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Home , Ab Osterhaus, Erasmus MC, Morbillivirus, Picobirnavirus

Human Respiratory : ‘new kids on the block’

Ab Osterhaus DVM PhD Director Research Center for Emerging Infections and Zoonoses (RIZ) University of Veterinary Medicine Hannover Chair One Health Platform Chair ESWI

10th GVN network meeting Fondation Merieux, les Pensieres November 2018 03.12.2018 1 1980 1990 2000 2010

Past decades: zoonoses at the origin of major human disease outbreaks

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 <100% Identification of viral pathogens based on surveillance activities: ErasmusMC / RIZ TiHo

1995 CDV as the cause of mass mortality in Serengeti lions 1996 -herpesvirus in seals (phocid herpesvirus-2) novel molecular techniques 1997 monk seal (MSMV-WA/G) 1997 A (H5N1) in humans 1998 lentivirus from Talapoin monkeys (SIVtal) 1999 influenza B virus in seals 2000 human metapneumovirus (hMPV) 2002 re-emerging PDV in Europe Funding: 2003 SARS CoV cause of SARS in humans (Koch`s postulates) EU: EMPERIE; ANTIGONE; 2003 influenza A (H7N7) virus in humans PREPARE; COMPARE… 2004 fourth human (CoV NL63) NL: VIRGO-FES… 2005 H16 influenza A viruses (new HA!) in black headed gulls 2008 dolphin herpesvirus DFG: N-RENNT; VIPER 2009 deer 2010 human astrovirus, human 2011 ferret coronavirus, ferret HEV, porcine picobirnavirus, stone marten anellovirus. influenza A (H1N1) virus in dogs 2012 human calicivirus, MERS CoV, boa 2013 seal parvovirus, seal anelloviruses, deer papillomavirus, fox hepevirus, fox parvovirus, turtle herpesvirus 2014 canine bocavirus, porcine bocavirus, python nidovirus, camel , phocid herpes virus-7 2015 influenza A (H10N7) virus seals 2017… , hepadnavirus Tinamou, rec.canine circovirus, rec.canine bocavirus, herpesvirus sperm whale, Batai virus seal, avian metapneumovirus, novel pestivirus… XXX human respiratory 03.12.2018 4 Parvoviruses: wide spectrum of disease in humans and animals alike

Asymptomatic Brain involvement Erythema infectiosum (Human B19)

Anemia Immune disorders (Human B19, (Aleutian mink disease, Human B19) non-human primate erythroviruses)

Hepatitis, myocarditis Respiratory disease (Canine parvovirus, Goose (Human bocavirus, parvovirus, B19) Canine bocavirus) Fetal hydrops Gastro-enteritis (Human B19, Porcine parvoviruses) (Canine parvovirus, Human bocavirus, Bufavirus) Virus discovery in pigs, dogs and seals with ENCEPHALITIS (comparative virology)

Novel (recombinant) canine bocaviruses

Novel porcine bocavirus

novel seal parvovirus

Bodewes et al., PLoS One 2013 / 2014; Vet Microbiol.2014 Piewbang et al., Vet Pathol. 2018 Moesker F. et al., Clin Microbiol Infect 2016 eradication: lessons for eradication? de Swart RL, Duprex WP, Osterhaus AD. Curr Opin Virol. 2012

Morbillivirus PDV RPV TuV CDV Henipahvirus MV hPIV3 HeV bPIV3 Paramyxovirinae NiV SeV hPIV1

Pneumovirinae hRSV NDV Avulavirus

bRSV LPMV Metapneumovirinae MuV Rubulavirus APV hPIV2 SV5 SV41 HMPV Jo Lei W. et al., Thesis & Curr.Opin.Virol. 2018 Morbilliviruses crossing species barriers a pandemic risk after measles eradication?

PDV: European Harbour seals CDV: Baikal seals CDV: Caspian seals Nature 1988 / Science 2002 Nature 1988 EID 2000

DMV: CDV: Serengeti lions Med. monk seals Vaccine 1994 DMV: Nature 1997 CDV: Fin Whale Denmark Should we continue Rhesus macaques JWD 2016 measles vaccination for ever? China, EID 2011 CD150 is the primary morbillivirus MV is predominately lymphotropicentry in vivoreceptor de Vries RD, et al., PLoS Pathog. 2012

spleen

03.12.2018 11 PVRL4 is the morbillivirus receptor infection with rMVonKSEGFP(3): epithelial buccal cells mucosa and tongue de Vries RD, et al., PLoS Pathog. 2012

Inner cheek DAPI/CYK/EGFP

Koplik spot EGFP

03.12.2018 12 RESEARCH

◥ We propose that, if loss of acquired immuno- REPORT logical memoryafter measlesexists,theresulting impaired host resistance should be detectable in theepidemiological datacollected during periods VACCINES when measles wascommon and [in contrast to previousinvestigationsthat focuson low-resource settings(5–12)] shouldbeapparent in high-resource Long-term measles-induced settings where mortality from opportunistic in- fections during acute measles immune suppres- sion waslow. Relatively few countries report the immunomodulation increases overall necessar y parallel measl es and mortality timese- ries to test this hypothesis. National-level data childhood infectious diseasemortality from England, Wales, the United States, and Denmark [Fig. 1, A to C; see supplementary F1 M ichael J. M ina,1,2* C. Jessica E. M etcalf,1,3 Rik L. de Swart,4 materials (SM) 1 for details], spanning the dec- A. D. M. E. Osterhaus,4 Bryan T. Grenfell 1,3 ades surrounding theintroduction of massmea- sl esvaccination campaigns,meet our datacriteria. Immunosuppression after measles is known to predispose people to opportunistic Toassesstheunderlyingimmunological hypo- infections for a period of several weeks to months. Using population-level data, we show thesis (Fig. 1D) using population-level data, we that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. required that first, nonmeasles mortality should We find that nonmeasles infectious disease mortality in high-income countries is tightly be correlated with measles incidence data, espe- coupled to measles incidence at this lag, in both the pre- and post-vaccine eras. We cially because the onset of vaccination reduces conclude that long-term immunologic sequelae of measles drive interannual fluctuations in thelat ter.Second,an immunememorylossmecha- nonmeasles deaths. This is consistent with recent experimental work that attributes the nism should present as a strengthening of this immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data association when measlesincidencedataaretrans- provide an explanation for the long-term benefits of measles vaccination in preventing formed to reflect an accumulation of previous all-cause infectious disease. By preventing measles-associated immune memory loss, measlescases(a measles“shadow”). For example, vaccination protects polymicrobial herd immunity. if immunememory loss(or morebroadly, immu- nomodulation) lasts 3 years, the total number easlesvaccines wereintroduced 50 years Pr oposed mechanisms for a nonspecific bene- of immunomodulated individuals (S)inthe nth agoand werefollowed by strikingreduc- fici al effect of measles vaccination range from quarter can becalculated asthesum of themea- tions in child morbidity and mortal ity suggestionsthat livevaccinesmaydirectlystimu- sles cases (M) over the previous (and current) (1,2). Measlescontrol isnow recognized late cross-reactive T cell responses or that they 12 quar ters: Sn = Mn–11 + Mn–10 + …+ Mn–1+ Mn. as oneof themost successful publichealth may train innate immunity to take on memory- In practice, we weighted the quarters using a Minterventions ever undertaken (3). Despite this, likephenotypes (13,18 –21). Although well described gamma function. Dividing Sby the total popula- in many countries vaccination targets remain by Aaby (11, 12)and others (22) in observational tion of interest thus provides the prevalence of unmet, and measles continues to take hundreds studies, primarily in low-resource settings, these immunomodulation (seeSM 2,fig. S1,and movie of thousands of lives each year (3). Even where effects may not fully explain the long-term ben- S1 for detailed methods). Third, the strength of control has been successful, vaccine hesitancy efitsobserved with measlesvaccination and can- thisassociation should begreatest when themean threatens the gains that have been made (1, 4). not explain the pre-vaccination associ ations of duration over which the cases are accumulated The introduction of mass measles vaccination measles and mortality we describe below. The matches the mean duration required to restore has reduced childhood mortality by 30 to 50% World Health Organization (WHO) recently ad- immunological memoryafter MVinfection.Fourth, in resource-poor countries (5–8) and by up to dressed this issue (22)and concluded that mea- theestimated duration should be consistent both 90%in themost impoverished populations(9,10 ). slesvaccination isassociated with lar gereduct ions with the available evidence of increased risk of Theobserved benefitscannot be explained by the in all-causechildhood mortality but that thereis mortality after MV, compared with uninfected prevention of primary measles virus (MV) infec- no firm evidence to explain an immunological children, and with the time required to build a tionsalone(11,12), and they remain acentral mys- mechanism for the nonspecific vaccine benefits. protectiveimmunerepertoirein earlylife(Fig.1D, tery (13 ). Recent work (17, 23)invoked a different hypo- fig. S2, and SM). MV infection is typified by a profound, but thesisthat alossof immunememorycellsafter MV To explicitly address whether the observed generally assumed to be transient, immunosup- infection resets previously acquired immunity, nonspecific benefits of vaccination can be attri- pression that renders hosts more susceptible to and vaccination preventsthiseffect .deVrieset al. buted to the prevention of MV immunomodula- other pathogens(14 –17). Thus, contemporaneous (17)reproduced transient measles immune sup- tion, evidence for the four hypotheses must be reductions in nonmeasl es mortal ity after vacci- pression in macaques, characterized by systemic present separately within the pre-vaccine eras. nation areexpected. However, reductions in in- depletion of lymphocytesand reduced innateim- Reductions in nonmeasles infectious disease fectiousdiseasemortality after measlesvaccination mune cell proliferation (24). Although peripheral mortality (SM 1) areshown in Fig. 1, for children can last throughout thefirst 5yearsof life(5–10 ), blood lymphocyte counts were restored within aged 1to 9 yearsin Europeand aged 1to 14 years which is much longer than anticipated by tran- weeksasexpected (25), theauthorshypothesized in the United States, shortly after the onset of sient immunosuppression,which isgenerallycon- that rapid expansionsof predominantly measles- massvaccination in each country. Thefall in mor- sidered to last for weeks to months (16 , 17). specific B and T lymphocytesmasked an ablated tality waslater in Denmark,correspondingtothe memory-cell population (17). In other words, MV introduction of measlesvaccination in the1980s, infection replaced thepreviousmemorycell rep- as compared to the late 1960s for the United 1Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA. 2Emory University School of ertoire with MV-specific lymphocytes, resulting Kingdom and United States. In all locations, Medicine, Mxxxx Sxxxx Txxxx Pxxxx Program, Emory in “immuneamnesia” (17)tononmeaslespathogens. measlesincidenceshowed significant (P<0.001) University, Atlanta, GA, USA. 3Fogarty International Center, Previous investigations of virus-induced memory- associationswith mortality (Fig. 1, E to G). How- National Institutes of Health, Bethesda, MD, USA. cell depletion suggest that recovery requires re- ever, effect si zes varied (fig. S3A), reflecting low 4Department of Viroscience, Erasmus University Medical Center, , . stimulation, either directly or via cross-reactive reportingin theUnited States[fig. S3B and (30)] *Corresponding author. E-mail: [email protected] antigens (26–29). and changesin health carepracticebetween eras.

SCI EN CE sciencemag.org 00 MONTH 2015 • VOL 000 I SSUE 0000 1

MSno: REaaa3662/CT/MEDICIN E

Measles immune suppression; lessons from the macque model. de Vries RD, et al., PLoS Pathog. 2012 CD45RA(-) memory T-lymphocytes and follicular B-lymphocytes killed Fig.5

Significant changes in the frequencies of different lymphocyte subsets after measles. Frequency ratios of a naive or memory lymphocyte subsets or b functionally distinct T and B cell subsets (n = 42 paired samples). The ratio was calculated as the frequency of a subset after measles divided by the frequency of the same subset before measles. Horizontal dashed line indicates no changes (‘ratio = 1’) in frequency after measles. Ratio ‘>1’ indicates increase and ratio ‘<1’ indicates decrease in lymphocyte subset frequency after measles. Vertical dashed lines separate different lymphocyte subsets. TH1/17: TH1TH17 cells. CD27+IgM+IgD− B cells are also known as IgM-only memory B cells. CD27+IgM+IgD+ B cells are also known as natural effector cells. TC: transitional B cells. Green box represents significant decrease. Orange box represents significant increase. Statistical differences in frequencies of lymphocyte subsets before and after measles were analysed by two-tailed paired t-test or Wilcoxon signed-rank test. Centre lines of the box plots represent medians. Lower and upper boundaries of the boxes represent first and third quartiles, respectively. Lower and upper whiskers represent the 10th and 90th percentiles of the data, respectively. Dots represent outliers. *P < 0.05; **P < 0.01; ***P ≤ 0.001 Morbillivirus DNA Maximum likelihood, Polymerase ORF PDVRPV TuV CDV Henipahvirus MV hPIV3 HeV bPIV3 Respirovirus Paramyxovirinae NiV SeV hPIV1

Pneumovirinae hRSV NDV Avulavirus

bRSV LPMV Metapneumovirinae MuV Rubulavirus APV hPIV2 SV5 SV41 0.1 hMPV Drosten et al., NEJM 2003 Rota et al., Science 2003 SARS-CoV v.d. Hoek et al., Nature Med., 2004 - Phylogeny - 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 To date: estimated >2260 cases in 27 countries with >800 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) Dromedary 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 protein

Fei Song et al. JV 2013

Haagmans et al., Science 2016 MERS-CoV MVA vaccination: ‘one stone - two birds’ approach

Fei Song et al. JV 2013

Haagmans et al., Science 2016 . I

IMI-ZAPI Last four 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 0.2-0.3 million deaths

A(H1N1) A(H2N2) A(H3N2) A(H1N1) Aquatic wild birds: Influenza A virus reservoir

Short et al. 2015 One Health 2015

03.12.2018 24 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/ 2003-18* >840 >450* Europe/W-Africa *CFR ~ 55% (increasing) H7N9 PR Chinahina 2013-18 >1500 >600 H9, H10, H6.. Asia… ongoing <10 <10 Avian Influenza: Asia ‘live bird markets’ Virus passaging in ferrets (P1 to P10, passages 1 to 10).

Sander Herfst et al. Science 2012

Munster et al., Science 2009 Russel et al., Science 2012

PublishedLinster by AAASet al., Cell 2014 High and low pathogenic A viruses H7N9

Laboratory confirmed: 1584 Deaths: 612 Recoveries: 972

Gao t al., 2013

Source: FAO 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

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 Crucial preparedness elements for emerging viruses to be developed in ‘peace time’:

• Disease surveillance in humans & animals • Virus surveillance / genetic characterization for humans & animals • Diagnostics development and distribution platforms • Mathematical modeling capacity • Animal model capacity (BSL3/4) • Pathogenesis and transmission platforms • Preventive intervention platforms (societal, vaccination, antiviral) • Therapeutics discovery platforms (antivirals, antibodies, BRM’s...) • Healthcare preparedness • Communication and distribution strategies Of key importance for their control:  International collaboration and coordination  Using all available technology and information AcknowledgementsAcknowledgements Respiratory Viruses Erasmus MC and TiHo

R. Fouchier/M.Ludlow Mol.Virology W.Baumgärtner Pathology M. Koopmans Epidemiology C. Boucher/E.vd Vries Antiviral research A vd Eijk/ P.Fraaij/E van Gorp Clinical / G. Rimmelzwaan/G.Verjans Viro- B. Haagmans Virology M.Ludlow/R.Bodewes/W.Jo/E.vd Vries Virus discovery studies SARS collaborations MERS and Flu collaborations Drosten C. Bonn University Germany Drosten C. Bonn University Germany Lim W QM Hospital Hongkong Farag E Supreme Health Council Qatar Peiris M University of Hongkong Bosch BJ Netherlands Guan Y University of Hongkong Sutter G Max. Univ. Münich Germany Tam JS Hongkong Polytech. University Segalis Q CRESA Barcelona Spain Rottier PJ Utrecht University Netherlands Zambon MC PHE London Rota PA CDC Atlanta Neubert A IDT Stöhr K WHO Geneva Tashiro M NIC Tokyo v.d. Werf S Pasteur Paris Zambon MC PHE London Forthcoming conferences dealing with outbreak preparedness

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