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Linda M. Stannard, University of Cape Town Flu and you: What influenza virus does when it infects and lessons from past & present S. Mark Tompkins, PhD Center for Vaccines and Immunology Department of Infectious Diseases March 20, 2017 1 Influenza viruses Orthomyxoviridae Classified as type A, B, or C, based upon their protein composition Type A Found in many kinds of animals Can cause epidemics and pandemics 2 Type B Type C Found in humans, pigs, and dogs Widely circulates in humans Causes mild respiratory infections Can cause epidemics Does not spark epidemics or pandemics. Influenza A virus A human, agricultural & zoonotic pathogen HA – 18 different serotypes* NA – 11 different serotypes e.g. H1N1, H3N2, H5N1 Segmented, (-) sense RNA virus Nature Reviews Microbiology 6, 143-155 (February 2008) Currently, H1N1 and H3N2 subtypes are circulating in humans, although zoonotic infections with other subtypes occur. Highly Pathogenic Avian Influenza H5N1 Avian H7N9 H3N2v (variant) swine viruses H1N2v swine viruses *Bat influenza: H17N10, H18N11 3 What’s in a name? Human • • • • A/Brisbane/59/2007 (H1N1) B/Florida/04/2006 A/Viet Nam/1203/2004 (H5N1) A/South Carolina/1/1918 (H1N1) 4 Non-human •A/Goose/Guangdong/1/96 (H5N1) •A/Mute Swan/MI/451072/2006 (H5N1) •A/Ck/PA/13609/1993 (H5N2) •A/Ck/TX/167280-4/2002 (H5N3) Influenza A virus Seal flu Seasonal Avian Swine Cow flu? Equine 5 Pandemic Canine The Impact of Seasonal Influenza Infects 5-15% of the world population >200,000 hospitalizations ~36,000 deaths in the US $37.5 billion in economic cost (influenza and pneumonia) 3-5 million cases of severe illness worldwide Up to ½ million deaths worldwide www.cdc.gov 6 Avian Influenza Avian influenza is everywhere and found in many aquatic bird species or their habitats Low Pathogenic (LPAI) and Highly Pathogenic (HPAI) viruses are a major concern to poultry production in the United States • HPAI outbreak in Pennsylvania in 1983 • 17 million birds destroyed at a cost of $65 M • LPAI outbreak in Virginia in 1997 • 5 million birds destroyed at a cost of >$130 M • >18 outbreaks of potential HPAI since 1997 • More on 2015 H5N2 to come 7 2015 H5N2 HPAI outbreak in North America Update on the Highly-Pathogenic Avian Influenza Outbreak of 2014-2015 223 48,091,293 Detections Reported Birds Affected Dec ‘14 – Jun ’15 $1.6 billion Length of Outbreak Turkey and Laying Hen Cost https://fas.org/sgp/crs/misc/R44114.pdf 8 Avian influenza virus in humans Infection of humans with avian influenza does not mean a pandemic will occur Avian influenza has spilled over into humans repeatedly Influenza virus requires host adaptation at a variety of levels before it can establish itself in a population 9 Human AI Virus infections: Non-H5N1 (excluding H7N9) Year Country Subtype Cases Deaths 1959 USA H7N7 LPAI 1 0 1978-9 USA H7N7 LPAI ? 0 1996 United Kingdom H7N7 LPAI 1 0 1999 China H9N2 LPAI 5 0 1999, 2003, 2007 Hong Kong H9N2 LPAI 4 0 2002-3 USA H7N2 LPAI 2 0 2003 Netherlands H7N7 HPAI 89 1 2004 Canada H7N3 LPAI / HPAI 2 0 2006 United Kingdom H7N3 LPAI 1 0 2007 United Kingdom H7N3 LPAI 4 0 Total 109 1 Adapted from slide by Dr. David Swayne, USDA 10 11 Avian Influenza A Virus Transmission to Humans in North America • H7N2 in Virginia, 2002 • A low pathogenic avian influenza A (H7N2) outbreak occurred among turkeys and chickens at commercial farms in Virginia • A person involved with culling activities developed influenza-like illness • H7N2 in New York, 2003 • A case of avian influenza A virus infection was detected in an adult male from New York, who was hospitalized for respiratory tract illness • A LPAI H7N2 virus was isolated from a respiratory specimen from the patient • The source of this person's infection is unknown • H7N3 in Canada, 2004 • • • • LPAI outbreak that evolved into an HPAI outbreak. Culling operations and other measures were performed in an effort to control the spread of virus Health Canada reported 2 cases of H7N3: one in culling operations and one in a poultry worker Both patients developed conjunctivitis (eye infection) and mild illness • H7N2 In New York, 2016 • Outbreak of avian lineage H7N2 influenza virus infection among cats in an animal shelter in NY City • A shelter worker having prolonged contact w/ cats was infected, had mild illness, and recovered 12 H7N9 2013 13 Pandemic Influenza in the 20th Century Spanish Flu (1918) Asian Flu (1957) • • • • • 70,000 deaths in the US • 1-4 million deaths worldwide 20-50% serious illness 675,000 deaths in the US >50 million deaths worldwide 2-5% of the world population died 14 SOURCE: The Threat of Pandemic Influenza: Are We Ready? A Workshop Summary, pp. 1-23. Hong Kong Flu (1968) • 34,000 deaths in the US • 1-2 million deaths worldwide Graphic from nih.gov 2009 H1N1 swine influenza pandemic • • • • From April 12, 2009 to April 10, 2010 60.8 million cases (range: 43.3-89.3 M) 274,304 hospitalizations (195,086-402,719) 12,469 deaths (8868-18,306) (all US numbers) Vaccine in arms Apr 15 May Jun Shrestha SS, et al., Clin Infect Dis. 2011 Jan 1;52 Suppl 1:S75-82. Jul Aug Let’s get back to seasonal flu What is the impact? What are we doing about it? What is driving the seasonal reoccurrence, outbreaks, infections across species, and the rare pandemics? 16 Periodicity of the flu season AN overlay of multiple years https://www.cdc.gov/flu/weekly/ 17 Association of seasonal febrile respiratory illness and influenza infection Positive cultures A/Port Chalmers A/Victoria B/Hong Kong A/Texas Patients A/Brazil A/Bangkok- B/Singapore B/Singa- A/England A/Bangkok pore Febrile respiratory illness 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 Surveillance in Houston, Texas, 1974-1983. Edwin Kilbourne, Influenza 18 Snapshot of the 2016 – 2017 season https://www.cdc.gov/flu/weekly/ 19 While the incidence of complications is not very high, numbers add up… ≥65 50 – 64 0–4 https://www.cdc.gov/flu/weekly/ 20 Focus on the individual and the virus 21 The first steps of influenza infection www.inscol.com 22 1. You inhale droplets containing influenza 2. These small particles enter airways and are trapped 3. The virus adheres to epithelial cells 4. The virus binds to specific receptors and initiates the replicative cycle 5. Your immune response is initiated 6. Innate responses hold the virus at bay 7. Adaptive responses clear the infection and establish immune memory 8. Bacterial co-infections and co-morbidities can result in hospitalization or death Influenza A virus life cycle http://www.nature.com/nrmicro/journal/v14/n8/box/nrmicro.2016.87_BX1.html 23 Not all infections are equal Viruses from different species can cause distinct disease By spread, they mean transmit 24 What makes avian and human influenza viruses different? Receptor specificity Route of transmission Host adaptation Other? 25 • Sialic acid linkage preference of avian versus human influenza viruses • Sialic acid expression in different species • Aerosol versus droplet versus contact • Tissue distribution of sialic acid receptors • Polymerase activity • Optimal temperature for replication Sialic acid linkage preferences of influenza viruses Avian influenza viruses preferentially bind to sialic acids with 2,3 linkages Human influenza viruses preferentially bind to sialic acids with 2,6 linkages http://employees.csbsju.edu/hjakubowski/classes/ch125/IB4_IMF_Carbohydrates.html 26 Influenza virus receptor density 2,6 27 2,3 But, don’t make the mistake of over-simplification!! Attachment of influenza viruses to human respiratory tissues 28 American Journal of Pathology. 2007;171:1215-1223 Sialic acid preference is not absolute Affinity is in the millimolar range (low) and binding relies heavily on the avidity of multimeric interactions There is weak binding of other sialic acids As few as 2 amino acid changes in the virus HA can alter specificity Specificity may not equate infection or transmission 29 Immune response to influenza virus infection 30 Influenza A virus antigens (not exhaustive) Variable (classical Ag) • Hemagglutinin • Neuraminidase Conserved • Nucleoprotein • Capsid (Matrix 1) • Polymerases • Pore (Matrix 2) • Non-structural (NS) Nature Reviews Microbiology 6, 143-155 (February 2008) 31 Life cycle of influenza virus and role of the adaptive immune response during infection Cartoon from Immunity (2006) 24:5 32 Course of immune response during influenza infection Serum antibody titers to 1918 Spanish Influenza were detected in survivors more than 90 years later!! From Immunity (2006) 24:5 33 After infection we are left with: Virus specific: • Serum and mucosal antibody responses, both virus neutralizing and non-neutralizing • Memory B cells • Memory CD4 and CD8 T cells These responses do not guarantee immunity • Non-neutralizing antibodies may be protective • T cell responses can help control infection • These responses provide heterosubtypic immunity • Heterosubtypic immunity will likely not protect from infection • Het may be relevant to protection from disease 34 We take advantage of the potent anti-HA neutralizing antibody response for vaccines • Vaccines since the 1940’s target the serum neutralizing antibody response to HA • This specific response can be measured by a serum hemagglutination inhibition assay • This is an established correlate of protective immunity • A 4-fold increase in HAI titer (or >1:40) is indicative of protection from influenza virus infection by a matched strain. 35 Hemagglutination inhibition assay When we combine virus with immune serum and RBCs, the absence of haze (a dot) means there are virus-specific antibodies Negative control Positive control Virus-specific antibodies Flavors of licensed influenza vaccines Vaccine Type Substrate Fluzone (Sanofi) Formalin inactivated, split, and purified Embryonated chicken eggs Flucelvax (Seqirus) β-propiolactone (BPL) inactivated, split, and purified Madin-Darby canine kidney (MDCK) cells FluBlok (Protein Sciences) rHA protein subunit, detergent extracted, purified SF9 (insect) cells Flumist (MedImmune) Live-attenuated, purified, and filtered Embryonated chicken eggs Inactivated (subunit) vaccines (IIV) • Target the HA eliciting neutralizing serum antibody responses • Most have “contaminating” antigens, including NA, but these are not quantitated or considered in immunogenicity or efficacy Live-attenuated influenza vaccine (LAIV) • Elicits mucosal and serum antibody, as well as cellular immune responses 37 To sum up • Multiple types and subtypes of influenza are circulating (and changing) in humans • Zoonotic influenzas are all around us posing potential threats • Not all influenzas are equal • Outcomes of infection are varied • Immunity to infection is potent, although potentially not long-lived 38 Questions? This is a mystery, and I don't like mysteries. They give me a bellyache, and I've got a beauty right now. – Captain James T. Kirk 39