influenza introduction

7/28/2019 Influenza Introduction

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Influenza

Seasonal and Pandemic

EPID 8500


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Lessons Learned formPast Pandemics

First outbreaks March 1918 in Europe, USA Highly contagious, but not deadly

Virus traveled between Europe/USA on troopships

Land, sea travel to Africa, Asia

Warning signal was missed

August, 1918 simultaneous explosiveoutbreaks in in France, Sierra Leone, USA 10-fold increase in death rate

Highest death rate ages 15-35 years Cytokine Storm?

Deaths from primary viral pneumonia, secondarybacterial pneumonia

Deaths within 48 hours of illness

Coincident severe disease in pigs

20-40 million killed in less than 1 year World War I 8.3 million military deaths over 4

years

25-35% of the world infected


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Pandemics are unpredictable

Mortality, severity of illness, pattern of spread A sudden, sharp increase in the need for medical care

will always occur

Capacity to cause severe disease in nontraditionalgroups is a major determinant of pandemic impact

Epidemiology reveals waves of infection Ages/areas not initially infected likely vulnerable in future

waves

Subsequent waves may be more severe 1918- virus mutated into more virulent form

1957 schoolchildren spread initial wave, elderly died insecond wave

Public health interventions delay, but do not stoppandemic spread Quarantine, travel restriction show little effect

Does not change population susceptibility

Delay spread in Australia

later milder strain causesinfection there

Temporary banning of public gatherings, closing schoolspotentially effective in case of severe disease and highmortality

Delaying spread is desirable Fewer people ill at one time improve capacity to cope with

sharp increase in need for medical care

Lessons Learned formPast Pandemics
http://www.history.navy.mil/photos/images/h41000/h41730.jpg


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Timeline of EmergenceInfluenza A Viruses in Humans

1918 1957 1968 1977 1997

1998/9

2003

H1

H1

H3

H2

H7

H5H5

H9

Spanish

Influenza

H1N1

Asian

Influenza

H2N2

Russian

Influenza

Avian

Influenza

Hong

Kong

Influenza

H3N2

2009

H1

Reassorted Influenza virus

(Swine Flu)

1976 Swine Flu

Outbreak, Ft. Dix


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Swine Influenza A(H1N1)Mexico Epidemic Curve Confirmed, by Day

4

5961

75

128127

148

126

112

90

168

22 4

217

214

20 1

176

199

22 1

27 0

29 0

40 0

38 5

30 9

26 2

15

310

76

3122

14 1014

4138

4276500 234210 3322111211017

38

122

186

77

158

92

6965

85

7176

595052

4136

3137

2933

2025

816

0

50

100

150

200

250

300

350

400

Day

No.ofConfirmedCases

Source: Secretaria de Salud, Mexico

Total Number of Confirmed Cases = 6,241*

As of June 09, 2009

*NOTE: 54 confirmed cases not included

Epidemiological Alert

School Closure

Suspension of Non-essential Activities

School Open


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Influenza Epidemic in the US

2008 - 2009


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Epidemic in Georgia


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All Respiratory InfectionsUniversity Health Center, UGA

2005 - 2009

Feb 2005Feb 2006

Feb 2007

Feb 2008

Aug 2009

Aug 2007

Aug 2006Aug 2005Aug 2008

R Forehand, MD

Medical Director UHC


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0

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6/17/09 6/24/09 7/1/09 7/8/09 7/15/09 7/22/09 7/29/09 8/5/09 8/12/09 8/19/09 8/26/09 9/2/09 9/9/09 9/16/0

Diagnosis=Influenzaor

ILI

Influenza-like IllnessUGA University Health Center

through Sep 16, 2009

First H1N1 rRT-PCR positive patient

occurred on June 17,2009

R Forehand, MD


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Influenza Transmission

Transmitted through respiratory route

Cough, sneezing, talking

Transmitted through direct and indirect contact with

respiratory secretions Caring for patient

Inanimate objects

Infectious for up to 24 hours before ill

30% of cases asymptomatic

Incubation period 1 4 days


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Reproductive Rate (R0)

Estimated R0:

1918 Influenza R0 = 1.8 - 4

1957 Influenza R0 = 1.9 - 2.1

1968 Influenza R0 = 1.89

How transmissible is this virus likely to be?

Epidemic : R0 >1

Epidemic H1N1: R0 = 1.4 at UGA


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UGA H1N1 Projected Epidemic


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Influenza Virus - Morphology

Virus are usually roughly spherical Viral genome is composed of eight segments of

single-stranded RNA

Each of which has to be present for successful

replication

Segmented genome is enclosed within an outer

lipoprotein envelop

Antigenic protein called matrix protein (MP 1)

which lines the inside of the envelope and is

chemically bound to the RNA

The envelop contains two highly important glycoproteins (protruding spikes) which

form a characteristic halo of projections

Neuraminidase (NA) of which there are 9 major antigenic types

Haemagglutinin (HA) of which there are 15 major antigenic types

http://www.chemsoc.org/exemplarchem/entries/2001/sanderson/immunology.htm


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Overview of Proteins HA, mediates binding to cellular receptors (sialic acid moieties)

NA, cleaves sialic acid, having a critical role in progeny virus release from host cells

M2, is an ion channel involved in viral entry and exit

The virus encodes two proteins excluded from virions: NS1 and PB1-F2.

NS1, blocks innate antiviral responses and contributes to viral gene expression

PB1-F2, functions remain to be firmly established; it appears to have an important

role in pathogenicity


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Haemagglutinin trimeric protein

Copyright Linda M Stannard, 1995.

The envelop contains two types of protruding spikes,which form a characteristic halo of projections

i. Neuraminidase (NA) of which there are 9 major

antigenic types

ii. Haemagglutinin (HA) of which there are 13

major antigenic types

Haemagglutinin functions during attachment of the

virus particle to the membrane of epithelial cells in the

upper respiratory tract

Lipoprotein bilayer envelope makes the virus rather

unstable susceptible to heat, drying, detergents and

solvents


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Life cycle of influenza virus - replication


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Antigenic Drift antigenic evolution natural mutations

occur that result in the accumulation ofamino acid substitutions in HA

RNA polymerase error-prone, no

proofreading function

the immune response to HA is critical in

virus neutralization

Small changes in HA can lead to loss ofimmune recognition

HA (side view) HA (top view)


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Influenza Virus Natural host

Three type of influenza viruses A,B and C

only types A and B cause

widespread outbreaks

Infuenza A viruses are classified

into subtypes based on antigenic

differences between their two

surface glycoproteins

Heamagglutinin (H1 H15)

Neuraminidase (N1 N9)

Only H1-3,and N1,N2 have

established stable lineages in human

populations since 1918

Only 1 subtype of NA and 1 of HA

are identified for influenza B viruses

Nicholson et al. 2003. The Lancet; Vol. 362


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Antigenic Shift

Antigenic shift, occurs when an entirely

new virus is introduced into the human

population from the animal reservoir.

Reassortment of viral genes occurs when

there are multiple viruses that infect the

same cell.

Segments from each of the viruses infecting

the same cell can be mixed and matched and

repackaged into new viruses


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Swine: The Viral Mixing Pot

S i l f I fl Vi


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Source: Bean B, et al. JID 1982;146:47-51

Survival of Influenza VirusSurfaces and Affect of Humidity & Temperature*

Hard non-porous surfaces 24-48 hours Plastic, stainless steel

Recoverable for > 24 hours

Transferable to hands up to 24 hours

Cloth, paper & tissue

Recoverable for 8-12 hours

Transferable to hands 15 minutes

Viable on hands


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Influenza Diagnosis Viral Culture

Respiratory secretions collected within 3 days of illness

Cultured in embryonated eggs or tissue culture

Viral growth occurs in 2 3 days

Viral typing

Antigen Detection Methods Enzyme-linked immunosorbent assay (ELISA) or immunofluorescence

Available in clinical setting within hours

Sensitivity and specificity low

Antibody Detection Methods 4-fold increase in antibodies in serum

ELISA, complement fixation tests, hemagglutination

inhibition


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Immunity to Swine Flu-H1N1

The immune response comprised of innateand adaptive immunity.

Innate immune system plays an essentialrole in limiting viral replication in the firstdays of infection.

Adaptive immunity includes the inductionof B and T cell responses.

Three IAV proteins elicit robust antibodyresponses during infection: NP, NA and HA.

M2 is less immunogenic, but is a promisingtarget for cross-protective vaccination,since its short extracellular target domain ishighly conserved


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Neutralizing Antibody Titers Against the 2009 Pandemic H1N1 Virus among

Serum Donors, According to Birth Decade (18802000)


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Hayden, F. G. N Engl J Med 2006;354:785-788

M2 Blockers (Adamantanes)


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Hayden, F. G. N Engl J Med 2006;354:785-788

M2 Blockers


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Moscona, A. N Engl J Med 2005;353:1363-1373

Neuraminidase Inhibitors


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Influenza Reporting

WHO and National Respiratory and Enteric VirusSurveillance System

125 collaborating laboratories

US and international

122 Cities Mortality Reporting system Count deaths from pneumonia

State and Territorial Epidemiologist

Sporadic, Regional, Widespread

US Sentinel Physicians Surveillance Network 260 physicians throughout the country voluntarily

report cases to CDC

Global Distribution of Reported Cumulative Laboratory Confirmed Cases of


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Global Distribution of Reported Cumulative Laboratory Confirmed Cases of

Swine Influenza A(H1N1) by Countries, June 11, 2009 (14:00 GMT)

Source: WHO


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Influenza Vaccines

Inactivated influenza A vaccine Contains 4 different strains

H1N1 (2009), H1N1 (1977), H3N2, Influenza B

Virus is killed Cannot transmit, mutate, or cause influenza in vaccinee

Injected, intramuscular

Single dose in adults, 2 does to children(immunologically nave)

Given annually


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Influenza Vaccines

Live-attenuated vaccines Contains 4 strains of influenza virus

H1N1, H3N2, Influenza B

Cold adapted live influenza viruses Infect humans

Produce infection (temperature regulated) but not

disease (attenuated)

Theoretical concerns about mutation to virulent virus

Nasal inhalation

Given annually


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Vaccine Efficacy

Vaccine Efficacy Comments

Inactivated 70 90% Laboratory

confirmed illness

Cold-adapted Live 85 92% Influenza

Vaccine Efficacy

- Underlying population studied

- Match between vaccine and circulating virus

- Type of endpoint used, e.g., laboratory-

confirmed disease, influenza-like illness,

hospitalization, death


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Influenza Vaccine

Vaccine Production

Virus grown on chorioallantoic membranes of

embryonated eggs

Allantoic fluids are ultracentrifuged to collect viralparticles

Inactivated by formaldehyde and processed to

ensure stability and sterility Titre antigen levels and assess antigenicity


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Influenza Vaccine

Vaccine Production

In January each year, WHO reviews the circulating

strains of influenza in Northern and Southern

hemispheres

Data collected through global surveillancenetwork

The most likely epidemic strain(s) are selected

Seed lots of virus are distributed to manufacturers Manufacturers produce vaccine in eggs and test,

license, package, and distribute by October

250 million doses produced each year


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Influenza Vaccine

Vaccine Strategy

Old approach to vaccinate children and adults,

those at greatest risk for severe or disease

complications New approach to vaccinate those who are likely to

transmit infection including healthy children and

adults.

See current CDC Website

http://www.cdc.gov/mmwr/pdf/rr/rr5908.pdf


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Vaccine Efficacy

A single 15g dose of

unadjuvanted 2009 H1N1

vaccineresulted in titers

of 1:40 or more on

hemagglutination-

inhibitionassay in 96.7%

of adult subjects

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Vaccine Efficacy

Reverse cumulative-

distribution curves of

antibody titers in serum

samples obtained on day

21 after first dosing of 7.5

g of MF59-adjuvanted

vaccine

40


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Signature Features of Influenza Pandemics

Three previous influenza pandemics

A/H1N1 from 1918 -1919, A/H2N2 from

1957 -1963, and A/H3N2 from 1968 1970

Past pandemics were characterized by:

1) shift in the virus subtype

2) shift of the highest death rates in elderly

to younger populations

3) successive pandemic waves

4) higher transmissibility than that of

seasonal influenza

5)differences in impact in differentgeographic regions


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Prevention: Exposure/Infection

Social Interventions:

Restrictions on travel A 90%, 99%, or 99.9% reduction in

imported infections might delay the peakof a pandemic by 1.5, 3, or 6 weeksrespectively

Border Restrictions unlikely to delay

spread of virus more then 2-3 weeksunless more than 99% effective(Ferguson, N. et al. 2006. Nature.)

School or workplace closures

School closure during the peak of apandemic can reduce peak attack rates

by up to 40%, but has little impact onoverall attack rates

(Ferguson, N. et al. 2006. Nature.)

Restrictions of Mass Public Gatherings


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Unconventional and Untested

Approach to Influenza Protection

influenza introduction

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