Monkepox Rapid Research Response

Lead Research Organisation: University of Surrey
Department Name: Microbial & Cellular Sciences

Abstract

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Technical Summary

The 200 kb MPXV genome is a challenging sequencing target due to repeated sequences near each genomic terminus and low GC (33%) content. A fast, reliable and low-cost method will be developed that can accurately reconstruct the genome for evolutionary analysis, genomic epidemiology and functional character-isation.
A panel of cell lines from a range of rodent and livestock species available at Pirbright will be used to examine the host range of MPXV. Virus growth in cell culture will be measured using classical methods and live-cell analysis systems.
We will determine MPXV evolution of tropism and hIFN-I antagonism, to predict virus human-to-human transmission.
We will evaluate the long-term immunity induced by MPXV infection in humans and define differences between vaccine-induced responses: immunodominance pattern, functional immunophenotype and if T cell responses to MPXV viral immediate early proteins exhibit better viral control than other specificities. Also, associations with antibody responses and clinical outcome will be evaluated.
We will establish and optimise antiviral screening pipelines to assess the antiviral efficacy of tecovirimat and brincidofovir, drugs with known activity against orthopoxviruses. We assess 26 FDA-approved drugs and a novel cyclosporine A derivative that inhibit VACV in vitro. Also, current MPXV isolates will be tested in cell culture for the rapid testing of circulating strains of MPXV for tecovirimat-resistance.
We will develop two rapid point of care diagnostic tests. Lateral flow Assay (LFA). An orthopoxvirus (OPV) LFA has been developed at Dstl, comprising 4 Mabs all reactive with old world OPVs. Making use of novel bead types we will provide data packs to enable rapid progress through regulatory pathways for licensure.
Loop-mediated isothermal amplification (LAMP)-based assay. LAMP is a rapidly maturing technology providing PCR levels of sensitivity and specificity without the need for thermal cycling.

Publications

10 25 50
 
Description Monkeypox virus (MPXV) is a rodent zoonotic orthopoxvirus (OPXV) that has recently emerged globally with unprecedented human-to-human transmission. Global MPXV (lineage B) is phylogenetically linked to West African endemic viruses with much lower transmissibility (lineage A). This suggests that despite its rodent origin, lineage B has adapted to infect, and transmit amongst, humans. We hypothesised that MPXV lineage B has evolved to defeat human host defences more effectively than lineage A, hence explaining its capacity to spread globally. Using a comparative virology approach, we have shown that both endemic and global MPXV effectively suppressed human antiviral innate immunity, with a major role for a viral protein termed poxin. Despite this evasion, human cells recognised MPXV infection and mounted an inflammatory response. Surprisingly, lineage B was less effective in bloking human defences, possibly explaining why this lineage is reportedly less aggressive than lineage A. Finally we have identified a compound termed diABZI with exteremely potent activity against MPXV, particularly in macrophages.
Exploitation Route The findings reveal differences between MPXV lineages, demonstrating this virus is evolving and may result in new variants if not eradicated. The findings pose questions on how virus attenuation and host inflammation affect transmissibility of poxviruses, hence providing understanding on virus pandemic potential and preparedness. The findigs also open the possibility of a new host-directed thereputic approach based on ABZI drugs and derivatives. We are in the process of understanding how MPXV is recognised by our cells to activate an inflammatory resonse and whether this response effectively curtails virus activities and replication. We are also exploring MPXV evolution and drug development in collaboration with others
Sectors Healthcare

 
Description Monkeypox virus evolution 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution This collaboration has given us access to different virus species to do comparative virology and evolutionary studies.
Collaborator Contribution Contributed viral species and intellectual input to yield new insights onto the evolution of currently circulating monkeypox virus and other poxvirus species.
Impact This is a multidisciplinary collaboration that involves virologists, bioinformatics and computational biology. Outcomes: publication Ndodo et al. (2023) Nature Medicine.
Start Year 2023
 
Description Monkeypox virus evolution 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution This collaboration has given us access to different virus species to do comparative virology and evolutionary studies.
Collaborator Contribution Contributed viral species and intellectual input to yield new insights onto the evolution of currently circulating monkeypox virus and other poxvirus species.
Impact This is a multidisciplinary collaboration that involves virologists, bioinformatics and computational biology. Outcomes: publication Ndodo et al. (2023) Nature Medicine.
Start Year 2023
 
Description Catalan Society for Virology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Delivered Opening lecture at the Annual Catalan Society for Virology meeting as world-leading expert on monkeypox virus.
Year(s) Of Engagement Activity 2023
 
Description Daily Mail July 2022 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Quoted as poxvirologist expert by newspaper Daily Mail on the evolution of the global monkeypox outbreak declared in May 2022.
Year(s) Of Engagement Activity 2022
 
Description El Pais July 2022 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Quoted as poxvirologist expert by Spanish newspaper El Pais on the global monkeypox outbreak declared in May 2022.
Year(s) Of Engagement Activity 2022
URL https://elpais.com/sociedad/2022-07-12/europa-amplia-la-vacunacion-contra-la-viruela-del-mono-a-las-...
 
Description El Pais September 2022 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Quoted as poxvirologist expert by Spanish newspaper El Pais on the evolution of the global monkeypox outbreak declared in May 2022.
Year(s) Of Engagement Activity 2022
URL https://elpais.com/sociedad/2022-10-01/los-contagios-de-la-viruela-del-mono-en-el-mundo-caen-a-la-mi...
 
Description El Pais September 2023 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interviewed by largest Spanish newspaper El Pais on evolution and eradication of Mpox in Europe.
Year(s) Of Engagement Activity 2023
URL https://elpais.com/sociedad/2023-11-16/asi-renuncio-europa-a-eliminar-la-viruela-del-mono-sera-una-e...
 
Description Lancaster University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact About 50 individuals from the Institute attended an invited talk on virus immunity and vaccines that was well received.
Year(s) Of Engagement Activity 2023
 
Description My University newspaper July 2022 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Wrote an educational piece on monkeypox virus for the University community.
Year(s) Of Engagement Activity 2022
 
Description Reuters July 2022 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Quoted as poxvirologist expert by main news agency Reuters on the evolution of the global monkeypox outbreak declared in May 2022.
Year(s) Of Engagement Activity 2022
URL https://www.reuters.com/business/healthcare-pharmaceuticals/eu-drugs-regulator-beefs-up-monkeypox-re...
 
Description Roslin invited seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact About 100 individuals from the Institute attended an invited talk on virus immunity and vaccines that was well received.
Year(s) Of Engagement Activity 2023
 
Description The Guardian August 2022 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Quoted as poxvirologist expert by newspaper The Guardian on the evolution of the global monkeypox outbreak declared in May 2022.
Year(s) Of Engagement Activity 2022
URL https://www.theguardian.com/world/2022/aug/15/smallpox-vaccines-protect-monkeypox-hiv-erode