INFLUENZA DIVISION

June 26, 2009June 26, 2009

Nancy J. Cox, Ph. D.Nancy J. Cox, Ph. D.Director, Influenza DivisionDirector, Influenza Division

Director, WHO Collaborating Center for Influenza Reference Director, WHO Collaborating Center for Influenza Reference and Researchand Research

Influenza Division, NCIRDInfluenza Division, NCIRDCenters for and PreventionCenters for and Prevention

Laboratory Characterization of Pandemic H1N1 Viruses and

Vaccine Development

The contents of this presentation are those of the presenter anddo not necessarily reflect the views of CDC

INFLUENZA DIVISION

Novel Influenza A (H1N1) Cases by Weekly Report Date as of 19 JUN 2009 (n=)*21,449

*Data for week ending 19 June 2009.Dates not available for 92 cases.

0 0 5 19

915

2,1441,879 1,710

3,289 3,164

4,638

0

500

1000

1500

2000

2500

3000

3500

4000

4500

500028

-Mar

4-Apr

11-A

pr

18-A

pr

25-A

pr

2-May

9-May

16-M

ay

23-M

ay

30-M

ay

6-Jun

13-Ju

n

Week Ending Date

Cas

es (n

)

First US CaseApril 15

RT-PCR kits to US labs 4/29 – 5/3

Kits to 233 US and 386International labs by 6/12

Vaccine candidates shipped to manufactures

INFLUENZA DIVISION

Reassortant Events Among Swine Influenza Viruses (SIV) in North America

1930

Slide courtesy of Dr. Amy Vincent, NADC, USDA

INFLUENZA DIVISION

Avian-human pandemic

reassortantvirus

Avianvirus

Humanvirus

Avian reassortant

virus

Avianvirus

Reassortmentin swine

Reassortmentin humans

Possible Pathways for Generation Pandemic Influenza Viruses

INFLUENZA DIVISION

Host and lineage origins for the gene segments of the 2009 A(H1N1) virus (Garten, et al Science 2009)

INFLUENZA DIVISION

A/Ohio/07/2009 H1N1A/New York/18/2009 H1N1A/California/05/2009 H1N1A/Texas/04/2009 H1N1A/Mexico/4108/2009 H1N1A/California/04/2009 H1N1

A/Swine/Indiana/P12439/00 H1N2A/swine/Guangxi/13/2006 H1N2

A/Wisconsin/10/1998 H1N1A/Wisconsin/87/2005 H1N1

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

A/swine/Korea/CAS08/2005 H1N1A/Iowa/CEID23/2005 H1N1

A/swine/Iowa/00239/2004 H1N1A/swine/Memphis/1/1990 H1N1

A/swine/Ratchaburi/NIAH1481/2000 H1N1A/Ohio/3559/1988 H1N1A/swine/Indiana/1726/1988 H1N1

A/Philippines/344/2004 H1N2A/swine/Iowa/2/1985 H1N1

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

A/swine/Ontario/4/1981 H1N1A/New Jersey/8/1976 H1N1

A/swine/Wisconsin/2/1970 H1N1A/swine/Wisconsin/1/1957 H1N1

A/swine/Iowa/15/1930 H1N1A/swine/Jamesburg/1942 H1N1

A/Minnesota/01/2009 H1N1A/Brisbane/59/2007 H1N1

A/Solomon Islands/03/2006 H1N1A/New Caledonia/20/1999 H1N1

A/New York/630/1995 H1N1A/USSR/90/77 H1N1

A/Memphis/16/1983 H1N1A/Fort Worth/50 H1N1

A/Denver/57 H1N1A/Weiss/43 H1N1A/Puerto Rico/8/34 H1N1

A/South Carolina/1/18 H1N1

0.02

Phylogenetic Tree of Hemagglutinin H1: Swine vs. Seasonal

Seasonal H1

Swine H1

Novel H1N1 OutbreakHuman cases of swine H1Seasonal H1

(Garten, et al Science 2009)

INFLUENZA DIVISION

STRAIN DESIGNATION NJ/8/76 WI/10* IL/9* CA/07 MX/4108 NY/18 TX/15 AS/59A/NEWJERSEY/8/1976 640 10 10 5 5 5 5 5A/WISCONSIN/10/98* 80 1280 1280 640 640 640 640 5A/ILLINOIS/9(33304)/2007* 160 1280 5120 2560 2560 1280 1280 5A/California/07/2009 10 320 1280 2560 1280 1280 1280 5A/Mexico/4108/2009 10 320 1280 2560 640 640 640 5A/New York/18/2009 5 320 640 1280 640 640 640 5A/TEXAS/15/2009 FATAL 10 640 2560 5120 2560 1280 1280 5A/BRISBANE/59/07 5 5 5 5 5 5 5 160TEST ANTIGENSA/CALIFORNIA/7/09 X-179A 5 640 2560 2560 1280 1280 2560 5A/TEXAS/5/2009 XPR8-IDCDC RG15 5 640 1280 2560 1280 1280 1280 5Utah 249817 FATAL 5 160 1280 2560 1280 1280 1280 5Washington V19-4347 FATAL 5 160 1280 1280 640 640 640 5Arizona PV09124151 FATAL 5 320 1280 2560 2560 2560 2560 5Montana 723335 10 320 1280 1280 1280 1280 1280 5Maine VSP-001799 10 640 2560 2560 2560 2560 2560 5Nevada 1050 5 640 1280 2560 1280 1280 1280 5Utah 243727 5 640 1280 2560 1280 1280 1280 5A/NONTHABURI/102/09 10 640 2560 2560 2560 1280 2560 5Guatemala 450 5 320 1280 2560 1280 640 1280 5Colombia 330 5 640 2560 2560 2560 2560 2560 5El Salvador 351 5 320 1280 2560 1280 1280 1280 5Mexico/4593/2009 40 1280 2560 5120 2560 1280 2560 5A/AUCKLAND/1/2009 5 640 1280 2560 1280 640 1280 5A/ENGLAND/195/2009 10 640 2560 5120 1280 1280 2560 5

INFLUENZA DIVISION

Summary of Genetic and Antigenic Analyses

• The combination of gene segments of nH1N1 viruses had not been reported previously

• Reassortment had occurred between EA swine and NA swine lineage triple reassortant viruses

• No genetic markers for severe disease in viral genes detected yet

• Genetically and antigenically homogeneous suggesting a single introduction in humans

• Homogeneity made selecting a reference vaccine virus easy

• Passage in eggs at limit dilution to select viruses that grow to high titers in eggs can result in antigenic and genetic variation

INFLUENZA DIVISION

Surveillance for Influenza Antiviral Resistance United States as of 24 JUN 2009

Resistant Viruses, Number (%)

Resistant Viruses, Number

(%)Isolates tested (n)

Isolates tested (n)

Oseltamivir Zanamivir Adamantanes

Seasonal Influenza A (H1N1) 1010 1055

(99.5%) 0 (0) 1012 6 (0.6%)

Influenza A (H3N2) 187 0 (0) 0 (0) 187 187 (100%)

Influenza B 550 0 (0) 0 (0) N/A* N/A*Global Novel Influenza A

(H1N1)216 0 (0) 0 (0) 216 216 (100%)

*The adamantanes (amantadine and rimantadine) are not effective against influenza B viruses.

INFLUENZA DIVISION

Serum Cross-reactive Antibody Response to a Novel Influenza A(H1N1) Virus After Vaccination

with Seasonal Influenza Vaccines, MMWR May 2009

INFLUENZA DIVISION

Serum Cross-reactive Antibody Response to a Novel Influenza A(H1N1) Virus After

Vaccination with Seasonal Influenza Vaccines, MMWR May 2009

INFLUENZA DIVISION

Pathogenesis and Transmissibility of Swine-Origin Influenza A(H1N1) Viruses in Ferrets

• Compared with seasonal A(H1N1) influenza, two novel H1N1 viruses caused– Increased morbidity– Replicated to higher titers in lung tissue– Recovered from the intestinal tract of intranasally

inoculated ferrets

• Results suggest higher virulence of novel H1N1 compared to seasonal H1N1 in the ferret model

Maines, et al. Unpublished data 2009, in submission

INFLUENZA DIVISION

InocContact

Contact

Contact

Inoculated

Inoculated

Inoculated

Transmission Experimental DesignTransmission Experimental Design

Respirtory Droplet (RD) Direct Contact (DC)

Cont

Inoc Cont

Inoc Cont

Maines, et al. Unpublished data 2009, in submission

INFLUENZA DIVISION

Respiratory Droplet TransmissionRespiratory Droplet Transmissionof Novel Influenza A H1N1of Novel Influenza A H1N1

1

2

3

4

5

6

7

8

1 3 5 7 9 1 3 5 7 9 11days post exposure

log1

0 PF

U/m

L

Inoculated Contact

Seasonal H1N1

Novel H1N1

1

2

3

4

5

6

7

8

1 3 5 7 9 1 3 5 7 9 11days post exposure

log1

0 PF

U/m

L

Maines, et al. Unpublished data 2009, in submission

INFLUENZA DIVISION

Novel influenza A(H1N1) Transmission in Ferrets

• Novel H1N1 viruses exhibited less efficient respiratory droplet transmission in comparison to seasonal H1N1 virus– Transmission in only 4 of 6 droplet contact pairs– Infection delayed compared with seasonal H1N1

• Lack of efficient respiratory droplet transmission suggests additional virus adaptation in humans may be required to reach the high-transmissible phenotype observed with seasonal H1N1 or H3N2 viruses

Maines, et al. Unpublished data 2009, in submission

INFLUENZA DIVISION

Preliminary Secondary Attack Rate among Households of Index Confirmed and Probable H1N1

Cases in 124 Households—California and Texas

Cases ARI* ILI* Confirmed and Probable

Overall 17.6% (72/408)

8.1% (33/408)

3.9% (16/408)

By age**<18 years 19.5%

(34/174)12.1%

(21/174)6.9% (12/174)

>18 years 17.0% (38/224)

5.4% (12/224)

1.8% (4/224)

*Acute respiratory infection (ARI) is 2 of the following 4 signs and symptoms: fever or feverishness, cough, runny nose, sore throat; Influenza-like illness (ILI) is fever and either cough or sore throat**10 non-ill household members were excluded from this analysis because they did not have age recorded

Preliminary, unpublished data, CDC 2009

INFLUENZA DIVISION

Conclusions• Genetic and antigenic characterization of viruses, serologic assays,

animal models, and epidemiologic assessments all critical components for public health risk assessment– Substantial consistency between laboratory and epidemiologic

results– Suggest novel H1N1 may not be fully adapted to humans

• Epidemiologic and virologic surveillance are important for identification of future changes in – Antigenic characteristics– Transmission characteristics– Severity of disease– Antiviral resistance– Intensity (surge) in US cases

• Limited understanding of diversity of influenza viruses in pigs globally is a major gap in pandemic preparedness– USDA’s efforts to initiate surveillance should be supported and

encouraged by public health, putting “One Health” concept into action

– Ensuring virus sharing between public health, animal health, academia and industry key component of planning

INFLUENZA DIVISION

Key Questions Remaining for Effective 2009 H1N1 Response

• Timing of expected fall wave of 2009 H1N1 in the NH?• Timing and dosing for 2009 H1N1 monovalent vaccine, if

recommended, based on clinical trial data?• Target populations for 2009 H1N1 vaccine?• Will reassortment occur with o-resistant seasonal influenza

viruses or with H5N1 viruses?• How will antiviral drugs be used, assuming they are effective?• Effectiveness of non-pharmaceutical interventions?

INFLUENZA DIVISION

Acknowledgements• State and Local Health Departments• WHO’s Global Influenza Surveillance Network

– National Influenza Centers (esp. Mexico and Canada’s NICs)– WHO CCs– WHO RO and HQ

• Influenza Division Staff, CDC– Office of the Director

• Carolyn B. Bridges, Associate Director for Science• Dan Jernigan, Deputy Director• Michael Shaw, Associate Director for Laboratory Science

– Epidemiology and Surveillance Branch• Joe Bresee, Chief

– Immunology and Pathogenesis Branch• Jackie Katz, Chief

– Viral Surveillance and Diagnostics Branch• Alexander “Sasha” Klimov, Chief

– Molecular Genetics Branch• Ruben Donis, Chief

• CDC Novel H1N1 Responders in our Emergency Ops Center