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
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)
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)
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
REFERENCE FERRET ANTISERA
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
REFERENCE FERRET ANTISERA
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
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/Kentucky/5/11Unadjusted 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/Brisbane/299/11Unadjusted 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/Victoria/362/11Unadjusted 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
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