What is influenza virus? 13,000 base RNA genome: 1/ the size of the human genome

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Emily Davidson
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2 What is influenza virus? 13,000 base RNA genome: 1/ the size of the human genome CDC

3 Principles of Virology, 4e

4 Neumann et al. Nature

5 Influenza virus is one of the most deadly viral pathogens facing humanity

6 Influenza virus is one of the most deadly viral pathogens facing humanity CDC; Molinari et al. Vaccine. 2007

7 The threat of influenza viruses is two-fold: Pandemic flu: animal viruses that gain the ability to transmit between humans Seasonal flu: human viruses that continuously circulate between people

8 The 1918 H1N1 pandemic

immune system has seen before Infection and

9 Pandemic flu Pandemics typically emerge from birds or pigs Pandemic viruses are unlike anything your immune system has seen before Infection and mortality rates are much higher due to lack of immune protection

10 Influenza viruses infect and transmit between a variety of animal hosts

11 Migratory waterfowl are primary host Lee et al. JVi

12 Michael A Johnson, North Dakota Game and Fish

13 High-path avian flu in the US

14 Influenza is actually dozens of different related viruses

15 Avian H5N1

16 Avian H7N9 Artois et al. EID. 2018

17 The CDC and WHO operate a global influenza surveillance network

18 Phylogenetics The use of genomic sequence data to infer evolutionary relationships Used to understand the evolutionary origins of a virus Defines the evolutionary pressures acting on viruses Wu et al. PNAS

19 Phylogenetic trees Graphical representation of highest probability geneaology Lindesmith et al. JVI

20 Dissecting epidemics Combining surveillance with phylogenetics can provide a powerful means to understand how epidemics begin and spread Dudas et al. Nature

21 Dissecting epidemics Combining surveillance with phylogenetics can provide a powerful means to understand how epidemics begin and spread Quick et al. Nature

22 Avian H7N9 Artois et al. EID. 2018

23 Tracking H7N9 and H9N2 Shi et al. Cell Host Microbe

24 Tracking H7N9 and H9N2 Shi et al. Cell Host Microbe

25 How do pandemics emerge into humans? In general, human-adapted viruses preferentially bind α2,6-linked SAs, while avian strains preferentially bind α2,3-linked Sas HA receptor specificity represents a major determinant of species tropism Ha et al. PNAS De Graaf and Fouchier. EMBO. 2014

26 Host differences in SA distribution Mutations in HA that determine relative avidity for different SA linkage structures are major determinants of species specificity Ha et al. PNAS De Graaf and Fouchier. EMBO. 2014

Understanding avian IAV adaptation to mammals Serial passage of avian H5N1 in ferrets allows the virus to adapt to mammalian replication in an

27 Understanding avian IAV adaptation to mammals Serial passage of avian H5N1 in ferrets allows the virus to adapt to mammalian replication in an unbiased way Deep sequencing of the virus after passaging allows the virus to tell you what is important during host adaptation Herfst et al. Science. 2012

28 Introduction of 5 mutations (HA: H103Y, T156A, Q222L, G224S; PB2: E627K) into avian H5N1 is sufficient to allow respiratory transmission in ferrets H5N1 HA:H103Y,T156A, Q222L, G224S; PB2: E627K H5N1 WT Herfst et al. Science. 2012

29 Adaptation through viral chatter BIRDS HUMANS EMERGENCE Adapted from Parrish et al. Microbiol. Mol. Biol. Rev

31 Pandemics in the 20 th century 2009 Successful pandemics become seasonal flu

32 Seasonal flu Seasonal flu infections kill hundreds of thousands globally each year, despite the existence of a vaccine

33 The threat of influenza viruses is two-fold: Pandemic flu: animal viruses that gain the ability to transmit between humans Seasonal flu: human viruses that continuously circulate between people

34 Vaccines are our best protection Either killed stocks of virus, or live attenuated Seasonal flu vaccine consists of 3-4 viruses (H1N1, H3N2, and 1-2 influenza B lineages) Must be re-administered every year Same technology can be used to target potential pandemic viruses

35 Vaccines have been hugely successful against similar viruses

36 Vaccines have been hugely successful against similar viruses Why not flu?

37 How do anti-flu vaccines work?

38 How do anti-flu vaccines work? Vaccines train your immune system to produce molecules called antibodies that bind to and block specific viruses

39 Protection via neutralizing antibodies HA Protection against flu is mediated by neutralizing anti-ha antibodies

40 Antibodies bind specific sites on the virus Xu et al. Science. 2010

41 Viruses can escape from antibodies MUTATION

42 Antigenic drift Seasonal flu is constantly evolving in the human population, allowing it to outrun our immune systems Time Bedford et al. elife. 2014

43 Antigenic drift is an evolutionary problem

44 Antigenic drift is an evolutionary problem Human H3N2 since 2002:

45 How do we choose vaccine strains? Human H3N2 since 2002:

47 Sometimes we guess wrong Chambers et al. Cell Reports. 2015

48 Sometimes we guess wrong Chambers et al. Cell Reports. 2015

49 Why was last year so bad?

50 Growth in eggs changes the vaccine Mutations in circulating H3N2: What was chosen to go into the vaccine Zost et al. PNAS. 2017

52 Growth in eggs changes the vaccine Mutations in circulating H3N2: What was chosen to go into the vaccine What went into the vaccine Zost et al. PNAS. 2017

53 We are not vaccinating against the virus we intended to Zost et al. PNAS Scott Hensley

54 Universal flu vaccines Protect against multiple strains, preventing the ability of the virus to evolve resistance Ideally, would also protect against zoonotic strains with pandemic potential

55 How do we get there?

56 Are there constraints on evolution? Head HA stalk is less able to tolerate escape mutations Stalk The stalk region is similar between different potential pandemic strains Ability to tolerate mutations (Red = high) Thyagarajan and Bloom. elife. 2014

57 Universal flu candidates targeting the stalk are in clinical trials Henry et al. Trends in Immuno

58 What do we still need to know: What are the virus weak points? How do we instruct your immune system to target those weak points?

59 ACKNOWLEDGMENTS University of Illinois Team VIPER: Fadi Alnaji, Ph.D. Brigitte Martin, Ph.D. Cris Vera, Ph.D. Meghan Diefenbacher Jiayi Sun Kelsie Green Connie Chang - MSU Geoff Zath Humberto Sanchez Zack Jay Laura Fabris - Rutgers Ruian Ke Los Alamos Katia Koelle - Emory Funding: BROOKELAB.ORG

Evolution of influenza

Evolution of influenza Today: 1. Global health impact of flu - why should we care? 2. - what are the components of the virus and how do they change? 3. Where does influenza come from? - are there animal