Influenza Seasonal and Pandemic

EPID 8500

Lessons Learned form

Past Pandemics

First outbreaks March 1918 in Europe, USA

Highly contagious, but not deadly Virus traveled between Europe/USA on troop ships Land, sea travel to Africa, Asia Warning signal was missed

August, 1918 simultaneous explosive outbreaks 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, secondary bacterial 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

Lessons Learned form

Past Pandemics
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 nontraditional groups 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 in second wave

Public health interventions delay, but do not stop pandemic spread

Quarantine, travel restriction show little effect
Does not change population susceptibility Delay spread in Australia later milder strain causes infection there

Temporary banning of public gatherings, closing schools potentially effective in case of severe disease and high mortality Delaying spread is desirable
Fewer people ill at one time improve capacity to cope with sharp increase in need for medical care

Timeline of Emergence
Influenza A Viruses in Humans
Reassorted Influenza virus (Swine Flu)
1976 Swine Flu Outbreak, Ft. Dix

H1 Avian Influenza

H9

H7 H5

H5
H1 H3 H2 H1
1918
Spanish Influenza H1N1

1957
Asian Influenza H2N2

1968
Hong Kong Influenza H3N2

1977
Russian Influenza

1997

2003

2009

1998/9

Swine Influenza A(H1N1)

Mexico Epidemic Curve Confirmed, by Day
As of June 09, 2009

Total Number of Confirmed Cases = 6,241*

Suspension of Non-essential Activities School Closure
400

400

School Open

385

No. of Confirmed Cases

350
309

300
262

290 270

250 200 150

Epidemiological Alert
12 2 18 6

221

224 2 17 2 14 19 9 2 0 1 17 6

16 8 15 8 14 8 12 8 12 7 12 6 112 90 92 85 76 71 69 65 75 61 5959 52 50

100
76

77

50
6 7 7 8 4 1 0 0 0 1 12 1 1 1 12 2 4 3 2 0 2 3 5 3 3 2 8 3 1 3 4 141510 1014

31 22

41 37 36

33 31 29 25 20 8

16 4

Day
*NOTE: 54 confirmed cases not included

Source: Secretaria de Salud, Mexico

Influenza Epidemic in the US 2008 - 2009

Epidemic in Georgia

20

40

60

80

100

120

160

140

R Forehand, MD Medical Director UHC

Aug 2005 Feb 2005 Aug 2006 Feb 2006

All Respiratory Infections

University Health Center, UGA 2005 - 2009

Aug 2007 Feb 2007 Aug 2008 Feb 2008

VISIT DATE -8/17/05 9/11/05 10/6/05 10/31/05 -12/20/05 1/17/06 2/11/06 3/8/06 4/5/06 4/30/06 5/31/06 7/7/06 8/13/06 9/8/06 10/3/06 10/29/06 11/26/06 1/2/07 1/28/07 2/23/07 3/23/07 4/18/07 5/14/07 6/18/07 7/24/07 8/24/07 9/19/07 10/17/07 11/12/07 12/11/07 1/18/08 2/13/08 3/11/08 4/6/08 5/1/08 6/4/08 7/11/08 8/20/08 9/15/08 10/10/08 11/8/08 12/8/08 1/14/09 2/10/09 3/10/09 4/6/09 5/2/09 6/5/09 7/13/09 8/15/09 9/10/09

Aug 2009

R Forehand, MD

Influenza-like Illness
UGA University Health Center through Sep 16, 2009

80

70

60

Diagnosis = Influenza or ILI

50

40

30

First H1N1 rRT-PCR positive patient occurred on June 17,2009

20

10

0 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

9/16/09

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

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

UGA H1N1 Projected Epidemic

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

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

Haemagglutinin trimeric protein

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
Copyright Linda M Stannard, 1995.

Lipoprotein bilayer envelope makes the virus rather unstable susceptible to heat, drying, detergents and solvents

Life cycle of influenza virus - replication

Antigenic Drift
antigenic evolution natural mutations occur that result in the accumulation of amino 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 of immune recognition
HA (side view) HA (top view)

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

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

Swine: The Viral Mixing Pot

Survival of Influenza Virus

Surfaces 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 <5 minutes only at high viral titers

Potential for indirect contact transmission

Humidity 35-40%, Temperature 28C (82F)

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

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

Immunity to Swine Flu-H1N1

The immune response comprised of innate and adaptive immunity. Innate immune system plays an essential role in limiting viral replication in the first days of infection. Adaptive immunity includes the induction of B and T cell responses. Three IAV proteins elicit robust antibody responses during infection: NP, NA and HA. M2 is less immunogenic, but is a promising target for cross-protective vaccination, since its short extracellular target domain is highly conserved

Neutralizing Antibody Titers Against the 2009 Pandemic H1N1 Virus among Serum Donors, According to Birth Decade (18802000)

M2 Blockers (Adamantanes)

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

M2 Blockers

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

Neuraminidase Inhibitors

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

Influenza Reporting
WHO and National Respiratory and Enteric Virus Surveillance 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 Swine Influenza A(H1N1) by Countries, June 11, 2009 (14:00 GMT)

Source: WHO

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

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

Vaccine Efficacy
Vaccine Efficacy Comments

Inactivated
Cold-adapted Live

70 90%
85 92%

Laboratory confirmed illness Influenza

Vaccine Efficacy - Underlying population studied - Match between vaccine and circulating virus - Type of endpoint used, e.g., laboratoryconfirmed disease, influenza-like illness, hospitalization, death

Influenza Vaccine
Vaccine Production
Virus grown on chorioallantoic membranes of embryonated eggs Allantoic fluids are ultracentrifuged to collect viral particles Inactivated by formaldehyde and processed to ensure stability and sterility Titre antigen levels and assess antigenicity

Influenza Vaccine
Vaccine Production
In January each year, WHO reviews the circulating strains of influenza in Northern and Southern hemispheres Data collected through global surveillance network 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

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

Vaccine Efficacy
A single 15g dose of unadjuvanted 2009 H1N1 vaccine resulted in titers of 1:40 or more on hemagglutinationinhibition assay in 96.7% of adult subjects

39

Vaccine Efficacy
Reverse cumulativedistribution curves of antibody titers in serum samples obtained on day 21 after first dosing of 7.5 g of MF59-adjuvanted vaccine

40

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 different geographic regions

Prevention: Exposure/Infection
Social Interventions:
Restrictions on travel A 90%, 99%, or 99.9% reduction in imported infections might delay the peak of a pandemic by 1.5, 3, or 6 weeks respectively Border Restrictions unlikely to delay spread of virus more then 2-3 weeks unless more than 99% effective
(Ferguson, N. et al. 2006. Nature.)

School or workplace closures School closure during the peak of a pandemic can reduce peak attack rates by up to 40%, but has little impact on overall attack rates (Ferguson, N. et al. 2006. Nature.) Restrictions of Mass Public Gatherings

Unconventional and Untested Approach to Influenza Protection