experience and lessons from pandemic...

Alexander Klimov, Ph.D., Sc.D.Alexander Klimov, Ph.D., Sc.D.Deputy Director, WHO Collaborating Center for InfluenzaDeputy Director, WHO Collaborating Center for Influenza

Influenza DivisionInfluenza DivisionNational Center for Immunization and Respiratory DiseasesNational Center for Immunization and Respiratory Diseases

Centers for Disease Control and PreventionCenters for Disease Control and Prevention

Experience and Lessons from Pandemic Response:

Review from WHO CCs

First Two Cases of 2009 H1N1 Collected Mar 31-Apr 1, USA (Identified Apr 15-17)

Collected Feb 24, Mexico (Identifies retrospectively)

WHO Global NIC Meeting, Hammamet, Tunisia 30 November 2010 - 3 December 2010

of 20

Swine, not avian From N. America, not South East

tr-H1N1, not highly pathogenic H5N1

Detection of First Cases of 2009 H1N1 -Tribute to Pandemic Preparedness:

H5N1, H7N7, H9N2, H7N2, H7N3, …

Severity, morbidity, mortality ?Methods for detection ?

Real time PCR? Rapid diagnostic tests?

BSL level ? Relation to seasonal H1N1 ?Relation to 1976 ?Vaccine ?Sensitivity to available antivirals ?

Questions that required immediate answers


of 20

WhatWhat’’s it name?s it name?As the outbreak evolved, so did its nameAs the outbreak evolved, so did its name

All of the following names/terms refer to theAll of the following names/terms refer to the2009 H1N1 Pandemic virus2009 H1N1 Pandemic virus

SwineSwine--Origin 2009 A(H1N1) Influenza virus (SOIV)Origin 2009 A(H1N1) Influenza virus (SOIV)Swine fluSwine flu

H1N1vH1N1vH1N1swlH1N1swl

2009 H1N12009 H1N1H1N1pdmH1N1pdm

LESSON LEARNED: Virus nomenclature should be updated

Severity, morbidity, mortality ?


of 20

Characteristics of 2009 H1N1 InfluenzaApril 15, 2009 to April 10, 2010

Cases61,000,000 (43M – 89M)

Hospitalizations274,000 (195K – 403K)

Deaths12,470 (8.9K – 19.3K)

0-4

5-24

25-4

9

50-6

4

≥65

Ap

pro

xim

ate

Rat

e p

er 1

00,

000

po

pu

lati

on

Number of Influenza-Associated Pediatric Deathsby Week of Death: 2007-08 season to present

0

5

10

15

20

25

30

35

20

07

-40

20

07

-46

20

07

-52

20

08

-06

20

08

-12

20

08

-18

20

08

-24

20

08

-30

20

08

-36

20

08

-42

20

08

-48

20

09

-01

20

09

-07

20

09

-13

20

09

-19

20

09

-25

20

09

-31

20

09

-37

20

09

-43

20

09

-49

20

10

-03

Week of Death

Nu

mb

er o

f d

eath

s

2007-08

88 Pediatric Deaths

2008-09

69 Pediatric Deaths

H1N1

337 Pediatric Deaths

4 – 5 times more than

prior seasons


of 20

LESSON LEARNED: Overall, pandemic cam be “mild”

However some groups can be at high risk

Methods of detection ?Real-time RT-PCR


of 20

CDC Real-Time RT-PCR “5 Targets” Assayand “Satellite” Assays

FDA approved“5 Target” rt-PCR Assay:

Influenza AInfluenza B

H1H3

H5 (Eurasian lineage)

A

A

LAIV

PB1

B

A

A

A

A

Sw N.Am.H1 HA, NP

(triple reassortant) H7 N.Am.

HA

H7 Eu

roHA

B/Vic

B/YamHA

H9

Asi

an

HA

1918HA

LESSON LEARNED: •Real time PCR for different subtypes is needed•“Risk assessment” for different potentially pandemic subtypes is desirable

FDA approved:Influenza AInfluenza B

H1H3

H1pdmH5 (Eurasian lineage)

H3sw?

H1av?

H9?H2?

H3can?

H7?H3av?


of 20

Specimens Received by CDC ID in 2009-10 (by Feb 08, 2010)(by Feb 08, 2010)

0

200

400

600

800

1000

1200

1400

Feb

Apr

Jun

Aug

Oct

Dec

Jan

Mar

May

Jul

Sep

Nov

Jan

Feb

B

H1

H3

H1pdm

Misc.


of 20

Diagnostic Testing of Suspect Specimens

• Shipping/receiving was complicated

• Priority ?

• Communication with epi

• Organization, data preparation, QC

• Reporting was time consuming and challenging

Enhanced Detection And Testing• Enhanced Surveillance

• Virologic surveillance – 7-10 fold increase in specimen submission

• Daily ILI, case reporting, mortality surveillance• PCR pan-H1N1 kits for testing

• Development at CDC, EUA at FDA, manufacture at ATCC, and ready to ship in ~ 2.5 weeks

• Distributed ~2500 rt RT-PCR kits for 2009 H1N1 detection• Domestic: >120 labs• DOD: 15 labs• International: >250 labs in 140 countries


of 20

Tuesday, April 28th , 2009Approval by FDA (Emergency Use Authorization) of CDC

rt-PCR Assay for Detection of 2009 Pandemic H1N1

Feb 2010: 2479 kits (i.e. ~2.5 million individual tests) for detectionof pandemic H1N1 distributed among:

• 156 domestic labs• 320 iInternational labs in 140 countries

LESSONS LEARNED: Algorithm for samples prioritization has to be developedDatabase system establishedSystem of reporting (additional trained staff and volunteers)Transparency in data exchangeCooperation with regulatory institutions (FDA) and industry for rapid production and distribution of reagents


of 20

Methods of detection ?Rapid Diagnostic Tests (RIDTs)

Sensitivity of Three Rapid Influenza Diagnostic Tests Compared To CDC rtRT-PCR CT Values*

*MMWR Aug 7, 2009 / 58(30);826‐829. CT = cycling time, or cycle threshold, required to detect the virus using PCR. Lower CT values indicate higher virus concentrations in the specimens tested.

Ct values

%


of 20

LESSONS LEARNED•RIDTs detect 2009 H1N1 viruses•Overall sensitivity of RIDTs is “sub-optimal”•Proper interpretation of RIDTs results depends upon on clear understanding of their limitations

•False positive results can occur•Rarely, but cross-reactivity with other respiratory agents can happen•Positive Predictive Value is high when influenza activity is high

Level of Bio-containment ?•Pandemic preparedness plans were prepared with HPAI H5N1 in mind

•BSL-3 was recommended by WHO at the beginning of the 2009 pandemic

No virus isolation by most NICsWHO CCs overfloaded by samplesDelays in sharing reference viruses withother labs and manufacturers

•Currently country authorities should determine the BSL level

LESSON LEARNED:Virus characteristics should play essential role in determining BSL level


of 20

A/California/04/09 2009712049Highest NT Identity by BlastHuman cases of H1 swineSeasonal H1

North American

Swine

Eurasian Swine

Seasonal

North American

Avian

A/swine/Iowa/00239/2004 H1N1A/Iowa/CEID23/2005 H1N1

A/Texas/14/2008 H1N1A/Iowa/01/2006 H1N1

A/swine/Korea/CAS08/2005 H1N1A/SW/MO/1877/01 H1N2

A/swine/Korea/CY02/02 H1N2A/SW/CO/17871/01 H1N2A/duck/NC/91347/01 H1N2

A/swine/North Carolina/98225/01 H1N2A/Ohio/01/2007 H1N1A/swine/OH/511445/2007 H1N1

A/Wisconsin/87/2005 H1N1A/swine/Minnesota/00194/2003 H1N2

A/swine/Kansas/00246/2004 H1N2A/swine/Korea/Asan04/2006 H1N2

A/swine/Korea/PZ14/2006 H1N2A/swine/Ohio/891/01 H1N2

A/swine/Illinois/100084/01 H1N2A/swine/Indiana/9K035/99 H1N2

A/Wisconsin/10/1998 H1N1A/Turkey/MO/24093/99 H1N2A/swine/Indiana/P12439/00 H1N2

A/California/04/2009 H1N1A/swine/Guangxi/13/2006 H1N2

A/swine/Guangxi/17/2005 H1N2A/swine/North Carolina/93523/01 H1N2

A/swine/Iowa/24297/1991 H1N1A/swine/Wisconsin/125/97 H1N1

A/Ohio/3559/1988 H1N1A/swine/Ratchaburi/NIAH1481/2000 H1N1A/Philippines/344/2004 H1N2

A/swine/Ratchaburi/NIAH550/2003 H1N1A/New Jersey/1976 H1N1

A/Wisconsin/301/1976 H1N1A/swine/Chachoengsao/NIAH587/2005 H1N1

A/swine/Chonburi/05CB1/2005 H1N1A/Thailand/271/2005 H1N1

A/swine/Iowa/15/1930 H1N1A/New Caledonia/20/1999 H1N1A/Florida/3/2006 H1N1

A/Solomon Islands/03/2006 H1N1A/Brisbane/59/2007 H1N1

A/Washington/10/2008 H1N1A/PuertoRico/8/34 H1N1

A/mallard/MD/161/2002 H1N1A/swine/Saskatchewan/18789/02 H1N1

A/mallard/Minnesota/Sg-00121/2007 H1N1A/duck/NY/13152-13/1994 H1N1A/duck/Italy/69238/2007 H1N1A/swine/Belgium/1/83 H1N1

A/swine/England/WVL14/1996 H1N1A/swine/England/WVL7/1992 H1N1

A/swine/Denmark/WVL9/1993 H1N1A/swine/Zhejiang/1/2007 H1N1A/swine/Spain/50047/2003 H1N1

A/swine/Spain/53207/2004 H1N1

0.02

Phylogenetic Tree of the H1 HA genePhylogenetic Tree of the H1 HA genePhylogenetic Tree of the H1 HA gene

Preliminary sequence analysis suggested swinebut different from previous US isolates

Relation to seasonal and 1976 H1N1 ?

Unprecedented Availability of 2009 H1N1 Gene Sequence Data

• Virus Genetic Characterization by CDC• > 1,720 genes sequenced from > 430 virus isolates

from 360 cases • 70 total genomes• Many more gene sequences and total viral genomes

contributed by laboratories globally• Search for direct ancestral viruses unsuccessful• “Un-sampled ancestry” for individual genes of 2009

H1N1 viruses from 9.2 - 17.2 years (Smith et al, Nature 2009)

• Precise nature of evolution and origin of 2009 H1N1 unlikely to be well defined due to lack of influenza surveillance in swine and other susceptible


of 20

STRAIN DESIGNATION NJ/8/76 WI/10 CA/07 MX/4108 NY/18 TX/15 AS/59

A/NEWJERSEY/8/1976 640 10 5 5 5 5 5

A/WISCONSIN/10/98 80 1280 640 640 640 640 5

A/CALIFORNIA/07/2009 10 320 2560 1280 1280 1280 5

A/MEXICO/4108/2009 10 320 2560 640 640 640 5

A/NEW YORK/18/2009 5 320 1280 640 640 640 5

A/TEXAS/15/2009 FATAL 10 640 5120 2560 1280 1280 5

A/BRISBANE/59/07 5 5 5 5 5 5 160

Relation to Seasonal and 1976 H1N1Antigenic Analysis

(Hemagglutination-Inhibition Test)

2009 H1N1 viruses are antigenically differentfrom seasonal H1N1 viruses as well as from 1976and recent classical triple reassortant swine viruses

April 15First caseIdentifiedA/California/4/2009

April 29First DiagnosticKits Shipped toState LabsCDC shares with WHO: Diagnostic Assay ; full genome sequencing strategy and primers

May 3First DiagnosticKits Shipped toWHO Network

May 23Vaccine StrainShipped toManufacturers

Late February–Early March First cases in Mexico

April 261st Egg isolate

A/California/07/2009

April 231st Full

genome

completed

Timeline of Reagents and Vaccines


of 20

Initial Panel of Pandemic H1N1 Vaccine Initial Panel of Pandemic H1N1 Vaccine Viruses Distributed to Vaccine ManufacturersViruses Distributed to Vaccine Manufacturers

Virus Institution Method HA & NA from Genotype

IDCDC-RG15

CDC Reverse genetics A/Texas/05/2009 6:2

X-179A NYMCClassical reassortant

A/California/07/2009 5:3

NIBRG-121 NIBSC Reverse genetics A/California/07/2009 6:2

IVR-153 CSL Classical reassortant

A/California/07/2009 5:2:1

• Virus shipments started May 26-27, 2009

• ~1 month after person-to-person transmission was confirmed

Antigenic cartography of HAI assays:Antigenic cartography of HAI assays:very little change in antigenicity between waves very little change in antigenicity between waves

Green - A/California/7/2009Blue - April 2009 to August 2009Red - September 2009 to January 2010


of 20

LESSONS LEARNED•Close cooperation between WHO, WHO CCs, NICs, FDA, other regulatory institutions and manufacturers from the very beginning is essential for quick development of pandemic vaccines

Antiviral Treatment of Novel H1N1 InfluenzaAntiviral Treatment of Novel H1N1 Influenza

Drug Amantadine Rimantadine Zanamivir Oseltamivir

Target M2 protein M2 protein Virus/cell release

Virus/cell release

Sensitivity/Resistance

Resistant Resistant Susceptible Susceptible*

* Resistant mutants isolated from patients treated with oseltamivir have been documented


of 20

Resistance to NA Inhibitors Resistance to NA Inhibitors OseltamivirOseltamivir

(CDC data)(CDC data)

Ntested

Resistant (%)(H275Y)

Virus Isolates 3863 28 (0.7%)

Clinical specimens* 3707 40 (1.1%)

Totals 7570 68 (0.9%)

Lessons Learned• Delay with diagnosis of first cases in Mexico• Sensitive and specific diagnostic rapid assays

(including rapid diagnostic tests) for diagnosisinfluenza are highly desirable;

• Holes in surveillance• Geographic (Asia, Africa and South America)• Animal-Human interface

• Early in the outbreak: lack of standardized guidanceon priority testing groups, specimens recommendedresulted in overwhelming testing demand

••DDevelopment of new drugs as well as rapid tests fordetection of drug resistant mutants are needed• Chance of acquiring and transmiting dual antiviralacquiring and transmiting dual antiviral

resistant mutantsresistant mutants


of 20

LESSONS LEARNED•Rapid development of resistance to M2 blockers in H3N2 viruses and to oseltamivir in seasonal (pre-pandemic) H1N1 viruses•Comprehensive surveillance to existing drugs is necessary•New drugs are needed

SummarySummary• Identification of the virus in a short time frame• Pandemic preparedness over the last several years

was essential for rapid detection of first 2009 H1N1 cases

• Molecular testing (Diagnostic reagents created for North Diagnostic reagents created for North American swine triple reassortants needed only small American swine triple reassortants needed only small modificationsmodifications)– Reagents for antigenic analysis– Surveillance for drug resistance – Reverse genetics for vaccine development

• Early and open notification about the first 2 cases of H1N1 in California

•• Increased surveillance (including surveillance for Increased surveillance (including surveillance for drug resistance) drug resistance)

•• Increased highIncreased high--throughput for sequencingthroughput for sequencing


of 20

SummarySummary•• Unprecedented international cooperation, opennessUnprecedented international cooperation, openness

and free sharing:and free sharing:•• Isolates (Isolates (924 vials of influenza A(H1N1)pdm reference

viruses including vaccine candidate viruses were sent to 224 nat’l and internat’l labs and vaccine manufactures

•• Tests systems (~2,500 to ~480 labs worldwide)Tests systems (~2,500 to ~480 labs worldwide)•• Reagents, ProtocolsReagents, Protocols•• Vaccine candidatesVaccine candidates

•• Currently circulating H1N1pdm viruses remainCurrently circulating H1N1pdm viruses remainantigenically and genetically similar to viruses antigenically and genetically similar to viruses circulated at the beginning of the pandemiccirculated at the beginning of the pandemic

Lessons Learned

• Delay with diagnosis of first cases in Mexico• Sensitive and specific diagnostic rapid assays

(including rapid diagnostic tests) for diagnosisinfluenza are highly desirable;

• Holes in surveillance• Geographic (Asia, Africa and South America)• Animal-Human interface

• Early in the outbreak: lack of standardized guidanceon priority testing groups, specimens recommendedresulted in overwhelming testing demand

• “Internal genes cassett” of swine triple reassortant• viruses is highly viable•• Surveillance, surveillance and surveillanceSurveillance, surveillance and surveillance

•• More virulent mutants can appearMore virulent mutants can appear


of 20

Becky Garten Steve LindstromBo Shu

Virus Surveillance and Diagnosis Branch, Influenza Division, CDC

AcknowledgementsAcknowledgements2009 pandemic H1N1 virus DISCOVERES:

Influenza Division, CDC, Atlanta, USAWHO Collaborating Centers for Influenza

London, UKMelbourne, AustraliaTokyo, JapanBeijing, ChinaSt. Jude Hospital, Memphis, USA

National Influenza CentersDivision of Virology, NIBSC, UKCenter for Biologics Evaluation and Research, FDA, USANew York Medical College, Valhalla, NY, USA

AcknowledgementsAcknowledgements


of 20

THANK YOU !


of 20

experience and lessons from pandemic...

Documents