1. 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 NATIONAL INFLUENZA CENTRES IN THE WESTERN PACIFIC AND SOUTH EAST ASIA REGIONS 18-20 August 2009 Beijing China

2. Global Influenza Programme Pandemic preparedness and response phases

3. Global Influenza Programme 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

4. Global Influenza Programme Timeline 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

5. Global Influenza Programme 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

6. Global Influenza Programme Cumulative total WHO Region DeathsCases* 1591 WHO Regional Office for Africa (AFRO) 1274102905 WHO Regional Office for the Americas (AMRO) 72346 WHO Regional Office for the Eastern Mediterranean (EMRO) 53over 32000 WHO Regional Office for Europe (EURO) 8311432 WHO Regional Office for South-East Asia (SEARO) 4328120 WHO Regional Office for the Western Pacific (WPRO) 1462177457Total Lab confirmed pandemic influenza A (H1N1) cases as of 6 Aug 2009

7. Global Influenza Programme Severity 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

8. Global Influenza Programme Age groups of confirmed cases Confirmed cases (Chile, EU and EFTA, Japan, Panama, Mexico)

9. Global Influenza Programme 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

10. Global Influenza Programme Lab-based situation monitoring FluNet reporting Southern hemisphere More reporting from GISN in the coming weeks will allow better observation of the trend

11. Global Influenza Programme 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

12. Global Influenza Programme 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

13. Global Influenza Programme Virological surveillance Genetic 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

14. 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 H1N1 0.05 HA gene Recent novel H1N1 Outbreak Highest NT Blast Human cases of H1 Swine Seasonal H1 North American Swine Eurasian Swine Seasonal North American Avian

15. Global Influenza Programme 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 surveillance Antigenic characterization

16. Global Influenza Programme 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 surveillance Antiviral susceptibility

17. Global Influenza Programme Pandemic vaccines WHO 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

18. Global Influenza Programme Pandemic vaccines Availability 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.htmlhttp://www.who.int/csr/disease/swineflu/guidance/vaccines/candidates/en/index.html

19. Global Influenza Programme Pandemic vaccines Growth 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

20. Global Influenza Programme 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 vaccines Vaccine potency reagents (1)

21. Global Influenza Programme 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 vaccines Vaccine potency reagents (2)

22. Global Influenza Programme Total annual capacity (10 6 doses) 2008 Northern hemisphere production (10 6 doses) 2009 Southern hemisphere production (10 6 doses) 2009 planned Northern hemisphere production (10 6 doses) Companies A560.1 (64%)299.6103.0322.8 Companies B316.4 (36%)170.4 9.5170.0 All companies876.4470.0112.5492.8 Companies A (n=7): with capacity to produce at least 2.10 6 doses of new H1N1 vaccine / week Companies B (n=18): other smaller companies Source: WHO survey Seasonal vaccine production capacity Pandemic vaccines Vaccine production capacity (1)

23. Global Influenza Programme All potential influenza A(H1N1) Vaccine Manufacturers

24. Global Influenza Programme 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 H1N1 doses Estimated H1N1 Vaccine Capacity At 1:1 yields, most dose-sparing formulation, full capacity Timeframe Source: WHO survey Pandemic vaccine production capacity Pandemic vaccines Vaccine production capacity (2)

25. Global Influenza Programme 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 vaccines Vaccination strategy

26. Global Influenza Programme Summary 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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