial carnivores in several regions worldwide, including Western Europe and much of North America. In addition, human vaccines, largely used for post-exposure treatments, have reduced the burden of rabies in endemic areas.
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http://dx.doi.org/10.20506/rst.37.2.2804DOI Listing
August 2018

Rabies pathogenesis and immunology.

Authors:
A C Banyard N Tordo

Rev Sci Tech 2018 Aug;37(2):323-330

Once clinical disease is manifest, the rabies virus is one of the few pathogens known to science with a near 100% fatality rate and, as such, this zoonotic pathogen has shaped both humanity and the history of science. However, today rabies is still considered to be a neglected tropical disease, despite the fact that it causes more than 59,000 human deaths each year. Although effective vaccines are available to combat the disease, the underlying mechanisms of its pathogenicity and immunology remain poorly defined. In this paper, the existing knowledge of the pathogenesis and immunological response to the rabies virus in infected hosts is described.
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http://dx.doi.org/10.20506/rst.37.2.2805DOI Listing
August 2018

Bats and Viruses: Emergence of Novel Lyssaviruses and Association of Bats with Viral Zoonoses in the EU.

Trop Med Infect Dis 2019 Feb 7;4(1). Epub 2019 Feb 7.

Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal and Plant Health Agency (APHA), KT15 3NB Weybridge-London, UK.

Bats in the EU have been associated with several zoonotic viral pathogens of significance to both human and animal health. Virus discovery continues to expand the existing understating of virus classification, and the increased interest in bats globally as reservoirs or carriers of zoonotic agents has fuelled the continued detection and characterisation of new lyssaviruses and other viral zoonoses. Although the transmission of lyssaviruses from bat species to humans or terrestrial species appears rare, interest in these viruses remains, through their ability to cause the invariably fatal encephalitis-rabies. The association of bats with other viral zoonoses is also of great interest. Much of the EU is free of terrestrial rabies, but several bat species harbor lyssaviruses that remain a risk to human and animal health. Whilst the rabies virus is the main cause of rabies globally, novel related viruses continue to be discovered, predominantly in bat populations, that are of interest purely through their classification within the lyssavirus genus alongside the rabies virus. Although the rabies virus is principally transmitted from the bite of infected dogs, these related lyssaviruses are primarily transmitted to humans and terrestrial carnivores by bats. Even though reports of zoonotic viruses from bats within the EU are rare, to protect human and animal health, it is important characterise novel bat viruses for several reasons, namely: (i) to investigate the mechanisms for the maintenance, potential routes of transmission, and resulting clinical signs, if any, in their natural hosts; (ii) to investigate the ability of existing vaccines, where available, to protect against these viruses; (iii) to evaluate the potential for spill over and onward transmission of viral pathogens in novel terrestrial hosts. This review is an update on the current situation regarding zoonotic virus discovery within bats in the EU, and provides details of potential future mechanisms to control the threat from these deadly pathogens.
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http://dx.doi.org/10.3390/tropicalmed4010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473451PMC
February 2019

A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis.

PLoS Negl Trop Dis 2018 10 29;12(10):e0006870. Epub 2018 Oct 29.

Jenner Institute, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.

Background: Estimates of current global rabies mortality range from 26,000 to 59,000 deaths per annum. Although pre-exposure prophylaxis using inactivated rabies virus vaccines (IRVs) is effective, it requires two to three doses and is regarded as being too expensive and impractical for inclusion in routine childhood immunization programmes.

Methodology/ Principal Findings: Here we report the development of a simian-adenovirus-vectored rabies vaccine intended to enable cost-effective population-wide pre-exposure prophylaxis against rabies. ChAdOx2 RabG uses the chimpanzee adenovirus serotype 68 (AdC68) backbone previously shown to achieve pre-exposure protection against rabies in non-human primates. ChAdOx2 differs from AdC68 in that it contains the human adenovirus serotype 5 (AdHu5) E4 orf6/7 region in place of the AdC68 equivalents, enhancing ease of manufacturing in cell lines which provide AdHu5 E1 proteins in trans. We show that immunogenicity of ChAdOx2 RabG in mice is comparable to that of AdC68 RabG and other adenovirus serotypes expressing rabies virus glycoprotein. High titers of rabies virus neutralizing antibody (VNA) are elicited after a single dose. The relationship between levels of VNA activity and rabies virus glycoprotein monomer-binding antibody differs after immunization with adenovirus-vectored vaccines and IRV vaccines, suggesting routes to further enhancement of the efficacy of the adenovirus-vectored candidates. We also demonstrate that ChAdOx2 RabG can be thermostabilised using a low-cost method suitable for clinical bio-manufacture and ambient-temperature distribution in tropical climates. Finally, we show that a dose-sparing effect can be achieved by formulating ChAdOx2 RabG with a simple chemical adjuvant. This approach could lower the cost of ChAdOx2 RabG and other adenovirus-vectored vaccines.

Conclusions/ Significance: ChAdOx2 RabG may prove to be a useful tool to reduce the human rabies death toll. We have secured funding for Good Manufacturing Practice- compliant bio-manufacture and Phase I clinical trial of this candidate.
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http://dx.doi.org/10.1371/journal.pntd.0006870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224154PMC
October 2018

Phase-locked responses to the vowel envelope vary in scalp-recorded amplitude due to across-frequency response interactions.

Eur J Neurosci 2018 11;48(10):3126-3145

National Center for Audiology, Western University, London, Ontario, Canada.

Neural encoding of the envelope of sounds like vowels is essential to access temporal information useful for speech recognition. Subcortical responses to envelope periodicity of vowels can be assessed using scalp-recorded envelope following responses (EFRs); however, the amplitude of EFRs vary by vowel spectra and the causal relationship is not well understood. One cause for spectral dependency could be interactions between responses with different phases, initiated by multiple stimulus frequencies. Phase differences can arise from earlier initiation of processing high frequencies relative to low frequencies in the cochlea. This study investigated the presence of such phase interactions by measuring EFRs to two naturally spoken vowels (/ε/ and /u/), while delaying the envelope phase of the second formant band (F2+) relative to the first formant (F1) band in 45° increments. At 0° F2+ phase delay, EFRs elicited by the vowel /ε/ were lower in amplitude than the EFRs elicited by /u/. Using vector computations, we found that the lower amplitude of /ε/-EFRs was caused by linear superposition of F1- and F2+-contributions with larger F1-F2+ phase differences (166°) compared to /u/ (19°). While the variation in amplitude across F2+ phase delays could be modeled with two dominant EFR sources for both vowels, the degree of variation was dependent on F1 and F2+ EFR characteristics. Together, we demonstrate that (a) broadband sounds like vowels elicit independent responses from different stimulus frequencies that may be out-of-phase and affect scalp-based measurements, and (b) delaying higher frequency formants can maximize EFR amplitudes for some vowels.
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http://dx.doi.org/10.1111/ejn.14161DOI Listing
November 2018

New human rabies vaccines in the pipeline.

Vaccine 2019 10 25;37 Suppl 1:A140-A145. Epub 2018 Aug 25.

Wistar Institute, Philadelphia, PA, USA. Electronic address:

Rabies remains endemic in more than 150 countries. In 99% of human cases, rabies virus is transmitted by dogs. The disease, which is nearly always fatal, is preventable by vaccines given either before and/or after exposure to a rabid animal. Numerous factors including the high cost of vaccines, the relative complexity of post-exposure vaccination protocols requiring multiple doses of vaccine, which in cases of severe exposure have to be combined with a rabies immune globulin, lack of access to health care, and insufficient surveillance contribute to the estimated 59,000 human deaths caused by rabies each year. New, less expensive and more immunogenic rabies vaccines are needed together with improved surveillance and dog rabies control to reduce the death toll of human rabies. Here, we discuss new rabies vaccines that are in clinical and pre-clinical testing and evaluate their potential to replace current vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2018.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863069PMC
October 2019

Anti-protein immunoglobulin M responses to pneumococcus are not associated with aging.

Pneumonia (Nathan) 2018 5;10. Epub 2018 Jun 5.

1Respiratory Infection Group, Liverpool School of Tropical Medicine, Liverpool, UK.

Background: The incidence of community-acquired pneumonia and lower respiratory tract infection rises considerably in later life. Immunoglobulin M (IgM) antibody levels to pneumococcal capsular polysaccharide are known to decrease with age; however, whether levels of IgM antibody to pneumococcal proteins are subject to the same decline has not yet been investigated.

Methods: This study measured serum levels and binding capacity of IgM antibody specific to the pneumococcal surface protein A (PspA) and an unencapsulated pneumococcal strain in serum isolated from hospital patients aged < 60 and ≥ 60, with and without lower respiratory tract infection. A group of young healthy volunteers was used as a comparator to represent adults at very low risk of pneumococcal pneumonia. IgM serum antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry was performed to assess IgM binding capacity. Linear regression and one-way analysis of variance (ANOVA) tests were used to analyse the results.

Results: Levels and binding capacity of IgM antibody to PspA and the unencapsulated pneumococcal strain were unchanged with age.

Conclusions: These findings suggest that protein-based pneumococcal vaccines may provide protective immunity in the elderly.

Trial Registration: The LRTI trial (LRTI and control groups) was approved by the National Health Service Research Ethics Committee in October 2013 (12/NW/0713). Recruitment opened in January 2013 and was completed in July 2013. Healthy volunteer samples were taken from the EHPC dose-ranging and reproducibility trial, approved by the same Research Ethics Committee in October 2011 (11/NW/0592). Recruitment for this study ran from October 2011 until December 2012. LRTI trial: (NCT01861184), EHPC dose-ranging and reproducibility trial: (ISRCTN85403723).
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http://dx.doi.org/10.1186/s41479-018-0048-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987460PMC
June 2018

Isolation, antigenicity and immunogenicity of Lleida bat lyssavirus.

J Gen Virol 2018 12 5;99(12):1590-1599. Epub 2018 May 5.

1​Animal and Plant Health Agency (APHA), Wildlife Zoonoses and Vector Borne Disease Research Group, (WHO Collaborating Centre for the Characterisation of Rabies and Rabies-Related Viruses, OIE Reference Laboratory for Rabies), Weybridge, New Haw, Surrey, KT15 3NB, UK.

The lyssaviruses are an important group of viruses that cause a fatal encephalitis termed rabies. The prototypic lyssavirus, rabies virus, is predicted to cause more than 60 000 human fatalities annually. The burden of disease for the other lyssaviruses is undefined. The original reports for the recently described highly divergent Lleida bat lyssavirus were based on the detection of virus sequence alone. The successful isolation of live Lleida bat lyssavirus from the carcass of the original bat and in vitro characterization of this novel lyssavirus are described here. In addition, the ability of a human rabies vaccine to confer protective immunity following challenge with this divergent lyssavirus was assessed. Two different doses of Lleida bat lyssavirus were used to challenge vaccinated or naïve mice: a high dose of 100 focus-forming units (f.f.u.) 30 µl and a 100-fold dilution of this dose, 1 f.f.u. 30 µl. Although all naïve control mice succumbed to the 100 f.f.u. 30 µl challenge, 42 % (n=5/12) of those infected intracerebrally with 1 f.f.u. 30 µl survived the challenge. In the high-challenge-dose group, 42 % of the vaccinated mice survived the challenge (n=5/12), whilst at the lower challenge dose, 33 % (n=4/12) survived to the end of the experiment. Interestingly, a high proportion of mice demonstrated a measurable virus-neutralizing antibody response, demonstrating that neutralizing antibody titres do not necessarily correlate with the outcome of infection via the intracerebral route. Assessing the ability of existing rabies vaccines to protect against novel divergent lyssaviruses is important for the development of future public health strategies.
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http://dx.doi.org/10.1099/jgv.0.001068DOI Listing
December 2018

Taxonomy of the order Mononegavirales: update 2018.

Arch Virol 2018 Aug 11;163(8):2283-2294. Epub 2018 Apr 11.

Integrated Research Facility at Fort Detrick (IRF-Frederick), Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), B-8200 Research Plaza, Fort Detrick, Frederick, MD, 21702, USA.

In 2018, the order Mononegavirales was expanded by inclusion of 1 new genus and 12 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV) and summarizes additional taxonomic proposals that may affect the order in the near future.
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http://dx.doi.org/10.1007/s00705-018-3814-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076851PMC
August 2018

Utilisation of Chimeric Lyssaviruses to Assess Vaccine Protection against Highly Divergent Lyssaviruses.

Viruses 2018 03 15;10(3). Epub 2018 Mar 15.

Wildlife Zoonoses and Vector Bourne Disease Research Group, Animal and Plant Health Agency, Woodham Lane, Weybridge, Surrey KT15 3NB, UK.

Lyssaviruses constitute a diverse range of viruses with the ability to cause fatal encephalitis known as rabies. Existing human rabies vaccines and post exposure prophylaxes (PEP) are based on inactivated preparations of, and neutralising antibody preparations directed against, classical rabies viruses, respectively. Whilst these prophylaxes are highly efficient at neutralising and preventing a productive infection with rabies virus, their ability to neutralise other lyssaviruses is thought to be limited. The remaining 15 virus species within the lyssavirus genus have been divided into at least three phylogroups that generally predict vaccine protection. Existing rabies vaccines afford protection against phylogroup I viruses but offer little to no protection against phylogroup II and III viruses. As such, work involving sharps with phylogroup II and III must be considered of high risk as no PEP is thought to have any effect on the prevention of a productive infection with these lyssaviruses. Whilst rabies virus itself has been characterised in a number of different animal models, data on the remaining lyssaviruses are scarce. As the lyssavirus glycoprotein is considered to be the sole target of neutralising antibodies we generated a vaccine strain of rabies using reverse genetics expressing highly divergent glycoproteins of West Caucasian Bat lyssavirus and Ikoma lyssavirus. Using these recombinants, we propose that recombinant vaccine strain derived lyssaviruses containing heterologous glycoproteins may be a suitable surrogate for wildtype viruses when assessing vaccine protection for the lyssaviruses.
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http://dx.doi.org/10.3390/v10030130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869523PMC
March 2018

In vitro and in vivo evaluation of a single chain antibody fragment generated in planta with potent rabies neutralisation activity.

Vaccine 2019 08 6;37(33):4673-4680. Epub 2018 Mar 6.

Institute for Infection and Immunity, St. George's Hospital Medical School, University of London, London, UK. Electronic address:

Rabies causes more than 60,000 human deaths annually in areas where the virus is endemic. Importantly, rabies is one of the few pathogens for which there is no treatment following the onset of clinical disease with the outcome of infection being death in almost 100% of cases. Whilst vaccination, and the combination of vaccine and rabies immunoglobulin treatment for post-exposure administration are available, no tools have been identified that can reduce or prevent rabies virus replication once clinical disease has initiated. The search for effective antiviral molecules to treat those that have already developed clinical disease associated with rabies virus infection is considered one of the most important goals in rabies research. The current study assesses a single chain antibody molecule (ScFv) based on a monoclonal antibody that potently neutralises rabies in vitro as a potential therapeutic candidate. The recombinant ScFv was generated in Nicotiana benthamiana by transient expression, and was chemically conjugated (ScFv/RVG) to a 29 amino acid peptide, specific for nicotinic acetylcholine receptor (nAchR) binding in the CNS. This conjugated molecule was able to bind nAchR in vitro and enter neuronal cells more efficiently than ScFv. The ability of the ScFv/RVG to neutralise virus in vivo was assessed using a staggered administration where the molecule was inoculated either four hours before, two days after or four days after infection. The ScFv/RVG conjugate was evaluated in direct comparison with HRIG and a potential antiviral molecule, Favipiravir (also known as T-705) to indicate whether there was greater bioavailability of the ScFv in the brains of treated mice. The study indicated that the approach taken with the ScFv/RVG conjugate may have utility in the design and implementation of novel tools targetting rabies virus infection in the brain.
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http://dx.doi.org/10.1016/j.vaccine.2018.02.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677913PMC
August 2019

Pathogenesis of bat rabies in a natural reservoir: Comparative susceptibility of the straw-colored fruit bat (Eidolon helvum) to three strains of Lagos bat virus.

PLoS Negl Trop Dis 2018 03 5;12(3):e0006311. Epub 2018 Mar 5.

Institute of Zoology, Zoological Society of London, London, United Kingdom.

Rabies is a fatal neurologic disease caused by lyssavirus infection. People are infected through contact with infected animals. The relative increase of human rabies acquired from bats calls for a better understanding of lyssavirus infections in their natural hosts. So far, there is no experimental model that mimics natural lyssavirus infection in the reservoir bat species. Lagos bat virus is a lyssavirus that is endemic in straw-colored fruit bats (Eidolon helvum) in Africa. Here we compared the susceptibility of these bats to three strains of Lagos bat virus (from Senegal, Nigeria, and Ghana) by intracranial inoculation. To allow comparison between strains, we ensured the same titer of virus was inoculated in the same location of the brain of each bat. All bats (n = 3 per strain) were infected, and developed neurological signs, and fatal meningoencephalitis with lyssavirus antigen expression in neurons. There were three main differences among the groups. First, time to death was substantially shorter in the Senegal and Ghana groups (4 to 6 days) than in the Nigeria group (8 days). Second, each virus strain produced a distinct clinical syndrome. Third, the spread of virus to peripheral tissues, tested by hemi-nested reverse transcriptase PCR, was frequent (3 of 3 bats) and widespread (8 to 10 tissues positive of 11 tissues examined) in the Ghana group, was frequent and less widespread in the Senegal group (3/3 bats, 3 to 6 tissues positive), and was rare and restricted in the Nigeria group (1/3 bats, 2 tissues positive). Centrifugal spread of virus from brain to tissue of excretion in the oral cavity is required to enable lyssavirus transmission. Therefore, the Senegal and Ghana strains seem most suitable for further pathogenesis, and for transmission, studies in the straw-colored fruit bat.
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http://dx.doi.org/10.1371/journal.pntd.0006311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854431PMC
March 2018

Antigenic site changes in the rabies virus glycoprotein dictates functionality and neutralizing capability against divergent lyssaviruses.

J Gen Virol 2018 02 4;99(2):169-180. Epub 2018 Jan 4.

Wildlife Zoonoses and Vector Bourne Disease Research Group, Animal and Plant Health Agency, Woodham Lane, Weybridge, Surrey, KT15 3NB, UK.

Lyssavirus infection has a near 100 % case fatality rate following the onset of clinical disease, and current rabies vaccines confer protection against all reported phylogroup I lyssaviruses. However, there is little or no protection against more divergent lyssaviruses and so investigation into epitopes within the glycoprotein (G) that dictate a neutralizing response against divergent lyssaviruses is warranted. Importantly, the facilities required to work with these pathogens, including wild-type and mutated forms of different lyssaviruses, are scarcely available and, as such, this type of study is inherently difficult to perform. The relevance of proposed immunogenic antigenic sites within the lyssavirus glycoprotein was assessed by swapping sites between phylogroup-I and -II glycoproteins. Demonstrable intra- but limited inter-phylogroup cross-neutralization was observed. Pseudotype viruses (PTVs) presenting a phylogroup-I glycoprotein containing phylogroup-II antigenic sites (I, II III or IV) were neutralized by antibodies raised against phylogroup-II PTV with the site II (IIb, aa 34-42 and IIa, aa 198-200)-swapped PTVs being efficiently neutralized, whilst site IV-swapped PTV was poorly neutralized. Specific antibodies raised against PTV-containing antigenic site swaps between phylogroup-I and -II glycoproteins neutralized phylogroup-I PTVs efficiently, indicating an immunodominance of antigenic site II. Live lyssaviruses containing antigenic site-swapped glycoproteins were generated and indicated that specific residues within the lyssavirus glycoprotein dictate functionality and enable differential neutralizing antibody responses to lyssaviruses.
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http://dx.doi.org/10.1099/jgv.0.000998DOI Listing
February 2018