Virus threats worldwide Albert Osterhaus - 1996-2003, WHO outbreak reports - Bornem 24-03-05 Emerging viruses “in a changing world” West Nile Yellow fever Dengue Avian influenza Lassa Meningitis Japanese encephalitis Ebola/Marburg Rift valley Polio Nipah SARS Venez. Eq. encephalitisCrimean-Congo HF VHFMonkeypox Hanta Enterovirus Emerging virus infections in the last decennia Emerging virus infections in the last decennia - Part 1 - - Part 2 - Facilitated by changes in: Facilitated by changes in: Social environment Ecology: - Behaviour (taboos, mores, i.v. drug abuse) - Animal contacts (wildlife, zoo, pets…) - Mobility (air travel, wars …) - Agriculture (deforestation…) - Demography (population density, urbanisation…) - Fisheries (predator migration…) - Socio-ecomic status (poverty, wealth) - Environmental pollution (immune suppression…) - Public health measures (breakdown…) - Global warming (flora and fauna…) Technology Virus: - Medical (transfusion, transplantation, vaccination) - Mutation (host range, virulence…) - Food production (recycling…) - Recombination/reassortment Bioterrorism? Emerging virus infections in the last decennia Lentiviruses - Part 2 - - Host range - Facilitated by changes in: Ecology: - Animal contacts (wildlife, zoo, pets…) - Agriculture (deforestation…) - Fisheries (predator migration…) - Environmental pollution (immune suppression…) - Global warming (flora and fauna…) Virus: - Mutation (host range, virulence…) - Recombination/reassortment Bioterrorism? Nature is the main bioterrorist!!! 1 Vectors for transmission of virus infections Aedes spec. Sandfly spec. Ixodus spec. - Yellow fever virus - Phlebovirus - Tick-borne - Dengue virus encephalitis - Omsk hemorrhagic fever virus Arbo-virus infections DHF in the Americas - Vector distribution - - 1970-1999 - 60 Distribution of Aedes aegypti Dengue hemorrhagic fever 50 1970 1997 <‘81 ‘81-’97 Aedes Aegypti 40 30 20 (Thousands) Reported Cases 10 0 1970s 1980s 1990s* West Nile Virus West Nile Virus - Hosts - - USA 1999-2002 - 2 West Nile Virus West Nile Virus - Symptoms - - Cases - Fatal: <0.1% of infections 1 CNS disease <1% CNS Year # Cases # States # Counties Onset Date Range = disease ~150 infections 1999 62 1 6 2 AUG – 24 SEP ~20% “West Nile Fever” 2000 21 3 10 20 JUL – 27 SEP 2001 66 10 39 13 JUL – 7 DEC ~80% 2002 4,156* 39 708 19 MAY – 14 DEC Asymptomatic * 284 deaths Virus infections Animals and animal products - Host range differences - ? blood ? Storage ? MBM Incinerate Food ? Burial Human (other species) Fat Cow Destructor Cosmetics Food ? Drugs Farm Gelatin ? Calf Milk Sewage Water MEAT Abattoir Meatproducts SRM Influenza pandemics of the 20th century Influenza A viruses Subtype divisions of influenza A viruses Virus Subtype Name Est. # deaths made on basis of HA (1-16) and NA (1-9) antigens 1918 H1N1 “Spanish Flu” > 40 million Genomic nucleic acid consists of 8 RNA segments, allowing gene reassortment during mixed infection 1957 H2N2 “Asian Flu” > 1 million Virulence of influenza virus depends on presence of presence of series of basic 1968 H3N2 “Hong Kong Flu” > 1 million amino acids adjacent to cleavage site of HA polypeptide 3 Influenza A virus Bird markets - Antigenic drift and antigenic shift - -Asia - Antigenic drift Antigenic shift Influenza A virus Influenza A virus - Man as a “mixing vessel” - - Surveillance in wild birds - Reassortant virus Human virus Avian virus Avian virus De Jong et al., Nature 1997 Claas & Osterhaus, Nature Medicine 1998 Influenza A virus surveillance Influenza A virus surveillance - Results 1999 & 2000 - - HA and NA subtypes - Order Family # Species # Samples HA Species NA Species Procellariiformes Procellariidae Fulmar 1 101 Anseriformes Anatidae Goose 6 1387 1 Mallard, Teal 1 Mallard, Teal Duck 12 2232 2 Mallard, White-fronted Goose 2 Mallard, Wigeon, Greylag Goose, Swan 2 73 3 Mallard, Teal White-fronted Goose, Guillemot Falconiformes Accipitridae Hawk, Eagle, Buzzard 3 26 4 Mallard 3 Black-headed Gull Gruiformes Rallidae Rail, Coot 4 281 Charadriiformes Charadriidae Plover, Lapwing 5 166 5 Mallard 4 Mallard, Wigeon Scolopacidae Sandpiper, Dunlin, Snipe 23 1977 6 Mallard, Wigeon, Greylag Goose, 5 Mallard Laridae Gull 5 886 White-fronted Goose, Guillemot 6 Mallard, Black-headed Gull Alcidae Auk 2 28 7 Mallard 7 Shoveler Burhinidae Oystercatcher 1 31 8 --- 8 Mallard, Teal, White-fronted Goose Passeriformes Alaudidae Lark 1 61 Prunellidae Accentor 2 67 9 --- 9 --- Muscicapidae Thrush, Warbler, etc. 26 740 10 Mallard Paridae Tit 4 99 11 Mallard, Teal, Shoveler Sturnidae Starling 1 52 12 --- Fringillidae Finch 5 99 13 Black-headed Gull Motacillidae Wagtail, Pipit 3 40 Others Others Others 17 35 14 --- Poultry 406 15 --- 123 ++8787 XX Black-headed Gull 4 Highly pathogenic avian influenza (HPAI) seriously suspected clinically: February 28th 2003 H7N7 in The Netherlands H7N7 in The Netherlands - Phylogeny of the HA gene - - Phylogeny of the NA gene - NL 2003 NL 2003 Chick/Germany/49 Mallard/NL/2/00 Mallard/NL/12/00 FPV/Weybridge duck/Manitoba/53 Teal/TW/98 Italy ‘99-’00 Swine/England/97 Equine/Praque/1/56 0.01 0.1 Equine ‘74 H7N7 in The Netherlands H7N7 in The Netherlands - Human cases - - Fatal case chest X-ray upon admission - 10 # cases 78 conjunctivitis 5 conjunctivitis + ILI 2 ILI (1 fatal) 5 4 no symptoms 86 primary cases 3 secondary cases 0 Mar 15 Mar 22 Mar 29 Apr 5 Apr 12 Mar 1 Mar 8 Apr 19 Date of onset of disease 5 H7N7 in The Netherlands Influenza A virus - Sequence analysis of full-length genomes - - Recent zoonoses - Virus # substitutions in Gene A/Netherlands/33/03 A/Netherlands/219/03 Subtype Country Year # Cases # Dead Segment Nucleotide Amino acid Nucleotide Amino acid 1 (PB2) 2 0 8 5 (S79I,V297I,R355K,Q563R,E627K) H7N7 UK 1996 1 0 2 (PB1) 0 0 2 0 H5N1 Hong Kong 1997 18 6 3 (PA) 0 0 5 1(F666L) H9N2 SE Asia 1999 >2 0 4 (HA) 0 0 4 3(I13S,A143T,K416R) H5N1 Hong Kong 2003 2? 1? 5 (NP) 0 0 1 0 H7N7 Netherlands 2003 89 1 6 (NA) 0 0 5 4(N308S, A346V, T442A, P458S) H7N2 USA 2003 1 0 7 (MA) 0 0 0 0 H7N3 Canada 2004 2 0 8 (NS) 1 1 (K126R)2 1 1(V137I)2 H5N1 SE Asia 2004 34 23 1. Sequences were compared to those of A/Chicken/Netherlands/1/03 2. Both mutations in NS1 Fouchier et al., PNAS 2004 Influenza A virus (H5N1) pathogenic for cats (Kuiken et al. 2004, Science) Avian influenza A (H5N1) virus fatal for tigers and leopards: J. Keawcharoen et al,submitted, 2004 Morbilliviruses Morbilliviruses - Seals - - Seals - Another phocid distemper outbreak in Europe 1988: Outbreak of seal disease in Northern Europe Jensen et al., Osterhaus, ADME, Nature 334: 301-302 (1988) Science 297:209, 2002 Osterhaus, ADME, Vedder, EJ, Nature 335: 20 (1988) Osterhaus, ADME et al, Nature 335: 403 (1988) Osterhaus, ADME et al, Nature 337: 21 (1989) 6 Order Mononegavirales, family Paramyxoviridae Newly discovered paramyxovirus - Electron microscopy - DNA Maximum likelihood, Polymerase ORF Morbillivirus PDVRPV TuV CDV Henipahvirus MV hPIV3 HeV bPIV3 Respirovirus - Pleiomorph Paramyxovirinae NiV SeV hPIV1 - Average size: 100-600 nm Pneumovirinae - Envelope projections: 13-17 nm hRSV NDV Avulavirus Pneumovirus - Paramyxovirus bRSV LPMV MuV Rubulavirus Metapneumovirus APV hPIV2 SV5 SV41 v.d. Hoogen et al., Nature Med. 2001 0.1 hMPV Human metapneumovirus Severe acute respiratory syndrome (SARS) - Risk groups - - A world-wide threat - - (Young) children ~ 10 % of children with RTI - Immunocompromised individuals (fatal cases!) -Elderly - Normal individuals > 2-3 % of RTI in community surveillance studies Osterhaus and Fouchier, The Lancet 2003 v.d. Hoogen et al., JID 2003 Novel coronavirus hMPV in SARS patients identified in SARS patients Hong Kong researchers announce fingings of Paramyxoviruses in SARS patients. Similar findings communicated from Canada through SARS etiology network 7 SARS coronavirus phylogeny HCoV-NL: a fourth coronavirus of humans (Rota et al., Science 2003) - phylogeny - Fouchier et al., PNAS 2004 Spike Full genome Replicase 1ab Matrix Nucelocapsid TM glycoprotein E TM glycoprotein SARS and the Koch’s postulates Cynomolgus monkeys (Macaca fascicularis) Two viruses have been isolated from SARS patients: SCV and hMPV Simultaneous SCV-hMPV Koch’s postulates modified for viruses by Rivers (1937): infection experiments: 1. Isolation from diseased hosts 2. Cultivation in host cells •SCV alone 3. Proof of filterability 4. Production of comparable disease in host or related species •hMPV alone 5. Reisolation of the virus •SCV followed by hMPV 6. Detection of specific immune response Fouchier et al.,Nature 2003 SARS coronavirus (SCV) in macaques Detection SCV in pulmonary lesions by IHC and TEM (Kuiken et al. 2003, Lancet) Histological lesions in lungs from cynomolgus macaques infected with SCV Kuiken et al. The Lancet 2003 8 SARS coronavirus in macaques Exclusion of hMPV as the primary cause of (Fouchier et al.,Nature 2003) SARS by macaque infection experiment Time after Macaque # 3 Macaque # 4 inoculation Koch’s postulates modified for viruses by Rivers: (days) Throat Nose Faeces IF Throat Nose Faeces IF 1.Isolation from diseased hosts 0 - - N.T. - - - N.T. - 2.Cultivation in host cells 2 + + N.T. N.T. + + N.T. N.T. 3.Proof of filterability 4 + + - N.T. + + + N.T. 4.No production of comparable disease in related species 6 - - - N.T. + + - N.T. 8 - - - N.T. + + - N.T. 5.Reisolation of the virus 10 - - - + - + - + 6.Detection of specific immune response 12 - - - N.T. - - - N.T. 14 - - - N.T. - - - N.T. SCV infected macaques subsequently inoculated with hMPV did not show 16 - - - + - - - + disease exacerbation + : IFA and VN titer >20 April 16, 2003 WHO Geneva Search for natural reservoir of SARS-CoV (Guan Yi et al. 2003 Science) Conference of SARS etiology network Official declaration of Species N PCR/ Antibody SARS-CoV as etiologic isolation agent of SARS Himalayan palm 6 6 3 civet Chinese ferret 2 0 1 badger Short- and mid-term objectives: Raccoon dog 1 1 1 Clarification of transmission routes and natural history Establishment and evaluation of diagnostic tools Hog badgers (3), beavers (3), domestic cats (3), Chinese hares (4), and Chinese muntjacs (2) all tested negative.