Download Tompkins-Flu-032017

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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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H7N9
2013
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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
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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?
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Periodicity of the flu season
AN overlay of multiple years
https://www.cdc.gov/flu/weekly/
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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
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Snapshot of the 2016 – 2017 season
https://www.cdc.gov/flu/weekly/
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While the incidence of complications
is not very high, numbers add up…
≥65
50 – 64
0–4
https://www.cdc.gov/flu/weekly/
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Focus on
the individual
and the virus
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The first steps of influenza infection
www.inscol.com
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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
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Not all infections are equal
Viruses from different species can cause distinct disease
By spread, they mean transmit
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What makes avian and human influenza
viruses different?
Receptor
specificity
Route of
transmission
Host
adaptation
Other?
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• 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
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Influenza virus receptor density
2,6
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2,3
But, don’t make the mistake of over-simplification!!
Attachment of influenza viruses to
human respiratory tissues
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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
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Immune response to
influenza virus infection
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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)
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Life cycle of influenza virus and role of the
adaptive immune response during infection
Cartoon from Immunity (2006) 24:5
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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
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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
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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.
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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
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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
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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
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