Preventing the next influenza pandemic Albert Osterhaus DVM

Preventing the next influenza pandemic Albert Osterhaus DVM Ph. D Professor/Director One Health Center Hannover (RIZ/D) Professor/Chair Artemis Wildlife Health Institute (NL/EU) Board Member Protein Sciences (US) CSO Viroclinics-Biosciences BV (NL) Chair ESWI (EU) 06. 11. 2020 2

Conflict of interest disclosure q I have the following, real or perceived direct or indirect conflicts of interest that relate to this presentation: Affiliation / financial interest Nature of conflict / commercial company name Tobacco-industry and tobacco corporate affiliate related conflict of interest Grants/research support (to myself, my institution or department): Honoraria or consultation fees: Viroclinics Biosciences B. V. Protein Sciences Participation in a company sponsored bureau: Stock shareholder: Viroclinices Biosciences B. V. certificates Protein Sciences options Spouse/partner: Other support or other potential conflict of interest: This event is accredited for CME credits by EBAP and speakers are required to disclose their potential conflict of interest going back 3 years prior to this presentation. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgment. It remains for audience members to determine whether the speaker ’s interests or relationships may influence the presentation. Drug or device advertisement is strictly forbidden.

Human influenza: three appearances Seasonal influenza (A: H 3 N 2, H 1 N 1; B) Avian influenza A: H 5, H 6, H 7, H 9, H 10… Pandemic influenza (A: H 1 N 1, H 2 N 2, H 3 N 2, H 1 N 1…? )

Influenza A viruses • Subtype divisions of influenza A viruses made on basis of HA (1 -16) and NA (1 -9) antigens (all found in migratory birds) • Genomic nucleic acid consists of 8 RNA segments, segments allowing gene re-assortment • Virulence of influenza virus in birds depends on presence of series of basic amino acids adjacent to cleavage site of the HA polypeptide (H 5 and H 7 subtypes only) H 17/18 N 10/11

The Global Circulation of Seasonal Influenza A (H 3 N 2) Viruses Science 2008, Russell et al.

Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution BF Koel et al, Science. 2013 Nov 22; 342(6161): 976 -9 Björn F. Koel, et al.

Creating an antibody landscape A) Antigenic map of A/H 3 N 2 showing virus strains color-coded by antigenic cluster. B) An additional dimension indicates the measured antibody titers as vertical impulses, and a smooth surface is fitted using locally weighted multiple linear regression C) The height of the landscape along the path in (A) shows a slice through the landscape D) The height of the landscape along the antigenic summary path in (C) is plotted to create a rotationindependent two-dimensional summary visualization of the landscape Published by AAAS J. M. Fonville et al. Science 2014; 346: 996 -1000

The olfactory nerve as route of entrance into the CNS Detection of influenza in the olfactory bulb of an immunocompromised child van Riel et al. , Evidence for Influenza Virus CNS Invasion Along the Olfactory Route in an Immunocompromised Infant. J Infect Dis. 2014 Different influenza viruses attach to the olfactory mucosa

H 5 N 1 virus CNS invasion via the olfactory nerve Olfactory mucosa Cerebellum Day 1 Olfactory bulb Cerebrum Day 7 Spinal cord Day 3 Day 5 Day 7 Schrauwen & van Riel 2012 J Virol

Results - Virus titers in tissues Van Riel et al. , in prep.

Most recent pandemics Year 1918 1957 1968 2009 Subtype H 1 N 1 H 2 N 2 H 3 N 2 H 1 N 1 Name Spanish Flu Asian Flu Hong Kong Flu Mexican Flu Estimated number of deaths 20 -40 x 106 1 x 106 7 x 105 2 x 104 – 3 x 105 Spanish Flu 1918

Aquatic wild birds: Influenza A virus reservoir De Jong et al. , Nature 1997 Claas & Osterhaus, Nat. Med 1998 Fouchier et al. , J Virol. , 2005 Munster et al. , EID. , 2005 Olsen et al. , Science. , 2006 BF Koel et al, Science. 2013 Short et al. 2015 One Health 2015 06. 11. 2020 13

Reported cases of zoonotic influenza virus infection characterized by virus isolation Reperant et al. 2012 Vaccine

Distribution of reported cases of zoonotic mammalian influenza virus infection Short et al. 2015 One Health

INFLUENZA A VIRUS Recent zoonotic transmissions from birds -confirmed human cases. Subtype H 7 N 7 H 5 N 1 H 9 N 2 H 5 N 1 H 7 N 7 H 7 N 2 H 7 N 3 H 5 N 1 Country Year # Cases # Deaths UK 1996 0 1 Hong Kong 1997 6 18 SE-Asia 1999 0 >2 Hong Kong 2003 1 2? Netherlands 2003 1 89 USA 2003 0 1 Canada 2004 0 2 SE-Asia/M-East/ 2003 -15* 840 447* *CFR ~ 55% (increasing) Europe/W-Africa >100 >600 2013 H 7 N 9 PR China <5 <5 ongoing 9, H 10, H 6. . Asia…

Highly pathogenic avian influenza A virus H 5 N 1 Countries with humans, poultry and wild birds infected with H 5 N 1. Countries with poultry or wild birds infected with H 5 N 1 and has reported human cases of H 5 N 1. Countries with poultry or wild birds infected with H 5 N 1. Ducatez et al. , Nature 2006 Keawcharoen et al. EID 2008 Wikipedia, as of 29 May 2013

Highly pathogenic avian influenza A virus H 5 N 1 in humans Laboratory confirmed: Deaths: Case fatality rate: 840 447 53%

Highly pathogenic avian influenza A virus H 5 N 1, H 5 N 2, H 5 N 6, H 5 N 8 in poultry in North America

H 5 N 2 and H 5 N 8 virus detections in poultry and wild birds in 2014. The almost simultaneous detection of closely related viruses in Asia, Europe, and North America suggests linkage with wild bird migration via a large region in Russia. Josanne H. Verhagen et al. Science 2015; 347: 616 -617 Published by AAAS

Clinical disease in diving ducks only (Keawcharoen et al. 2008 Emerg Infect Dis) Species No. inoculated Mild signs Severe signs Tufted duck 7 4 3 Pochard 7 3 1 Mallard 8 0 0 Teal 8 0 0 Wigeon 8 0 0 Gadwall 8 0 0 no spreading? IHC H&E

Antigenic Variation of Clade 2. 1 H 5 N 1 Virus Is Determined by a Few Amino Acid Substitutions Immediately Adjacent to the Receptor Binding Site Björn F. Koel, et al. , m. Bio 2014

Attachment to upper or lower respiratory tract Seasonal H 3 N 2 Pandemic H 1 N 1 van Riel et al. , Science 2006 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. , PLo. S Path. 2011 HPAIV H 5 N 1 transmission

Transmission set up - Ferrets - Munster et al. , Science 2009 Herfst et al. , Science 2012 Russel et al. , Science 2012 Linster et al. , Cell 2014

Virus passaging in ferrets (P 1 to P 10, passages 1 to 10). Sander Herfst et al. Science 2012 Published by AAAS

• • Five substitutions are sufficient for airborne transmission of A/H 5 N 1 between ferrets Two substitutions in PB 1 and PB 2 increased RNA transcription and virus replication Three HA substitutions altered receptor binding preference and lowered p. H of fusion Strong selective advantage of substitutions responsible for airborne transmission Linster M et al. , Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H 5 N 1 Virus Cell, 2014

Virus titers immunocompetent individual Zoonotic influenza virus infection Probability of evolution of a transmissible variant Time Russell et al. Science 2013 Ability of a transmissible variant to grow in titer Reperant et al. The Lancet 2014

Virus titers immunocompromised individual Zoonotic influenza virus infection Time Probability of evolution of a transmissible variant Reperant et. al. Vaccine 2015 Ability of a transmissible variant to grow in titer Reperant et al. The Lancet 2014

Low pathogenic avian influenza A virus H 7 N 9 Gao et al. , 2013 Laboratory confirmed: Deaths: Recoveries: 593 105 488 http: //virologydownunder. blogspot. com. au/2014/11/influenza-ah 7 n 9 -virus-detection-numbers. html

Low pathogenic avian influenza A virus H 7 N 9 http: //virologydownunder. blogspot. com. au/2014/11/influenza-ah 7 n 9 -virus-detection-numbers. html

Low pathogenic avian influenza A virus H 7 N 9 Past six months

Novel avian-origin influenza A (H 7 N 9) 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 H 7 N 9 influenza A virus between ferrets. Limited human-to-human transmission: Small clusters! Chen Z, et al. , Emerg Infect Dis. 2014

Avian influenza A/H 10 N 7 virus-associated mass deaths among seal 425 deaths March- October 2014 152 deaths June-August 2014 (Anholt) ? About 1400 deaths September- November 2014 First cases in the Netherlands: November 2014, Zohari et al Eurosurveillance 2014, Krog et al EID 2015, Bodewes et al EID 2015

Origin of the virus? HA & NA HA Zohari et al Eurosurveillance 2014, Krog et al EID 2015, Bodewes et al EID 2015 NA

2009(H 1 N 1) pandemic vaccine preparation - response time - It takes too long to produce “tailor made” vaccines!

Recommendations are in place but overall coverage is low in older age groups 100 90 Vaccine coverage, % 80 Reported seasonal influenza vaccination coverage rates in older age groups (2008/09, 2009/10, 2010/11 and 2011/12 influenza seasons) WHO target for 2012/EU target for 2014/15 influenza season 70 2008/09 60 2009/10 50 2010/11 2011/12 40 30 20 10 N et he rla n En ds gl an Fr d an c Sp e ai n G er Italy m an y Ire ** Sw land e D den e † Lu nm xe ar m k b N urg or w Po ay* rtu g Fi al nl an d M H alta un ga Ic ry el Sl and ov R akia om a Sl nia ov en Po ia Li lan th d ua ni a La t Es via to ni a 0 ECDC 2014 Technical report Implementation of the Council Recommendation on seasonal influenza vaccination. Available at: http: //www. ecdc. europa. eu/en/publications/Publications/Implementation-seasonal-influenza-vaccination-Council-Recommendation-Jan-2014. pdf. Accessed April 2014.

Science 2009 Public-Private Collaboration to develop intervention strategies against pdv H 1 N 1 2009 Rappuoli et al. 2009, Science

Influenza proteins as vaccine targets for universal vaccine development • • • HA NA M 2 e NP M 1 NS 1 PB 2 PA • Antibody induction (HAI, VN, ADCC…) (HA , NA, M 2 e) • T cell induction (CD 4; CD 8, CTL, Th, T reg. ) (NP, M 1, NS 1, PB 2 and PA) • Protection in ferrets / clinical testing EU FP 7: FLUPAN / FLUNIVAC

(Pre)clinical testing MVA-based vaccines - H 5 N 1: Mice, macaques, humans - 2009 (H 1 N 1): Ferrets - H 7 N 9: Ferrets Kreijtz et al. J. Inf. Dis. 2007, 195: 1598 -606 Kreijtz et al. PLo. S One. 2009, 12; 4(11): e 7790 Kreijtz et al. J. Inf. Dis. 2009, 199: 405 -13 Kreijtz et al. J. Gen. Virol. 2010, 91: 2745 – 2752 Kreijtz et al. , Lancet ID, in press

Gross pathology Kreitz et al. , JID 2008

Human H 5 N 1 Phase I/IIa Trial HI – VN/1194/04 HI – IND/5/05 Kreijtz et al Lancet ID 2014 EU FP 7: FLUPAN/FLUNIVAC

Influenza A(H 1 N 1)pdm 09 vaccination policies and coverage in Europe Mereckiene J et al. Euro Surveill. 2012 Jan 26; 17(4). pii: 20064

Pandemic Influenza Vaccine Procurement • Some countries currently have Advanced Purchase Agreements in place with vaccine producing companies. • In post-pandemic era, governments are hesitant to openly communicate about agreements with vaccine producing companies. • Joint Procurement Agreement in place since 20 June 2014 è On 22 September 2015, France became the 22 nd EU country to sign the agreement

Antiviral stockpiling: current antiviral drugs for influenza Class/Antiviral drug M 2 -channel inhibitors Ø Amantadine Ø Rimantadine Neuraminidase inhibitors Ø Oseltamivir Ø Zanamivir Ø Peramivir * Ø Laninamivir * * Not licensed in Europe Brand name Symmetrel Flumadine Tamiflu Relenza Peramiflu Inavir Route Oral Inhaled IV Inhaled

Antiviral stockpiling Large-scale antiviral stockpiling since 2005 due to intense fears of an imminent H 5 N 1 avian influenza pandemic Controversy has arisen due to: • ‘mild’ course of 2009 H 1 N 1 pandemic • questions of effictiveness è • It is now unclear whether individual countries are maintaining stockpile level to ensure continued preparedness

Health Care Capacity • Although primary care and hospital care systems were able to cope with all patients in all surveyed countries, many countries were close to 100% occupation of hospital capacities. • Hhospital capacity would have been overstretched if the pandemic would have been worse. • Lack of hospital capacity in case of severe pandemic is not covered in pandemic preparedness plans

Pandemic Influenza Communication • Several European countries chose not to install a single flu spokesperson to inform the public at large. • Trial and error communication during pandemic left room for confusing messages on social media • There was a clear need for concerted ommunication on an international level in order to spread uniform messages Where are we now?

At conferences In Journals

COMMUNICATION = STRATEGY (ad hoc shouting does not necessarily work)

Conclusions EU pandemic preparedness • Flu viruses are unpredictable and are constantly changing • European policy makers are -in general- too complacent to develop decisive pandemic response plans, based on lessons learnt during the 2009 pandemic • Revised pandemic preparedness plans are often extremely flexible: “The most appropriate course of action would depend on the particular circumstances. ” • • EU countries await actions by WHO (revision pandemic phases), ECDC and DG SANTE (vaccine procurement initiative) • Challenges lie ahead in terms of antiviral stockpiles, vaccine procurement (APA’s in place) and healthcare capacity (lack of emergency response plans)

Crucial preparedness elements, to be developed in ‘peace time’: Syndrome surveillance in humans & animals Virus discovery / identification platforms for humans & animals Diagnostics development and distribution platforms Mathematical modeling capacity Animal model capacity (BSL 3/4) Pathogenesis study platforms for new infections (transmission…!) Preventive intervention platforms (societal, vaccination, antiviral) Therapeutics discovery platforms (antivirals, antibodies, BRM’s. . . ) Communication strategies

Crucial preparedness elements, to be developed in ‘peace time’: Syndrome surveillance in humans & animals Virus discovery / identification platforms for humans & animals Diagnostics development and distribution platforms Mathematical modeling capacity Animal model capacity (BSL 3/4) Pathogenesis study platforms for new infections (transmission…!) Preventive intervention platforms (societal, vaccination, antiviral) Therapeutics discovery platforms (antivirals, antibodies, BRM’s. . . ) Communication strategies International collaboration and coordination v using all available technology (classic and novel!!!) v are of key importance for their control !!!

Influenza research - team leaders Prof. R. Fouchier / Dr. S. Herfst Mol. Virology Prof. T. Kuiken Pathology Prof. M. Koopmans /Dr. C. Reusken Epidemiology Prof. C. Boucher / Dr, E. vd Vries Antiviral research Drs A. van der Eijk / P. Fraaij / Clinical / Pediatric research Prof. E van Gorp Prof. G. Rimmelzwaan Dr. B. Haagmans Viro-Immunology Viro-pathogenesis Drs. M. Schutten / S. Pas Diagnostics Dr. A. Andeweg Genomics Dr. J. Kreijtz Vaccinology Dr. K. Stittelaar / Dr R. Bodewes Animal studies Dr. E. van der Vries EU FP 7: NOVAFLU; FLUBIRD; ERC; ARCAS; FLUPIG; EMPERIE; ANTIGONE; ERC: FLUPAN NIAID: CEIRS. NWO: VIRGO; FES.

ACKNOWLEDGEMENTS: EU FP 7 -HEALTH NOVAFLU NEWFLUBIRD NIH-NIAID CEIRS* EMPERIE ANTIGONE FLUNIVAC FLUPAN Ministerie LNV / ELI* * Erasmus MC coordinated