1. Update on Pandemic Vaccine Development 3 rd WHO WPRO/SEARO NIC Meeting 18-20 August, 2009, Beijing Masato Tashiro, MD., PhD. Director, WHO Collaborating Centre for Reference and Research on Influenza NIID, Tokyo Update on Pandemic Vaccine Development 3 rd WHO WPRO/SEARO NIC Meeting 18-20 August, 2009, Beijing Masato Tashiro, MD., PhD. Director, WHO Collaborating Centre for Reference and Research on Influenza NIID, Tokyo

2. State-of-the-Art H5N1 Vaccine Developments and Clinical Trials

3. 1.H5N1 vaccines-specific issues # Wild-type virus: highly pathogenic Vaccine seeds to be modified to low pathogenic # Low immunogenic in humans A high dose of antigens required # Antigenic divergence among clades Less cross-immunity # Adjuvant is needed and beneficial Better immunogenicity Antigen sparing Cross protection

4. 2.Vaccine formulations (20~ clinical trials) a. Inactivated split vaccines # Plain split vaccines (egg-grown) [Sanofi] Less immunogenic 90  g HA x 2 shots insufficient in young adults 45  g  HA x 2 shots similar with elderly and children

5. a. Inactivated split vaccines (cont.) # Adjuvanted split vaccines (egg-grown) Alum less beneficial [Japan, Sanofi, Novartis] MF-59 (oil-in-water emulsion) [Novartis] 3.8; 7.5~  g x 2 shots efficient in adults, elderly, children AS03 (oil-in-water emulstion) [GSK] 3.8~  g x 2 shots efficient in adults, elderly,

6. b. Inactivated whole virus vaccines # Plain whole virus vaccine Vero cell-grown, wild-type virus [Baxter] 3.8; 7.5~  g x 2 shots efficient in adults and children (Alum rather reduced immunogonicity) # Adjuvanted whole virus vaccines (eggs) Alum phosphate [Omni] 6  g x 2 shots in adults Alum hydroxide [Japan, Sinovac, CSL, Microgen] 5~15  g x 2 shots in adults

7. c. Live attenuated vaccines # ca A/Ann Arbor/6/60 [MedImmune] Less immunogenic due to restricted replication of reassortant H5N1 in URT d. Component vaccines [Protein Science] # rHA protein produced in silk worm by a baculovirus vector Priming effect to a different clade virus more than 10 years

8. 3. Routes of immunization # i.m. local reactions less obvious # s.c. local reactions more visible # intradermal Antigen retention for a long period No ~ remarkable benefit # Skin patch; jet injectors New devices in trials # intranasal ca-LAIV Inactivated vaccines Mucosal adjuvants (TLR3 agonist) Applicating devices

9. 1) Standardization of neutralizing test and harmonization of expression of antibody titers 2) Correlation between serum Ab titers and protective effect? 3) Establishment of evaluation criteria for efficacy of pandemic vaccines in clinical trials 4) Duration of serum antibodies? 5) Cross-protection against different Clades and subclades as well as antigen-drifted viruses? 6) Children, pregnancy, elderly, high risk groups? 7) Prime-boost effects by different formulation vaccines? Remaining issues of H5N1 vaccines

10. 4. Cross reactive immunity Serum antibodies cross-reactive with different clades and subclades of H5N1 viruses were induced by; Alum-adjuvanted whole virus vaccines New adjuvant-mixed split vaccines Vero cell-grown, wild-type whole virus vaccine Stockpiling of pre-pandemic vaccines and prime-boost strategies became realistic.

11. A(H1N1)2009 pandemic  A(H1N1)pdm virus Low pathogenic (different from H5N1) No genetic markers for severe disease (different from H5N1 and Spanish flu) Higher virulence in animal models than seasonal flu Not yet well-adapted to humans (less transmissible) Genetically and antigenically homogeneous among isolates worldwide, similar to a reference virus; A/California/07/2009(H1N1)pdm No genetic and phenotypic difference for fatal cases. Distinguishable from seasonal viruses and seasonal vaccines will not be effective.

12. A(H1N1)2009 pandemic  Disease burden and social impact In most cases, mild illness similar to seasonal flu Moderate disease burdens (particularly in high risk groups), but far less than H5N1 Impact on health care systems in several countries Not yet real pandemic (herald wave ~1 st wave) But, bigger outbreaks likely in the near future. Resistant to admantanes. Sensitive to NA inhibitors. But drug-resistant virus has appeared sporadically.

14. Pandemic vaccine viruses (WHO) Reassortant viruses: 10 – Classical NYMC-X179A and IVR-153 (from A/California/7/2009) – Reverse Genetics NIBRG-121 (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/England/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

15. Recent development of high yield vaccine viruses NIBRG-121xp – 13 passaged of NIBRG-121 in eggs – A 2.5-fold increase in yield in preliminary evaluation Similar to normal seasonal H1N1 component – Further evaluation ongoing by manufacturers, ERLs and CCs X-181 series; new reassortants of X-179A, – 30- 50% compared to normal seasonal H1N1 component Similar to poor growing B component – 2-fold increase in yield in eggs Wild type vaccine viruses – A/California/7/2009 – similar to normal seasonal H1N1 component in Vero-cell To change or to remain the vaccine seed virus? Less efficient recovery of viral proteins of current vaccines

17. 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 Vaccine potency reagents (1)

18. Available pandemic vaccine reagents: – First available reference antigen Egg-based (NYMC X-179A) Prepared by CSL and labelled by TGA (9000 vials) – First available reference antiserum A/California/7/2009 (egg) First lot prepared by NIBSC (2000 vials) Limited ongoing distribution: Larger distribution on going Subsequent development – Reference antigen Egg-based by NIBSC, CBER and NIID Vero cell-based by NIBSC – Antisera CBER and TGA recommend to source from NIBSC A/California/7/2009 (egg) by NIID Vaccine potency reagents (2)

21. Clinical studies of A(H1N1)2009 pandemic vaccines (1) 1. Conventional seasonal vaccine formulation (Egg-grown split vaccine without adjuvant) To answer three primary questions (USA, CSL, others): Safety in healthy people of various ages? To determine a vaccine dose and vaccination times needed to induce a protective immune response? Safety and efficacy of simultaneous administration with seasonal influenza vaccine?

22. 2. Adjuvanted vaccines with reduced antigens AS03 [GSK] MF59 [Novartis] Mock-up dossier of H5N1 pre-pandemic vaccines [EMEA] 3. Tissue culture cell-derived vaccines Vero cell-derived [Baxter] 4.Cold-adapted live vaccine [MedImmune] Clinical studies of A(H1N1)2009 pandemic vaccines (2)

23. Increase influenza vaccine production and supply  IFMPA to increase production capacity of trivalent vaccine from 800 million to1 billion doses by 2012 (2007).  Global pandemic vaccine production capacity to increase to ~4.5 billion in 2010 (2008)  WHO provided grants to 6 countries for establishing pilot production of H5N1 vaccine (Brazil, India, Indonesia, Mexico, Thailand, and Vietnam), and technical assistance to others (2007).  WHO has prepared international stockpile of H5N1 vaccines (2008) – Target of 150 million doses 50 million : rapid containment operations 100 million : maintain essential services in low/middle income countries

26. Three objectives : 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. The following groups for consideration (countries need to determine their order of priority) – 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. post-marketing surveillance/ information(quality/efficacy, safety) Vaccination strategy for Pandemic vaccines (SAGE Reccomendations, July 2009)

27.  Demand for pandemic vaccines: A(H1N1)2009 pandemic likely moderate, similar to Asian flu (1957) or Hong Kong flu (1968) Larger outbreaks with more disease burdens and social impact likely occur in the near future. Seasonal influenza may not disappear, still causing substantial burden and impact. Balance with seasonal flu  By risk assessment and priority groups identification, how many doses are actually needed urgently? A(H1N1)2009 pandemic vaccines

28.  Vaccine antigens likely highly immunogenic (similar to seasonal flu; different from H5N1) Seasonal vaccine formulations likely work. From technical point of view, approaches taken for H5N1 vaccines are not necessarily required. high dose; new adjuvants  Adjuvants are benefitial for antigen-sparing and supply of more vaccines in a short time. However, there are safety concerns, high price and logistics issues about new adjuvanted vaccines.  New adjuvants are actually needed when considering the vaccine demand and the benefit, risk, and cost of adjuvanted vaccines? A(H1N1)2009 pandemic vaccines

29. Pandemic Influenza Vaccines (1) Based on; Seasonal influenza vaccination policy surveillance (disease/social/economic burdens) policy making and decision establishment implementation and achievement technology/production/QAQC capacity access to vaccines vaccination logistics surveillance and monitoring (epi. and virus, efficacy, adverse events)

30. Pandemic Influenza Vaccines (2) Specific issues; Secured access to vaccines Vaccine demand: by all countries Production capacity: limited in a short time Supply: gradually and short in time Competition for early/sufficient/prioritized Advanced contract of purchase Cost/contract Equitable supply of affordable vaccines Rich countries vs. low income countries

31. Principles to Guide Global Allocation of Pandemic Vaccine (Yamada, Bill and Melinda Gates Foundation, NEJM, 2009) 1. The global community should take steps to protect all populations, including those without resources to protect themselves. 2. Vaccination should be considered in the context of comprehensive pandemic preparedness and response efforts in all nations. 3. Developed countries and vaccine manufacturers should urgently agree upon a mechanism to ensure access to vaccine by developing countries. 4. Influenza vaccine manufacturers should identify strategies such as tiered pricing and donations to make pandemic vaccine more accessible to developing nations. 5. Pandemic vaccines allocated to developing nations should become available in the same time frame as vaccines for developed nations.

32. 6. The global community should obtain data to help establish a consensus on the safety and efficacy of adjuvants, and efforts should be made to ensure the fullest use of this and other dose- sparing strategies. 7. All countries obtaining pandemic vaccine should ensure that mechanisms are in place to provide the vaccine to their populations, to ensure that this scarce resource is not wasted, and donors should be prepared to provide resources and technical assistance to help countries bolster these mechanisms. 8. The World Health Organization is uniquely positioned to lead the global response to a pandemic virus and should support governments and industry in their efforts to implement these principles.