A Brief Update of Global Situation and Response to Pandemic Influenza A(H1N1) 2009 Wenqing Zhang MD Global Influenza Programme WHO HQ THE 3rd MEETING OF

A Brief Update ofGlobal Situation and

Response to Pandemic Influenza A(H1N1) 2009

Wenqing Zhang MDGlobal Influenza Programme WHO HQTHE 3rd MEETING OF NATIONAL INFLUENZA CENTRES IN THE WESTERN PACIFIC AND

SOUTH EAST ASIA REGIONS18-20 August 2009 • Beijing China

Global Influenza Programme

Pandemic preparedness and response phases

Pandemic preparedness and response phases


Pandemic requirements Pandemic requirements

Global outbreak of disease

Emergence of a novel influenza virus– With efficient human-to-human transmission– No immunity in human population

! Now we are in a pandemic !

Phase 6 is characterized by community level outbreaks of the same virus in at least 1 other country in a different WHO region.

Designation of this phase would indicate that a global pandemic is under way


Timeline of pandemic A(H1N1) 2009Timeline of pandemic A(H1N1) 2009

April 12: an outbreak of influenza-like illness in Veracruz, Mexico reported to WHO

April 15-17: two cases of the new A(H1N1) virus infection identified in two southern California counties in U.S.A.

April 23: novel influenza A (H1N1) virus infection confirmed in several patients in Mexico.

April 24: HQ SHOC activated (first TC at 4:00 AM with Mexico)

April 26: IHR Emergency Committee convened and WHO declares a Public Health Emergency of International Concern

April 27: WHO increases pandemic alert phase from 3 to 4 and concludes geographic Containment not feasible

April 29: WHO raises pandemic alert phase from 4 to 5

June 11: WHO declares pandemic phase 6 (spread to 2 WHO regions)

In 9 weeks, all WHO 6 regions reporting cases of pandemic A(H1N1) 2009


WHO Responses WHO Responses

Emergency response rooms – mobilised – 24/7

Operations– Field teams– GOARN network activated

Situation monitoring and assessment– Development/update/distribution of laboratory diagnostic protocols and reagents– GISN intensive functioning – lab confirmation and virus characterization– Triage of information and follow up of alerts, coordination with Regions and National Focal Points (NFP)

Antiviral Taskforce– Oseltamivir stockpile distribution to regions and 72 priority countries (including Mexico)– Consultation with manufacturers

Technical guidance – Guidelines on surveillance, lab and diagnostic, infection control, health care management, pandemic response plan,

vaccines made available to the public– Analysis of available data, including modelling

Vaccine Taskforce – WHO recommendation on pandemic vaccine viruses and reassortant vaccine virus development– Regulatory response to pandemic– Broad consultation on issues related to the switch from seasonal vaccine to pandemic vaccine production– Broad efforts to improve global supply of pandemic vaccine

Communications


WHO Region

Cumulative total

Cases * Deaths

WHO Regional Office for Africa (AFRO) 591 1

WHO Regional Office for the Americas (AMRO) 102905 1274

WHO Regional Office for the Eastern Mediterranean (EMRO) 2346 7

WHO Regional Office for Europe (EURO) over 32000 53

WHO Regional Office for South-East Asia (SEARO) 11432 83

WHO Regional Office for the Western Pacific (WPRO) 28120 43

Total 177457 1462

Lab confirmed pandemic influenza A (H1N1) cases as of 6 Aug 2009

Lab confirmed pandemic influenza A (H1N1) cases as of 6 Aug 2009


Severity of the diseaseSeverity of the disease

Majority of cases show mild disease - resolves without treatment

Asymptomatic cases reported

So far overall severity falls within seasonal flu boundaries– Hospitalization and case fatality in young adults higher than

seasonal flu

CFR: < 1% of confirmed cases


Age groups of confirmed casesAge groups of confirmed cases

0%

5%

10%

15%

20%

25%

30%

35%

40%

0-9 10-19 20-29 30-39 40-49 50+

Age groups

Per

cen

t o

f ca

ses

Confirmed cases (Chile, EU and EFTA, Japan, Panama, Mexico)


Monitoring the viruses globally – Scientific, consistent

19 Apr – 1 Aug– A total of 73 countries– 61,742 positive specimens

• 35,758 - pandemic H1N1 (58%)• 4267 – seasonal H1N1• 7120 - H3N2 (12%)• 11,661 - A (subtype was not reported)• 2804 - B

Last reporting week– 5449 positive specimens

• 3898 - pandemic H1N1(72%)• 102 - seasonal H1N1• 992 - H3N2 (18%)• 428 - A (subtype was not reported) • 29 - B

Lab-based situation monitoring FluNet reporting





Number of specimens positive for influenza by subtypes (from 19 April to 1 August)

26

1

49

2015

11

43

7784

91 89 89 87

0

200

400

600

800

1000

1200

1400

1600

1800

17 (7, 42%) 18 (9, 43%) 19 (10, 45%) 20 (9, 44%) 21 (10, 45%) 22 (9, 40%) 23 (7, 37%) 24 (7, 37%) 25 (7, 31%) 26 (6, 30%) 27 (6, 30%) 28 (4, 5%) 29 (4, 5%) 30 (4, 5%) 31 (2, 3%)

Week number, 2009

Num

ber of

spe

cim

ens

posit

ive

for in

fluen

za

0

20

40

60

80

100

Seasonal A (H1) Seasonal A (H3)A (Not subtyped) B (Yamagata lineage)B (Victoria lineage) B (Lineage not determined)Pandemic A (H1N1) A (H5)Proportion of all influenza that were pandemic A (H1N1) 2009l

Southern hemisphere

More reporting from GISN in the coming weeks will allow better observation of the trend


Epidemiological situation (1)Southern hemisphere

Epidemiological situation (1)Southern hemisphere

Temperate areas passing through their winter season now.

This season, pandemic H1N1 has been the predominant influenza virus in nearly all of the temperate regions of southern hemisphere

– South Africa an exception

Rapid increases in cases of pandemic influenza early in their winter season. Now decreases in the numbers of people seeking care and being admitted to hospital.

Overall trends downward– Pandemic virus still circulating in these areas and spreading into areas not

affected earlier

South Africa– an early influenza season with H3N2 predominating. – When reaching its peak in early to mid June and began to decline, pandemic

influenza H1N1 appeared and has now become the dominant subtype


Epidemiological situation (2)Northern hemisphere and tropical areas

Epidemiological situation (2)Northern hemisphere and tropical areas

In temperate areas including North America and Europe

– Virus continues to spread to new areas – Overall trend downward

Tropical areas– Now increases, for example in tropical areas of Central and

South America and in South and South East Asia


Virological surveillanceGenetic characterization

Virological surveillanceGenetic characterization

Genetic make‐up not previously detected among viruses infecting either swine or human populations

So far, genetically all viruses analyzed in GISN are homologues to A/California/7/2009

PB2

PB1

PA

HA

NP

NA

MP

NS

Human infections with H1N1 triple

reassortants

PB2

PB1

PA

HA

NP

NA

MP

NS

Outbreak of the recent novel H1N1

Influenza

Classical Swine – North American Lineage

Eurasian Swine Lineage

Avian – North American Lineage

Seasonal H3N2

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

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

A/swine/Korea/CAS08/2005 H1N1 A/SW/MO/1877/01 H1N2 A/Swine/Korea/CY02/02 H1N2

A/SW/CO/17871/01 H1N2 A/duck/NC/91347/01 H1N2

A/Swine/North Carolina/98225/01 H1N2 A/Swine/North Carolina/93523/01 H1N2

A/swine/OH/511445/2007 H1N1 A/Ohio/01/2007 H1N1

A/Wisconsin/87/2005 H1N1 A/swine/Minnesota/00194/2003 H1N2

A/swine/Kansas/00246/2004 H1N2 A/swine/Korea/PZ14/2006 H1N2 A/swine/Korea/Asan04/2006 H1N2

A/Swine/Ohio/891/01 H1N2 A/Swine/Illinois/100084/01 H1N2

A/Swine/Indiana/9K035/99 H1N2 A/Wisconsin/10/1998 H1N1 A/Turkey/MO/24093/99 H1N2 A/Swine/Indiana/P12439/00 H1N2

A/swine/Guangxi/17/2005 H1N2 A/swine/Guangxi/13/2006 H1N2

A/California/05/2009 H1N1 A/California/06/2009 H1N1 A/Mexico/4482/2009 H1N1

A/California/09/2009 H1N1 A/California/04/2009 H1N1

A/California/07/2009 H1N1 A/Texas/04/2009 H1N1 A/Texas/05/2009 H1N1 A/Mexico/4486/2009 H1N1 A/Mexico/4108/2009 H1N1

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

A/Ohio/3559/1988 H1N1 A/swine/Ratchaburi/NIAH1481/2000 H1N1 A/Philippines/344/2004 H1N2

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

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

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

A/swine/Iowa/15/1930 H1N1 A/PuertoRico/8/34 H1N1

A/Washington/10/2008 H1N1 A/Brisbane/59/2007 H1N1

A/Solomon Islands/03/2006 H1N1 A/Florida/3/2006 H1N1 A/New Caledonia/20/1999 H1N1

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

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

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

A/swine/Denmark/WVL9/1993 H1N1 A/swine/Zhejiang/1/2007 H1N1

A/Swine/Spain/50047/2003 H1N1 A/swine/Spain/53207/2004 H1N10.05

HA gene

Recent novel H1N1 OutbreakHighest NT Blast

Human cases of H1 SwineSeasonal H1

North American Swine

Eurasian Swine

Seasonal

North American

Avian


HI tests using post-infection ferret antisera, antigenically: – homogeneous – most closely related to A/California/7/2009(H1N1)v viruses– distinct from currently circulating seasonal influenza A (H1N1) viruses – similar to North American lineage triple-reassortant A (H1N1) swine

influenza viruses• represented by A/Illinois/09/2007• circulated in pigs over the last 10 years in the USA, and occasionally infected humans

Viruses from severe cases do not show differences – genetically and antigenically

Virological surveillanceAntigenic characterization

Virological surveillanceAntigenic characterization


GISN continuous monitoring antiviral susceptibility – > 500 isolates and 180 clinical specimens tested

Neuraminidase Inhibitors– Resistant to Oseltamivir: 8 cases (4 from Japan, 1 each from Hong Kong,

Denmark, Canada and Singapore)• Cases in Denmark, Japan and Canada had received prophylactic treatment, while the

Hong Kong traveller returning USA had not been treated with oseltamivir. • All 8 cases did not have severe disease and all subsequently recovered. • Resistant viruses have not been detected in close contacts of these individuals. • Sensitive to Zanamivir

– Otherwise, mutations previously identified to confer resistance to oseltamivir or zanamivir not observed in the NA gene of the viruses characterized to date

• Sensitive to both these antiviral drugs

M2 Inhibitors– All viruses tested so far in GISN resistant to Admantine (Amantadine and

Rimantadine)

Virological surveillanceAntiviral susceptibility

Virological surveillanceAntiviral susceptibility


Pandemic vaccinesWHO recommendation on vaccine viruses

Pandemic vaccinesWHO recommendation on vaccine viruses

An A/California/7/2009-like virus – 26 May

The recommendation based on comprehensive analysis of available data from the WHO Global Influenza Surveillance Network and other sources

WHO, with its Network and other partners, continuously monitoring the evolution of the virus, reviewing the recommendation. Will update whenever needed


Pandemic vaccinesAvailability of vaccine virusesPandemic vaccinesAvailability of vaccine viruses

Reassortant viruses: 10– Classical

• NYMC-X179A and IVR-153 (from A/California/7/2009) – Reverse Genetics

• NIBRG-121 and NIBRG-121xp (from A/California/7/2009)• CBER-RG2 (from A/California/4/2009)• IDCDC-RG15 and IDCDC-RG20 (from A/Texas7/2009)• NIBRG-122 (from A/Engliand/195/2009)• IDCDC-RG18 (from A/Texas/5/2009 and A/New York/18/2009)• IDCDC-RG22 (from A/New York/18/2009)

Wild type viruses– A/California/7/2009– A/California/4/2009– A/Texas/5 /2009– A/England/195/2009– A/New York/18/2009

All above vaccine viruses are available from WHO CCs and ERLs – by 6 Aug a total of 418 shipments made– http://www.who.int/csr/disease/swineflu/guidance/vaccines/candidates/en/index.html


Pandemic vaccinesGrowth property of vaccine viruses

Pandemic vaccinesGrowth property of vaccine viruses

NIBRG-121xp – recently available – By NIBSC through extended passages in eggs – A 2-3 fold increase in yield in preliminary evaluation

• Similar to normal seasonal H1N1 component– Further evaluation ongoing by manufacturers, ERLs and CCs

Other reassortant vaccine viruses– X-179A better than others– 30- 50% compared to normal seasonal H1N1 component– Comparable to poor growing B component

Wild type vaccine viruses– A/California/7/2009 – similar to normal seasonal H1N1 component in Vero-

cell


General preparation process– Prepared independently by 4 ERLs (CBER/FDA, NIBSC, NIID and

TGA)– Reference antigen – large amount of bulk antigen from

manufacturers• Egg-based for testing of egg-based vaccines• Cell-based for testing of cell-based vaccines

– Reference antiserum – from sheep by ERLs or for ERLs by local manufacturers

• Small amount of purified HA – Distribution

• Exchange among ERLs immediately for calibration• Once available, antigen and antisera distributed to requesting manufactures

in parallel to the calibration among ERLs• Requests directly to originating ERLs

Pandemic vaccinesVaccine potency reagents (1)Pandemic vaccinesVaccine potency reagents (1)


First available pandemic vaccine reagents:– First available reference antigen

• Egg-based (NYMC X-179A)• Prepared by CSL and labelled by TGA• 9000 vials filled and capped from Jul 8• Distribution started Jul 10-15 to requesting manufactures

– First available reference antiserum• A/california/7/2009• First lot prepared by NIBSC on Jun 24 – 2000 vials• Limited ongoing distribution: 50 vials per ERL; 30 vials per manufacturers upon request• Larger distribution from subsequent larger lots

Subsequent development– Reference antigen

• Egg-based by NIBSC – calibration value this week• Egg-based by CBER – calibration value sent last week• Cell-based by NIBSC – to be filled next week

– Antisera• Both CBER and TGA recommend to source from NIBSC

Pandemic vaccinesVaccine potency reagents (2)Pandemic vaccinesVaccine potency reagents (2)


Total annual capacity

(106 doses)

2008 Northern hemisphere production

(106 doses)

2009 Southern hemisphere production

(106 doses)

2009 planned Northern

hemisphere production

(106 doses)

Companies A 560.1 (64%) 299.6 103.0 322.8

Companies B 316.4 (36%) 170.4 9.5 170.0

All companies 876.4 470.0 112.5 492.8

Companies A (n=7): with capacity to produce at least 2.106 doses of new H1N1 vaccine / weekCompanies B (n=18): other smaller companies

Source: WHO survey

Seasonal vaccine production capacity

Pandemic vaccinesVaccine production capacity (1)Pandemic vaccines

Vaccine production capacity (1)


All potential influenza A(H1N1) Vaccine Manufacturers

All potential influenza A(H1N1) Vaccine Manufacturers


95 M410 M

2,459 M

4,918 M

.0 B

1.0 B

2.0 B

3.0 B

4.0 B

5.0 B

6.0 B

Weekly Monthly 6-month Annual

Assumptions / Methodology

Survey sent to 36 potential influenza vaccine manufacturers

– 100% response rate– All 21 current influenza vaccine

producers responded– 26 manufacturers that intend to

produce pandemic vaccines– Includes LAIV and one recombinant

vaccine capacity

Survey assumes– 1:1 H1N1 to seasonal yields– Most dose sparing formulation for

each manufacturer– Use of full production capacity

H1N

1 d

ose

s

Estimated H1N1 Vaccine CapacityAt 1:1 yields, most dose-sparing formulation, full capacity

TimeframeSource: WHO survey

Pandemic vaccine production capacity

Pandemic vaccinesVaccine production capacity (2)Pandemic vaccines

Vaccine production capacity (2)


SAGE recommend in July:– Three different objectives to develop vaccination strategy:

• Protect the integrity of the health-care system and the country's critical infrastructure; • Reduce morbidity and mortality; and • Reduce transmission of the pandemic virus within communities.

SAGE suggested the following groups for consideration (countries need to determine their order of priority based on country-specific conditions):

– Pregnant women – Above 6 months with one of several chronic medical conditions – Healthy young adults of 15 to 49 years of age – Healthy children – Healthy adults of 50 to 64 years of age and – Healthy adults of 65 years or above.

Important of post-marketing surveillance of the highest possible quality and rapid sharing of the results of immunogenicity and post-marketing safety and effectiveness studies

Pandemic vaccinesVaccination strategy

Pandemic vaccinesVaccination strategy


SummarySummary

The pandemic situation is evolving

Efficient response: global, multisectoral, collaborative, timely sharing …– Well-coordinated global efforts is key

Pandemic influenza – at its core a virus problem– Concerns of co-circulating seasonal and pandemic viruses– Concerns of continuous H5N1 infections in human, and its implication– Concerns of unpredictable mutation of the pandemic virus

Challenges on timely available effective vaccines and improvement of vaccine supply

More information is needed to fully understand the virus, the disease and efficacy of various measures

– Human knowledge on influenza limited– Respect science

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A Brief Update of Global Situation and Response to Pandemic Influenza A(H1N1) 2009 Wenqing Zhang MD Global Influenza Programme WHO HQ THE 3rd MEETING OF