What is influenza virus? 13,000 base RNA genome: 1/ the size of the human genome
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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
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
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
30
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:
46
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
51
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
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