Influenza Virus: Bird Flu, Pandemics, Yearly Outbreaks and Vaccines

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Influenza Virus Bird Flu, Pandemics, Yearly
Outbreaks and Vaccines
E. John Wherry, Ph.D. Assistant Professor The
Wistar Institute and Wistar Vaccine Center
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• Yearly influenza virus infections
• Pandemics and Avian influenza
• Vaccines and vaccine approaches

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10 to 20 of Americans get influenza each
yr. November-April - Flu season
100,000-200,000 hospitalizations 36,000
deaths People over 65, those with chronic
medical conditions, very young children more
susceptible.
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Influenza infection in the elderly

• Over 65 age group much more susceptible
• Vaccine less effective in the elderly
• Changes in the immune system with age poorly
  understood

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How does the vaccine or immunity to influenza
work?
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Antibody to influenza virus (e.g. from vaccine)
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How does influenza virus change from year to
year?
- Drift- Shift
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Antigenic Drift
-Subtle changes in virus that avoid SOME immunity
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Antigenic Shift
-Radical changes in virus that avoid ALL immunity
Viruses from other species
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New influenza virus vaccines are made each year

• Virus mutates rapidly - last years immunity is
  no loner protective (usually Drift not Shift)
• Occasionally Shift -16 subtypes of influenza
• The three most likely flu strains to emerge are
  picked 9 months ahead
• Vaccine lots are made in eggs
• We must pick correctly!!
• Takes time (6-9 months, once strains are picked)

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Influenza vaccines from a business prospective.

• Vaccines are costly to produce (esp Flu)
• Only two companies currently produce the
  traditional flu vaccine
• Global market for a vaccine 6 Billion
• Global market for a drug 340 Billion
• Over three years, Wyeth lost 50 Million on
  unsold vaccines
• Why should companies chose to make vaccines?
• The burden for vaccine innovation is on the
  public sector (e.g. federal funding)

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From yearly flu to pandemic influenza and bird flu
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PANDEMIC INFLUENZA Caused by an influenza
virus that is new to people Likely to be more
severe than seasonal influenza The timing is
difficult to predict A severe pandemic could
change daily life for a time including
limitations on travel and public gatherings
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Recent Influenza Virus Pandemics
20-100 million
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Recreating the 1918 Influenza virus strain
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Why the Concern Today? Bird Flu - H5N1 is
devastating bird populations Disease has spread
from poultry to humans Disease in humans often
fatal Death in 50 of those infected By
comparison 1918 Spanish Flu 2!! To develop
more effective vaccines, we need to understand
why these viruses are so dangerous
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Why are the 1918 virus and H5N1 so lethal?
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H5N1 - Avian Flu First isolated in 1997 in
China Deadly in birds Important similarities to
the 1918 virus Still mutating - 1997 strain is
quite different from 2006/2007 isolates Has
not (yet) spread efficiently from person to
person! Surveillance efforts and preparedness
are increasing
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The Solution for H5N1

• Cull bird populations in affect areas
• Better surveillance
• Make a vaccine to H5N1!!

Being done
Major economic implications
Problematic for wild bird populations
Also being done
North America, Europe, etc fairly good
Asia, Africa, Middle East, very difficult
Also, being done with standard egg approach
But, virus continues to change!!
New approaches in the pipeline
H5N1 is not the only Avian influenza virus!!
Others will likely eventually emerge. Can we
make a Universal Flu Vaccine?
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What can we do?

• Surveillance and pandemic preparedness
• Simple hygiene and common sense
• Antivirals
• Vaccines

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Vaccines
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Efficacy and shortcomings of current Flu vaccines

• Inactivated subunit (all ages gt0.5y) and live
  attenuated (0.5-49y) vaccines have high efficacy
  in children and adults (70-90 protection against
  illness) if there is a good match between vaccine
  and circulating strains.

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One vaccine approach Stockpile current type of
vaccines for all virus subtypes
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Other Current Vaccine Research

• Traditional vaccines based on current H5N1
• Vaccines targeting more conserved parts of the
  virus
• Chimeric/Engineered Vaccines
• Vaccines designed to induce immunity in the
  elderly

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Influenza virus vaccine research at Wistar

• Studying immunity to influenza in the elderly
• Developing two new types of vaccines for
  universal protection from influenza virus
• Developing vaccine approaches tailored to induce
  more effective immunity in the elderly

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Antibody to influenza virus (e.g. from vaccine)
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New approaches for a universal Flu vaccine at
Wistar
New vaccine against highly conserved M2
protein (W. Gerhard - Wistar)
Assessing how to generate optimal immune
responses in the elderly (Wherry lab - Wistar)
HIV Proteins
Flu Proteins
Chimeric Flu Vaccine (H. Ertl - Wistar)
HIV Vaccine
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Membrane proteins of influenza A virus
Hemagglutinin (HA)
Matrix protein 2 (M2)
Neuraminidase (NA)
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Low sequence diversity of M2e amongst human virus
isolates (1918-2005)
Region recognized by murine M2e-specific mAbs.
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Understanding Immunity to influenza virus and
other viruses in the elderly

• Vilma Decman, PhD
• Tony Polley
• Douglas Dolfi, PhD

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Overview

• Compare antiviral responses in young and aged
  mice
• Identify and characterize influenza virus
  specific T cell responses in young and elderly
  humans
• Identify differences (defects?) in T cell
  responses in aged - opportunities for enhanced
  vaccines

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Experimental Approach
Young 2-4 mo
Evaluate T cell response Quantitative Qualitative
Response to challenge
Flu - X31-GP33 PR8-GP33
Aged 22-24 mo
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Increased morbidity and mortality in aged mice
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Delayed primary CD8 T cell response in aged mice
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Can T cells in immunized old mice respond
effectively to challenge infection?
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Challenge with PR8
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Failure of protective immunity to influenza virus
in old mice
Young Immune
Young Naive
Old Immune
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Old mice have increased negative
immuno-regulatory pathways
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Day 10 post influenza virus infection
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Compromised immunity to influenza virus animal
studies

• Delayed primary immune responses
• Severely compromised secondary responses (i.e.
  protection by immunological memory
• Clear differences in negative immuno-regulatory
  pathways in aged mice
• Working to overcome negative regulation and
  enhance positive accessory pathways

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Human antiviral T cell responses in young and
elderly
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Influenza NP and M Elispot

• 246 aged patients already screened
• 47 young patients already screened
• Exhibiting a response to flu peptides by elispot
• 31.9 of young patients
• 21.6 of aged patients

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Tetramer analysis
HLA-A2/Flu GIL
CD28
CD27
CD8
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Negative regulatory pathway expressed by
influenza virus-specific T cell in humans
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Summary - Human studies

• Influenza virus-specific T cell responses can be
  identified by Elispot and then characterized by
  flow cytometry
• Negative regulatory pathways also appear to be
  altered in elderly humans
• Studies are ongoing to determine how these
  pathways impact human influenza virus-specific
  immunity

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Acknowledgements
Collaborators on Flu projects
Wherry Lab
Gundi Ertl (Wistar) Sarah Abdula Lauren
DiMenna Walter Gerhard (Wistar) Jan Erikson
(Wistar) Wolfgang Weninger (Wistar) Gordon
Freeman (Harvard) Arlene Sharpe (Harvard) Ken
Schmader (Duke) Mike Betts (UPenn)
Mohammed Ali Shawn Blackburn Alison
Crawford Vilma Decman Doug Dolfi Charlly
Kao Brian Laidlaw Antonio Polley Maanasi
Samant Haina Shin
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