The WHO Vaccine Strain Selection Process: Review of the ... · PDF fileThe WHO Vaccine Strain...

The WHO Vaccine Strain Selection

Process: Review of the Evidence

Jacqueline Katz, PhD

Influenza Division

Centers for Disease Control and Prevention

WHO Collaborating Center for Surveillance,

Epidemiology and Control of Influenza

WHO Vaccine Strain Selection Process for

Seasonal Influenza

Complex, year around virological surveillance is

conducted by the Global Influenza Surveillance and

Response System (GISRS)

– WHOCCs, NICs, ERLs, H5 Reference Laboratories

Two annual WHO Consultations for N. and S.

Hemisphere (Feb and Sept, respectively)

– Review, analyse and summarize data and make

recommendation within 3 days

– Communicated to Industry and summary posted on WHO

website

WHO’s Global Influenza Surveillance and

Response Network

National Influenza Centers (NICs)

( 140 Laboratories in 110 Countries)

World Health Organization

(Geneva)

Vaccine Producers

International Collaborating Centers

(Atlanta, London, Melbourne, Tokyo

and Beijing) • Isolate influenza viruses

• Identify viruses and send to International

Collaborating Center(s)

• Collect epidemiologic information

• Collect information for the Weekly Epidemiological

Record and WWW for distribution

• Make annual vaccine recommendations

• Analyze influenza viruses received

• Provide data for annual vaccine

strain recommendations

• Prepare and distribute candidate

vaccine strains and reagents

0

200

400

600

800

1000

40 42 44 46 48 50 52 02 04 06 08 10 12 14 16 18 20

H1N1

B

H3N2

Week

Time is a Major Constraint Respiratory Specimens Positive for Influenza in the US and

Vaccine Selection, 2007-08

Vaccine production

WHO Influenza Vaccine Virus Recommendations

February - N. Hemisphere & September - S. Hemisphere

• Are there new antigenic variants?

• Antigenic (HAI and VNT) and genetic characterization

• Are new variants spreading?

• Monitoring influenza disease activity and virus isolation

• Are current vaccines able to induce antibodies to the new variants?

• Serological evaluation of vaccinated individuals

• Are any new variants useful for vaccine production?

• Substrate for virus isolation (egg isolates required now)

• High growth reassortants needed

Considerations for New Vaccine Recommendations

A(H3N2) Viruses Sept 2011 – Feb 2012

GISRS: Percentage of influenza viruses by subtypes (From 4 September 2011 – 28 January 2012)

Data source: FluNet, (www.who.int/flunet), Global Influenza Surveillance and Response System (13 February 2012)

http://www.who.int/flunet

Number of A(H3N2) viruses detected by GISRS

0

1,000

2,000

3,000

1 5 9 13 17 21 25 29 33 37 41 45 49 53

Week of the year

2010 2011 2012

Data source: FluNet, (www.who.int/flunet), Global Influenza Surveillance and Response System (13 February 2012)

http://www.who.int/flunet

H3N2 viruses characterized during the past

2 Northern Hemisphere seasons

0

100

200

300

400

500

600

CDC CNIC NIID NIMR VIDRL

Sept 2010 to Jan 2011 Sept 2011 to Jan 2012

Hemagglutinin Focused Virological Surveillance

• Virus entry and infection

– Host restriction / species barrier

• Main antigenic target for immune system

• Antigenic drift on H3 seasonal influenza strains

– Mutation rate random but selective

– ~3.4 amino acid residues per year

• Genetic changes may effect:

– Antigenic drift

– Strucure and receptor specificity

– Immune escape/Vaccine Effectiveness

Glycosylation

RBS

Carbohydrates

Antigenic drift

TM

WHO test of choice

Reliable, relatively simple and inexpensive

Fast: A few hours to perform

Many viruses can be tested relatively quickly

Based on the binding of antibodies to HA

Proper virus titration is essential for analysis

Requires characterized set of reference viruses and ferret

antisera

Hemagglutination Inhibition (HAI) Test

No

inhibition

HA

inhibition

TM

Antigenic Characterization Using HAI Testing:

Older Example of a New Antigenic Variant

Date

REFERENCE ANTIGENS BR/10 UR/716 VIC/208PERTH/16 HK/26560 collected

1 A/BRISBANE/10/2007 1280 1280 40 20 80 26/06/07

2 A/URUGUAY/716/2007 1280 2560 20 20 20 6/21/2007

3 A/VICTORIA/208/2009 80 10 1280 320 1280 6/2/2009

4 A/PERTH/16/2009 10 <10 320 320 640 4/7/2009

5 A/HONG KONG/26560/2009 10 <10 320 160 640 9/18/2009

REFERENCE FERRET ANTISERA

HAI titers demonstrate a 2-way ≥8-fold reduction in titers between

Brisbane/10/2007-like and Perth/16/2009-like viruses

HI Reactions of Influenza A(H3N2) Viruses

(Guinea Pig Red Blood Cells; 2-12-12)

BRIS/ 10 PERTH/ 16

1 5

HA Date

REFERENCE ANTIGENS BR/ 10 PER/ 16 BA/ 5071 S.AS/ 3 TH/ 277 OR/ 9 MT/ 5 NZ/ 28 BR/ 299 KY/ 5 group collected Passage

1 A/ BRISBANE/ 10/ 2007 320 40 80 80 80 40 80 40 20 80 02/ 06/ 07 E2/ E2

2 A/ PERTH/ 16/ 2009* 20 640 160 640 320 160 640 320 320 640 1 04/ 07/ 09 E3/ E2

3 A/ BANGLADESH/ 5071/ 2011* 80 80 320 640 320 320 160 320 320 320 3B 05/ 19/ 11 CX/ C2

4 A/ SOUTH AUSTRALIA/ 03/ 2011* 40 160 320 320 320 160 160 160 320 320 3C 06/ 10/ 11 C2/ C2

5 A/ CHIANG RAI/ 277/ 2011* 20 80 20 160 320 80 80 160 80 80 3C 09/ 20/ 11 C1/ C2

6 A/ OREGON/ 09/ 2011 40 80 40 160 160 160 160 160 160 160 3C 10/ 27/ 11 M1/ C2

7 A/ MONTANA/ 05/ 2011 5 80 40 160 160 80 320 160 160 320 5 03/ 02/ 11 E2

8 A/ CHRISTCHURCH/ 28/ 2011* 5 160 160 320 320 160 320 640 320 640 6 08/ 05/ 11 E5/ E2

9 A/ BRISBANE/ 299/ 2011 40 160 80 80 160 160 320 160 160 80 6 08/ 13/ 11 C4/ C2

10 A/ KENTUCKY/ 05/ 2011* 10 80 20 160 160 80 160 320 160 160 6 11/ 04/ 11 X1/ C2

TEST ANTIGENS

11 A/ MISSISSIPPI/ 02/ 2012 10 320 320 1280 1280 640 320 320 640 640 01/ 12/ 12 C2

12 A/ TEXAS/ 13/ 2012 80 320 160 640 640 320 640 640 640 640 01/ 18/ 12 C2

13 A/ CALIFORNIA/ 01/ 2012 40 80 40 160 160 80 160 160 320 160 5 01/ 04/ 12 C2

14 A/ COLORADO/ 05/ 2012 20 80 20 160 160 160 160 80 160 80 01/ 11/ 12 C1

15 A/ FLORIDA/ 02/ 2012 20 80 80 160 160 160 160 160 320 160 6 01/ 09/ 12 C1

16 A/ IOW A/ 04/ 2012 20 80 40 160 160 80 80 160 80 160 01/ 13/ 12 C2

17 A/ KENTUCKY/ 05/ 2011 5 80 80 160 160 160 320 80 160 80 6 11/ 04/ 11 NC2E5

18 A/ OREGON/ 01/ 2012 80 80 160 320 160 160 160 160 320 320 01/ 04/ 12 M1/ C2

19 A/ TEXAS/ 06/ 2012 40 80 80 160 320 160 320 320 320 320 6 01/ 05/ 12 M1/ C1

20 A/ W YOMING/ 01/ 2012 20 80 40 160 160 80 160 160 160 80 6 01/ 10/ 12 C2

21 A/ IOW A/ 01/ 2012 20 40 20 80 160 80 80 160 160 160 3B 01/ 03/ 12 C2

22 A/ IOW A/ 05/ 2012 10 40 40 80 160 80 80 80 160 80 01/ 18/ 12 C2

23 A/ NEBRASKA/ 01/ 2012 20 40 40 80 80 80 80 80 80 80 3B 01/ 14/ 12 C1

24 A/ TEXAS/ 10/ 2012 10 40 40 80 80 80 80 80 80 80 3C 01/ 16/ 12 C2

25 A/ VIRGINIA/ 03/ 2012 20 40 20 160 160 80 160 80 80 80 3C 01/ 23/ 12 M1/ C1

26 A/ W ASHINGTON/ 05/ 2012 10 40 40 80 80 80 40 80 160 80 01/ 11/ 12 C1

27 A/ CALIFORNIA/ 09/ 2012 10 20 20 40 80 40 40 80 80 40 01/ 18/ 12 C1

28 A/ BRITISH COLUMBIA/ 4791/ 2011 40 80 40 320 160 160 160 160 160 80 3B 12/ 13/ 11 X1/ C1

29 A/ SASKATCHEW AN/ RV0019/ 2011 40 80 40 160 160 160 80 80 80 80 3B 12/ 20/ 11 X1/ C1

30 A/ ASTRAKHAN/ 65/ 2011 160 320 640 640 640 640 640 640 640 640 3B 12/ 15/ 11 C3/ C1

31 A/ ENGLAND/ 258/ 2011 20 80 40 160 160 80 160 160 160 40 3C 11/ 07/ 11 S1S1/ C1

32 A/ BRISBANE/ 299/ 2011 IVR-164 5 640 640 1280 1280 320 2560 640 320 640 3C REASS EX/ E1

33 A/ BRISBANE/ 299/ 2011 5 320 320 640 640 320 640 640 640 640 3C 08/ 13/ 11 E5/ E4

34 A/ HONG KONG/ 4913/ 2011 20 40 20 80 160 80 80 160 80 80 3C 11/ 29/ 11 C3/ C1

35 A/ KENYA/ 7503/ 2011 20 160 80 320 320 160 320 320 320 640 11/ 22/ 11 C1/ C1

Sequence in GISAID *Serology antigen

3 6

VIC/ 208


Influenza A(H3N2) Isolates Characterized by CDC

U.S.A. North

America Europe Asia

Cent/So America

Africa, Australia,

New Zealand

Total (%)

September 2010 – February 2011

A/Perth/16/2009-like* 743 21 3 105 61 28 961 (65%)

A/Perth/16/2009-like** 332 34 2 54 33 12 467 (32%)

A/Perth/16/2009-like (low)*** 38 6 1 2 2 49 (3%)

Total 1477

March 2011 – August 2011

A/Perth/16/2009-like* 190 3 1 43 163 17 417 (76%)

A/Perth/16/2009-like** 58 1 2 21 46 128 (23%)

A/Perth/16/2009-like (low)*** 3 1 4 (1%)

Total 549

September 2011 – February 2012

A/Perth/16/2009-like* 134 1 2 16 10 3 166 (37%)

A/Perth/16/2009-like** 160 26 10 13 209 (46%)

A/Perth/16/2009-like (low)*** 57 4 1 8 6 76 (17%)

Total 451

Total 1715 70 12 275 325 80 2477 * < 4-fold low to vaccine strain Preliminary Data 02/23/2012 ** = 4-fold low to vaccine strain *** ≥ 8-fold low to vaccine strain

HA genetic group 1 6 HA DATE

VIRUSES PER/16/09 S. AUS/03/11 TH/277/11 KY/05/11 group COLL.

1 A/PERTH/16/2009 2560 1280 640 1280 1 2009-04-07

2 A/BANGLADESH/5071/2011 320 1280 640 1280 3 2011-05-19

3 A/UTAH/12/2011 320 1280 640 1280 3 2011-11-06

4 A/S. AUSTRALIA/03/2011 640 2560 1280 2560 3 2011-06-10

5 A/CHIANG RAI/277/2011 640 2560 640 1280 3 2011-09-20

6 A/VICTORIA/361/2011 160 320 320 320 3 2011-10-24

7 A/KENTUCKY/05/2011 320 1280 640 1280 6 2011-11-04

8 A/BRISBANE/299/2011 640 2560 1280 1280 6 2011-08-13


3

Virus Neutralization: Plaque Reduction Assay

for Influenza A(H3N2) Viruses (CDC)

Evolutionary Relationships Among Influenza A (H3N2) Hemagglutinin (HA) Genes, 2011-12

Current Northern

Hemisphere

Vaccine Strain

LR- Low Reactor to

A/Perth/16/2009

(≥ 8 fold)

# Egg Isolate

F - CDC Reference

Antigen

$- CDC Serology

Antigen

October 2011

November 2011

December 2011

January 2012

February 2012

A/Christchurch/28/2011 Aug # F $ aus A/Brisbane/299/2011 IVR-164 #

A/Brisbane/299/2011 Aug F $ A/Iowa/19/2010 Dec # F

A/Iowa/19/2010 Dec F A/Georgia/01/2011 Feb F

usafsam A/Alaska/1250/2012 Jan A/Wisconsin/01/2012 Jan

usafsam A/Puerto Rico/1216/2012 Jan A/Texas/06/2012 Jan LR A/Chile/64/2011 May F

A/Kentucky/05/2011 Nov F $ A/Kentucky/05/2011 Nov # LR

cnic A/Guangdong-Jinping/1334/2011 Sep A/California/01/2012 Jan LR

A/Perth/10/2010 # F A/Montana/05/2011 Mar # F

A/Ontario/RV0064/2011 Jan F usafsam A/Florida/633/2011 Dec

A/Alabama/04/2011 Dec aus A/Victoria/8/2010 Aug #

A/Rhode Island/01/2010 Jan # F nimr A/Baden-Wurttemberg/1/2012 Jan

A/Pennsylvania/15/2011 Nov spn A/Valencia/S01030G/2012 Jan

A/Washington/01/2012 Jan A/Idaho/02/2012 Jan

A/Saskatchewan/RV0019/2011 Dec LR usafsam A/Japan/1307/2012 Jan usafsam A/Korea/1078/2012 Jan usafsam A/Ohio/1325/2012 Feb

A/British Columbia/4791/2011 Dec LR H3N2 HA Consensus 2011-12

A/Bangladesh/5071/2011 May F $ A/Nebraska/01/2012 Jan LR

A/Utah/12/2011 Nov F A/California/34/2011 Nov LR

nimr A/Finland/190/2011 Nov A/Texas/10/2012 Jan

usafsam A/Illinois/1263/2012 Jan A/Oregon/09/2011 Oct F

A/South Australia/03/2011 Jun F $ A/Victoria/361/2011 Oct # F $

A/Hong Kong/4913/2011 Nov LR A/Chiang Rai/277/2011 Sep LR F $

cnic A/Hunan-Yueyanglou/1320/2011 Oct A/Nonthaburi/279/2011 Sep LR

A/Minnesota/25/2011 Dec nimr A/Berlin/3/2012 Jan

usafsam A/Korea/1222/2012 Jan usafsam A/Kyrgyzstan/1407/2012 Jan

A/Shanghai-Luwan/1440/2011 Nov LR A/Victoria/208/2009 Jun #

A/Alabama/03/2011 Apr A/Perth/16/2009 # F $

A/Victoria/210/2009 Jun # F A/Victoria/210/2009 X-187 # F

cnic A/Shanghai-Luwan/188/2011 Feb # A/Chungbuk/644/2011 Nov

niid A/Incheon/668/2011 Dec

0.002

6

5

3B

3C

3A

4

2

1

7

A/V

icto

ria/2

08/2

00

9-lik

e

A/P

erth

/16/2

00

9

-like

K158N

N189K

T212A

D53N

Y94H

I230V

E280A

K173Q

I361R

A198S

N312S S45N

ADD GLY

T48I

D487N

N144D

LOSS GLY

N145S

D487N

V223I N145S

Q33R

N278K

N145S

S45N

ADD GLY

S199A

I217V

E62K

N144K

LOSS GLY

K158N

N189K I260M

R261Q

P162S S9G N171K

F193S Y195Y/N

Recent Group 3

180° rotation

S214I

T212A

A198S

K62E

K144N* L183H

V223I

N312S

Q33R

N278K

S45N

T48I

H3 Hemagglutinin Structure

Antigenic Cartography: NIMR

H3 HA gene

evolution

Current Northern

Hemisphere

Vaccine Strain

LR- Low Reactor to

A/Perth/16/2009

(≥ 8 fold)

# Egg Isolate

F - CDC Reference

Antigen

$- CDC Serology

Antigen

October 2011

November 2011

December 2011

January 2012

February 2012

Evolutionary Relationships Among Influenza A (H3N2) Neuraminidase Genes, 2011-12

A/Kentucky/05/2011 Nov F LR $ A/Kentucky/05/2011 Nov # LR

cnic A/Guangdong-Jinping/1334/2011 Sep A/Iowa/19/2010 Dec F

A/Iowa/19/2010 Dec # F A/Perth/10/2010 # F

A/Georgia/01/2011 Feb F A/Ontario/RV0064/2011 Jan F

niid A/Hiroshima-C/53/2011 Oct A/Montana/05/2011 Mar # F

A/Chile/64/2011 May F A/California/01/2012 Jan LR

A/Texas/06/2012 Jan LR A/Christchurch/28/2011 Aug # F $

aus A/Brisbane/299/2011 IVR-164 # A/Brisbane/299/2011 Aug F $

aus A/Victoria/8/2010 Aug # A/Rhode Island/01/2010 Jan # F

A/Oregon/09/2011 Oct F A/Washington/01/2012 Jan

A/Idaho/02/2012 Jan A/Saskatchewan/RV0019/2011 Dec LR

A/Utah/12/2011 Nov F A/California/34/2011 Nov LR

H3N2 NA Consensus 2011 niid A/Kobe/241/2011 Oct

A/Bangladesh/5071/2011 May F $ A/British Columbia/4791/2011 Dec LR

A/Nebraska/01/2012 Jan LR nimr A/Finland/190/2011 Nov

A/Texas/10/2012 Jan A/Victoria/361/2011 Oct # F $

A/South Australia/03/2011 Jun F $ A/Shanghai-Luwan/1440/2011 Nov LR

A/Hong Kong/4913/2011 Nov LR cnic A/Hunan-Yueyanglou/1320/2011 Oct A/Minnesota/25/2011 Dec

A/Chiang Rai/277/2011 Sep LR F $ nimr A/Berlin/3/2012 Jan

A/Nonthaburi/279/2011 Sep LR A/Alabama/04/2011 Dec

spn A/Valencia/S01030G/2012 Jan A/Pennsylvania/15/2011 Nov

nimr A/Baden-Wurttemberg/1/2012 Jan A/Chungbuk/644/2011 Nov niid A/Incheon/668/2011 Dec

cnic A/Shanghai-Luwan/188/2011 Feb # A/Perth/16/2009 # F $

A/Victoria/210/2009 Jun # F A/Victoria/210/2009 X-187 # F

A/Alabama/03/2011 Apr A/Wisconsin/15/2009 Jun # F

A/Victoria/208/2009 Jun #

0.002

3A

3B

3C

1 AND 2

5 AND 6

4

7 D147N

D151/D/N/V/G/S/A

(N ADD GLY)

I215V

D127N

I307M

L338F

N342D

N402D

LOSS GLY

L81P

D93G

N402D

LOSS GLY

S367N

ADD GLY

K369T

I464L

WHO information meeting on influenza vaccine composition for northern hemisphere 2012-2013 23 February 2012 • EB Room WHO HQ Geneva

HI ANTIBODY RESPONSES TO THE A(H3N2) COMPONENT –

GMT ratio plots

Data from NIBSC

H3N2 - A/Victoria/361/11Unadjusted GMT Ratios with Confidence Limits

Reference strain A/Victoria/210/09

country AU CH JP UK US

GM

T R

atio

0.062

0.125

0.25

0.5

1

2

4

8

16

Panel

AU_A AU_E CH_A CH_E CH_P JP_A JP_E UK_A UK_E US_A US_E

H3N2 - A/Christchurch/28/11Unadjusted GMT Ratios with Confidence Limits



GM

T R

atio

0.062

0.125

0.25

0.5

1

2

4

8

16

Panel


H3N2 - A/Kentucky/5/11Unadjusted GMT Ratios with Confidence Limits



GM

T R

atio

0.062

0.125

0.25

0.5

1

2

4

8

16

Panel


H3N2 - A/Brisbane/299/11Unadjusted GMT Ratios with Confidence Limits



GM

T R

atio

0.062

0.125

0.25

0.5

1

2

4

8

16

Panel


H3N2 - A/Victoria/362/11Unadjusted GMT Ratios with Confidence Limits



GM

T R

atio

0.062

0.125

0.25

0.5

1

2

4

8

16

Panel


Influenza A(H3N2) Virus Summary (Sept. 2011- Jan. 2012)

Influenza A(H3N2) viruses circulated in many countries during this period

A(H3N2) viruses analyzed from were antigenically and genetically

heterogeneous

An increasing proportion of viruses showed reduced reactivity with ferret

serum against A/Perth/16/2009-like viruses and higher titers with antisera

against A/Vic/361/2011 reference virus in HI and PRMN assays

The HA genes of most recent H3N2 viruses fall in genetic groups 3 and 6

Vaccines containing A/Perth/16/2009-like antigens stimulated anti-HA

antibodies of lower titers against recent A(H3N2) viruses than the vaccine

virus

The A(H3N2) component recommendation for the 2012-2013

(N. Hemisphere) influenza season was: A/Vic/361/2011-like virus

Conclusions

• GISRS Surveillance for vaccine strains selection is a continual and complex process • Collection of scientific evidence in a limited time frame for decision making • Evidence focused on antigenic characterization of HA

• Supported by genetic and human serology data • Contemporary H3N2 viruses

• Problems with growing in eggs • Receptor-binding changes that may influence HAI results • Increased use of neutralization assays

• New approaches are needed and may include: • Cell based vaccines • Broader spectrum of vaccine candidates • Reverse genetics vaccine viruses

• Influenza Division, CDC

• WHO COLLABORATING CENTERS:

• London

• Melbourne

• Tokyo

• Beijing

• Essential Regulatory Laboratories

• University of Cambridge

• National Influenza Centers

• Other laboratories participating in GISRS

Acknowledgements

The WHO Vaccine Strain Selection Process: Review of the ... · PDF fileThe WHO Vaccine Strain...

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