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"Pandemieën Bij Mens En Dier: Zijn We Er Op Voorbereid?" Prof. Ab Osterhaus DVM

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"Pandemieën bij mens en dier: zijn we er op voorbereid?" Prof. Ab Osterhaus DVM PhD Director Research Center for Emerging Infections and Zoonoses (RIZ) University of Veterinary Medicine Hannover, Germany MSD Webinar, januari 22 2021 Rinderpest 1745: The Netherlands 2003: Last case in Mauretania 2011: Eradicated 1980 1990 2000 2010 2020 Past decades: zoonoses at the origin of major human disease outbreaks pandemics Adapted from: Reperant LA, Cornaglia G, Osterhaus AD Curr Top Microbiol Immunol.2013 The importance of understanding the human-animal interface: from early hominins to global citizens Most recent outbreaks of avian influenza as reported to the OIE in the last 6 months. African swine fever African swine fever Crucial elements for pandemic preparedness to be established in ‘peacetime’ • Early warning systems • Pathogen discovery and characterization platforms • Diagnostic platforms • Mathematical models • Animal models in BSL3 facilities • Clinical trial platforms • Non-pharmaceutical intervention and treatment strategies • Pharmaceutical intervention strategies •antiviral platforms •vaccine platforms •BRM platforms • Communication 8 25.01.2021 Last four influenza pandemics Credit: US National Museum of Health and Medicine 1918 1957 1968 2009 “Spanish Flu” “Asian Flu” “Hong Kong Flu” “Mexican flu” >40 million deaths 1-4 million deaths 1-4million deaths 0.2-0.6 million deaths A(H1N1) A(H2N2) A(H3N2) A(H1N1) Within a few weeks, the 2009 H1N1 pandemic spread around the world affecting all countries April 2009 May 2009 START June 2009 March 2009 July 6 2009 Cumulative cases 1–10 11–50 51–500 500–5000 Air traffic from Mexico >5000 De Jong et al., Nature 1997 Claas & Osterhaus, Nat.Med 1998 Fouchier et al., J Virol., 2005 Munster et al., EID., 2005 Aquatic wild birds Olsen et al., Science., 2006 Influenza A virus reservoir BF Koel et al, Science. 2013 H17/18 N10/11 Haemagglutinin (16 subtypes) Neuraminidase (9 subtypes) Avian Influenza: Asia Recent zoonotic transmissions from birds -confirmed human cases- Subtype Country Year # Cases # Deaths H7N7 UK 1996 1 0 H5N1 Hong Kong 1997 18 6 H9N2 SE-Asia 1999 >2 0 H5N1 Hong Kong 2003 2? 1 H7N7 Netherlands 2003 89 1 H7N2 USA 2003 1 0 H7N3 Canada 2004 2 0 H5N1 SE-Asia/M-East/ 2003-20* >1000 >500* Europe/W-Africa *CFR ~ 55% (increasing) H7N9 PR Chinahina 2013 >1500 >600 H9, H10, H6.. Asia… ongoing <5 <5 Highly pathogenic avian influenza A virus H5N1 Countries with humans, poultry and wild birds infected with H5N1 . Countries with poultry or wild birds infected with H5N1 and has reported human cases of H5N1. Countries with poultry or wild birds infected with H5N1. Ducatez et al., Nature 2006 Keawcharoen et al. EID 2008 Wikipedia, as of 29 May 2013 Clinical disease in diving ducks only (Keawcharoen et al. 2008 Emerg Infect Dis) Species No. Mild Severe inoculated signs signs Tufted 7 4 3 duck Pochard 7 3 1 Mallard 8 0 0 Teal 8 0 0 Wigeon 8 0 0 IHC H&E Gadwall 8 0 0 no spreading? spreading? Attachment to upper or lower respiratory tract Seasonal H3N2 Pandemic H1N1 HPAIV H5N1 van Riel et al.,Science 2006 transmission van Riel et al., Am J Pathol 2007 van Riel et al., Am J Pathol 2009 van Riel et al., Am J Pathol 2010 van Riel et al.,PLoS Path. 2011 HPAIV H5N1 HPAI H5N1 virus passaging in ferrets - toward transmissibility - Five substitutions are sufficient for airborne transmission between ferrets Munster et al., Science 2009 Herfst et al., Science 2012 Russel et al., Science 2012 Linster et al., Cell 2014 Published by AAAS Highly pathogenic avian influenza A virus in poultry/wild birds H5N1 H5N2 H5N5 H5N6 H5N8 H7N3 H7N9 Source: FAO, as of 24 Aug. 2017 High and low pathogenic avian influenza A viruses H7N9 Laboratory confirmed: 1584 Deaths: 612 Recoveries: 972 Gao t al., 2013 2013 2014 2015 2016 2017 Source: FAO, as of 23 Aug. 2017 Novel avian-origin influenza A (H7N9) virus attaches to epithelium in both upper and lower respiratory tract of humans. D van Riel et al. Am J Pathol. 2013 Oct;183(4):1137-43 Richard M. et al., Nature. 2013. Limited airborne transmission of H7N9 influenza A virus between ferrets. Limited human-to-human transmission: Small clusters! Chen Z, et al., Emerg Infect Dis. 2014 Bodewes et al J.Virol 2016 HA Avian influenza A/H10N7 virus-associated mass deaths among seals HA Bodewes et al EID 2015 Testing MVA-based inluenza vaccines - H5N1: Mice, macaques, humans - 2009 (H1N1): Ferrets - H7N9: Ferrets • Kreijtz et al. J. Inf. Dis. 2007 • Kreijtz et al. PLoS One. 2009 • Kreijtz et al. J. Inf. Dis. 2009 • Kreijtz et al. J. Gen. Virol. 2010 • Kreijtz et al., Lancet ID, 2014 Basis for EU project ENDFLU For universal flu vaccine 2009 pandemic vaccine preparation - response time - It took too long to produce “tailor made” vaccines for the southern hemisphere! SARS-CoV Drosten et al., NEJM 2003 Rota et al., Science 2003 - Phylogeny - v.d. Hoek et al., Nature Med., 2004 Fouchier et al., PNAS 2004 Woo et al., J.Virol., 2005 hMPV as the cause? Fouchier et al.,Nature 2003 Kuiken et al., Lancet 2004 April 16, 2003 WHO Geneva Press conference of SARS etiology network Official declaration of SARS-CoV as the etiologic agent Short- and mid-term objectives: - clarification of transmission routes and natural history - establishment and evaluation of diagnostic tools lick to edit Master title style 350 300 250 200 150 SCV eq/ml SCV 100 50 0 * * * Day: 0 2 4 0 2 4 0 2 4 Control Prophylactic Post exposure group group group Eosinophil counts in the bronchus of macaques vaccinated with inactivated SARS CoV with alum 50 45 40 35 30 25 20 15 10 Number of eosinophils per field per eosinophils Numberof 5 0 AI042 AF437 AG865 AH246 AH444 AH494 AH547 AH635 AH639 AH647 AG958 AH451 AH531 AH799 AH081 AH260 AH638 AG927 AG940 AH439 AH514 AH201 AH622 AH625 buffer adjuvant 10*5.9 virus 10*5.9 virus + 10*6.9 virus 10*6,9 virus + adjuvant adjuvant ENHANCED DISEASE? Eosinophils in the bronchus of macaques vaccinated with inactivated SARS CoV with alum Marshall and Enserink (Science 2004) To date: estimated >2000 cases in >26 countries with >700 deaths Saudi Arabia, Malaysia, Jordan, Qatar, Egypt, the United Arab Emirates, Kuwait, Oman, Algeria, Bangladesh, the Philippines, Indonesia (none confirmed), UK, and USA MERS-CoV KSA Korea Zaki et al NEJM 2012 Other countries Antibodies in dromedary camels (Reusken et al Lancet ID 2013) Dromadary camels: carriers of MERS-CoV (Haagmans et al., Lancet ID 2013) Identification of the CD 26 MERS-CoV receptor (Raj et al., Nature 2013) MVA expressing the MERS-CoV spike Click to editprotein Master title style Fei Song et al. JV 2013 Haagmans et al., Science 2016 MVA expressing the MERS-CoV spike Click to editprotein Master title style Fei Song et al. JV 2013 Haagmans et al., Science 2016 Induction of antibodies that neutralize MVA but also camel pox virus (CPV) Killing two birds with one stone MERS-CoV virus neutralization titers MVA neutralization CPV neutralization Haagmans et al.,Science 2016 ONE HEALTH VACCINE INITIATIVES: from ZAPI to CEPI Human Outbreak Vaccines based on Animal Vaccine Candidates • EU Horizon 2020; IMI ZAPI (BI) • MERS-CoV • RVFV • Schmallenberg virus • CEPI MVA based MERS-CoV vaccine (IDT) • Phase 1 ongoing • Phase 1/2a startedsubmitted • MVA based SARS-CoV-2 vaccine (IDT) • Phase 1 ongoing • CEPI LARISSA (WUR) LAV Rift Valley Fever vaccine • Phase 1/2a trials planned • I Chimeric humanized heavy chain only Ab ‘Single heavy chain’ IMI-ZAPI 38 39 16-10-2001 41 SARS-CoV-2: Malayan pangolin? SARS-CoV-1: Palm civet Public health and social measures contribute to stopping individual chains of transmission and preventing outbreaks, and are therefore critical in limiting further spread of COVID-19, particularly while vaccines and therapeutics are not yet available. These measures include the following: • Personal measures • Physical and social distancing measures • Movement measures • Special protection measures Find every case; Isolate every case; Test every case; Care for every case; Trace and quarantine every contact. TTT+Q TTT+Q strategy to control the COVID-19 pandemic South Korea’s widespread and digital TTT+Q strategy • Testing: as of 6 April 2020, almost ten RT-PCR tests per thousand inhabitants, • Tracking: after testing suspected cases, the ones testing positive are tracked and provided with treatment free of charge • Tracing: Korea has developed a diverse digital crowd-sourced contact tracing strategy. Singapore’s universal TTT+Q strategy • Testing: Singapore initiated a large testing strategy for all suspected cases since the early days of the outbreak, reaching 2 200 tests (RT-PCR) a day for a population of 5.7 million. • Tracking: A network of more than 800 public health preparedness clinics was activated in the primary care setting • Tracing: All identified contacts presenting symptoms were referred to hospitals for isolation and testing, and then placed under 14 days quarantine. Source: OECD Policy Responses to Coronavirus (COVID-19) Daily Coronavirus Cases in Different Chinese Provinces Pueyo,T., Medium, 2020 Daily new Coronavirus cases in East Asia Pueyo,T., Medium, 2020 Pueyo,T., Medium, 2020 Crucial elements for pandemic preparedness to be established in ‘peacetime’ • Early warning systems • Pathogen discovery and characterization platforms • Diagnostic platforms • Mathematical models • Animal models in BSL3 facilities • Clinical trial platforms • Non-pharmaceutical intervention and treatment strategies • Pharmaceutical intervention strategies •antiviral platforms •vaccine platforms •BRM platforms • Communication 55 25.01.2021.
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