Crimean – Congo Haemorrhagic Fever Virus – an Arbovirus of International Concern?
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World Health Organization Collaborating Centre for Virus Research & Reference (Arboviruses & VHFs) Porton Down 1978 Crimean – Congo Haemorrhagic fever virus – an arbovirus of international concern? Prof. Roger Hewson Virology & Pathogenesis Group Lead Head: WHO Collaborating Centre for Virus Reference and Research (Arboviruses & VHFs) Dangerous Infections: New Public Health England - Microbiology Services Solution – A Look into the Future Porton Down, Oct 2-3 2019 Salisbury, UK Summary o Background • Taxonomy • Bunyavirales / Nairovirus / Orthonairovirus • CCHF disease / Transmission / Outbreaks • Historical perspective o Laboratory containment o Virus biology / Evolutionary potential o Human activity (increased zoonotic events) o Diagnostics o Vaccines o Conclusions Order Bunyavirales • Single stranded –ve sense RNA • Lipid enveloped • Segmented genome [Small, (Medium) Large] • Arthropod borne (x Hanta x Arena) • Human disease (some) • 10 Families Arenaviridae (3), Cruliviridae (1), Fimoviridae (1) Hantaviridae (3) Mypoviridae (1) Nairoviridae (3) Peribunaviridae (4) Phasmaviridae (5) Phenuiviridae (12), Wupedeviridae (1) Genus Mammarenavirus Orthohantavirus Orthobunyavirus Orthonairovirus Phlebovirus Banyangvirus Species 34 35 49 14 9 1 Host / Res Rodents Rodents Rodents Rodent / rum / tick Ruminant Rum / tick Vector Rodents Rodents Mosquito Ticks Mosquito Ticks Disease e.g. Lassa / Junin HFRS / HPS Oropuche fever CCHF RVFV SFTS 3 Bunyavirales – medically (& veterinary, agriculturally) important order Family Nairovirus Genus Orthonairovirus Dugbe virus orthonairovirus Qalyub orthonairovirus Kupe virus •Bandia virus •Qalyub virus Nairobi sheep disease orthonairovirus •Nairobi sheep disease virus Dera Ghazi Khan orthonairovirus •Ganjam virus •Dera Ghazi Khan •Abu Hammad virus Sakhalin orthonairovius •Clo Mor virus Hughs orthonairovirus •Sakhalin virus •Hughes virus Thiafora orthonairovirus •Puffin Island virus •Erve virus Hard ticks •Solado •Thiafora virus •Keterah orthonairovirus •Burana orthonairovirus •Issyk-Kul virus •Kasokero orthonairovirus •Burana virus •Tamdy virus Hazara orthonairovirus Soft ticks Crimean-Congo haemorrhagic fever orthonairovirus 4 Orthonairovirus: Tick borne members some of which are medically / veterinary important Crimean - Congo Haemorrhagic Fever • Severe human infection. • Fatality rate 30% (>80% nosocomial infections). • No FDA or European approved vaccine or treatment. • ACDP - Hazard Group 4 pathogen. • Reservoired in ticks & wild life mammals, amplified in cattle sheep, goat, camel [No disease in animals] • Transmission by tick bite or direct / indirect contact with infected blood/body fluids. 5 CCHF Preclinical – A Tick development borne VHF [ofPics the - PHESalih CCHFAhmeti vaccine Kosovo & Farida PHE Tishkova, pipeline Tajikistan] fund PLF 1516/108/MR CCHF - Clinical Disease • Incubation period 2-9 days • Haemorrhagic state develops 3 - 5 days • Petechial rash / ecchymoses in the skin • Bleeding from the mucous membranes Epitaxsis, Haematuria, Haemoptysis • Loss of blood pressure - shock • Death 7-9 days [massive bleeding / cardiac arrest] 6 [Pics - Salih Ahmeti Kosovo & Farida Tishkova, Tajikistan CCHF - Clinical Disease 7 [Pics - Salih Ahmeti Kosovo & Farida Tishkova, Tajikistan ….also subclinical infections Bordur et al 2012 >80% Tky] Transmission cycle & annual distribution of cases Drop off & Molt Nymph Ungulates / livestock Adults Small mammals Larva (& birds) Ovipositation & Hatching Tick activity Humans Nosocomial transmission Inc. H2H 8 Transmission cycle modified from Bente et al., 2013 Annual cases – permission from Turkish MoH Human – Human transmission of CCHFV 9 Chronology of events during a CCHFV outbreak 10 CCHF – Historical Perspective (i) 1st Descriptions of Central Asian Haemorrhagic fever • 1136 Tajikistan / (Zayn al-Din Sayyed) • 11th century A.D. Abu Ali Al-Husayn ibn Abd Allah ibn Sina 11 Historical perspective 1 CCHF – Historical Perspective (ii) 1st Descriptions of Crimean Haemorrhagic fever • 1941 Crimea modern medical description • 1944 Viral origin - passage through human volunteers M.P Chumakov et al., Isolation / registration - Yale 1968 (Crimean HF) 12 Historical perspective 2 CCHF – Historical Perspective (iii) 1st Descriptions of Congo fever Kisangani Entebbe Kinshasa • Stanleyville March 1956: 13 year old presented with fever / bruising • Isolated / adapted to mice / maintained by passage - Unidentified • Sent to EAVRI / Entebbe 1957 13 Historical perspective 3 East Africa Virus Research Institute (EAVRI) Dir: Sandy Haddow: John Woodall, David Simpson: New virus (1956) Woodall et al., 1962 Simpson et al., 1967 Registered - Arbovirus catalogue Yale 1961 - Congo Virus MP Chumakov: 1968 Isolation of Crimean HF virus Registration at Yale 1969 - Identical to Congo 1973 – CCHF virus 14 CCHF – a political name coined in the cold war David Simpson: Director Virology Porton Down // 1960 - 82 • Name synonymous with CCHF virus • WHO & future VHF outbreaks (inc. EVD) Global distribution of CCHF • Amassed wide range of different strains • Part of Special Pathogens Reference collection - WHO CC 15 DI Simposin @ Porton Down VHFs - High consequence pathogens Hazard Group 4 viruses • Virus Country Date Natural Mortality Highly infectious first host rate recognised (humans) • H2H transmission Arenaviridae Lassa Nigeria 1969 Rodent 15% Old & New world Lujo Zambia 2008 Rodent 80% • Hazard to employees arenaviruses Guanarito Venezuela 1989 Rodent 30% Junin Argentina 1957 Rodent 25% • Spread within community Machupo Bolivia 1962 Rodent 30% Sabia Brazil 1990 Rodent 40% • No effective intervention Chapare Bolivia 2003 Rodent 30% Nairoviridae Crimean – Congo Congo 1968 Ticks 30-80% European directive 2000/54/EC http_eur-lex.europa.pdf Haemorrhagic fever Hazard / Risk Group 4 Filoviridae Eboa Zaire Congo 1976 Bats 90% Ebola Ebola Sudan Sudan 1976 Bats 50% • Endemic in many regions of the world Taï Forest Ivory coast 1994 Bats 40% Ebola Reston USA 1989 Bats Sub-clinical Bundibugyo Uganda 2007 Bats 35% • Risk of acquisition to EU: Marburg Marburg Germany 1967 Bats 50% Imported in patients (Travel related) Herpesviridae Herpes B virus Worldwide 1932 Macaques 80% Imported animal products Paramyxoviridae Nipah Malaysia 1999 Bats 40% Laboratory infections Hendra Australia 1994 Bats 60% Falviviridae Russian Spring Russia 1937 Ticks 30% Climate change (vector / reservoir distributions) Summer Encephalitis Other anthropogenic factors Kyasanur Forest India 1957 Ticks 10% Omsk Russia 1990 Rats 20% Viral emergence Orthopoxviradae Variola Eradicated Humans 30% 16 Biosafety classification / sources of introduction into the EU High Containment CL3 & CL4 labs CL4 (in-vitro) CL3 (in-vitro) CL4 (in-vivo) CL4 (in-vivo) 17 High containment facilities at PHE CCHF - Geographic Distribution 50° North limit for the geographic distribution of genus Hyalomma ticks • Spain [2016] • Mongolia [2012] Country with low risk (presence of vector) • India [2011] Country at risk (serological evidence + vector) • Greece [2008] 5 to 15 cases per year • Turkey [2002] 20 to 49 cases per year 50 to 200 cases per year 18 Global distribution of CCHF Crimean - Congo Haemorrhagic Fever virus X20,000 19 CCHFV Morphogenesis Maturation and budding into the Golgi HPA Golgi membranes fuse with plasma membrane releasing HPA particles 20 Budding into the Golig and release from the plasma membrane S Segments ML SegmentsSegments Hazara Hazara Hazara AP92 Greece Europe 2 VLG- TI29414 Europe 1 30908 S Russia Asia 2 DAK 8194 Senegal Kosovo/9553/2001 M4 Africa 1 Europe 1 Semunya Uganda SR3 Africa 2 K229Europe-243 S. Russia 2 Drosdov Russia SPU41-84 Europe 1 HU29223 Russia IbAr10200 Baghdad Iraq 66019 China XinJiang AfricaSPU128 1 -84 Asia 1 88166 China XinJiang U2-2-002--U-6415 Matin Pakistan 8402 China XinJiang Asia 1 Baghdad M2 HY13 China XinJiang 75024 Semunya Uganda Africa 2 75024 China XinJiang 7803 7803 China XinJiang Asia 2 Hodzha Africa 2 C68031 China Hodzha Uzbekistan Tadj-HU8966 TADJ/HU8966 Asia 2 66019 Tajiki 2010 TADJ/HU8966Africa 3 Hodzha Uzbekistan Matin Evidence of 79121 China XinJiang IbAr10200 NigeriaHY13 segment 7001 China XinJiang M1 8402 7 CCHF S genotypes Baghdad-12 Iraq reassortment Tajiki 2010 SPU128/81/7 S. Africa Matin Pakistan Asia 1 SEMUNYA Africa 3 JD206 Pakistan IbAn10248 CONGONigeria SR3 Pakistan M5 UG3010 SPU4/81 S. Africa Africa 3 SPU4/8179121 S. Africa IbAr10200 Nigeria 0.1 0.10.1 7001 M3 21 Phylogeny of CCHF viruses CCHF Segment reassortment between strains L L L S S S L S L L M S S + M M • Co-replication of two strains in the same cell / organism L • Ticks are suitable hosts to support reassortment S L M S Global & dynamic reservoir of CCHF virus 22 Reassortment in CCHF viruses could lead to new viruses and new disease… Budding reassortant L Exchange of M segments S viruses S L M influence host range L S S L M Envelope glycoproteins L S M influence M cellular tropism L S N altered pathogenicity 23 Diagnostics should be based on strains isolated globally Alternative pathology observed in some forms of CCHF…. e.g.Tajikistan “..alternative clinical presentation” visceral tropic form of CCHF Prof F Tishkova Tajik Ministry of Health Institute of Preventive Medicine Dushanbe 24 Autochthonous CCHF in Spain Positive Hyalomma ticks identified in: 2011, 2013, 2014, 2015 Ávila 2016 Livestock districts Positive municipality Negative +ve in previous years • 1st case • Tick bite / hiking in Ávila • 2nd case • Hospital transmission / Madrid • Genotype Africa 3 25 Two human cases (2016) - Ávila 2ndry hospital