1. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Improving influenza vaccine virus selection process - report from a WHO informal consultation 14-16 June 2010 Improving influenza vaccine virus selection process - report from a WHO informal consultation 14-16 June 2010 Wenqing Zhang 5 th WPR and SEAR NIC Meeting 7 – 10 June 2011 Vientiane

2. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Context 1971 - 1 st formal WHO recommendation on influenza vaccine composition 1986, 17-18 Feb - First documented WHO annual consultation on influenza vaccine composition and meeting with industries 1998 – from annual to biannual 2004 – periodic review of selection and development of H5N1 and other subtype viruses – pandemic preparedness April-May 2009 – selection of pandemic A(H1N1) vaccine virus  Increasing awareness of influenza and demands for vaccines  Development and availability of new technologies

3. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Scope and objectives A timely opportunity to review the complex process WHO held an informal consultation 14-16 June 2010 to: –review the current vaccine virus selection process –identify opportunities for improving surveillance and virus sharing –assess the potential for improving the assays and technologies used –assess the potential impact of new vaccine technologies Participants: 129 from GISRS, national regulatory authorities, public health agencies, academia, influenza vaccine manufacturers, and veterinary laboratories and organizations

4. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Review of current process Improving the process Impact of new vaccine technologies

5. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Current process highlights The process based on –Data generated and analysed by GISRS –All year around surveillance by GISRS Time constraints: decision of vaccine composition required almost one full year in advance of the peak of the targeted season –Crucial to include most recent viruses characterized in WHOCC right before WHO consultations on vaccine composition – Feb and Sept Complex and collaborative: GISRS, vaccine manufacturers, national regulatory agencies

6. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Current process role of NICs Specimen collection in the country Preliminary laboratory diagnosis –PCR –Virus isolation and characterization using WHO kits –Antiviral susceptibility monitoring –Sequencing Selecting and shipping representative viruses to WHO CCs – essential step –Criteria: temporal, geographical, age-group distribution, severity of cases, viral characteristics Active communications –CCs –Reporting to FluNet H5, H7 and H9 Timeliness is key  the value of NIC work on public health

7. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Detailed antigenic and genetic characterization of viruses from GISN –Seasonal, pandemic, H5N1 and other subtypes Antigenic characterization –Vaccine virus selection primarily based upon the antigenic characterization of HA Prime importance in immunity - antibodies to HA Their level correlated with the level of protection HAI - a visual readout – ability of specific antibodies  prevent attachment of HA to RBC –A surrogate for more-complicated and time-consuming neutralization assay –Likely to remain the assay of choice for the foreseeable future –Ferret antisera produced, reference viruses selected Neutralization assay used to clarify antigenic relationships among variants Current process role of WHO CCs

8. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Genetic characterization –10-20% of isolates for sequencing of HA and NA –Phylogenetic analyses: genetic heterogeneity, new genetic clades –Sequences uploaded in GISAID Antigenic/phenotypic variants defined in genetic groups –Identifying individual AA substitutions associated with phenotypic changes –Particularly helpful with limited data available for WHO consultations Comparison of sequences of clinical specimens and virus isolates Serological studies using human sera –CCs and ERLs –Sera from vaccinees  antibody induced by vaccines vs. current circulating viruses Current process role of WHO CCs

9. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Principle criteria to recommend changes to composition: –Emergence of an antigenically and genetically distinct variant among circulating viruses –Evidence of the geographical spread of the variant and its association with outbreaks of diseases  future epidemiological significance –Reduced ability of existing vaccine-induced antibodies to neutralize the variant, and –Availability of suitable candidate vaccine viruses Current process WHO recommendations

10. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Teleconferences: 4-5 weeks, 1-2 weeks before Consultations –Share most recent virological and epidemiological data. –Facilitate collaborative studies –Identify potential candidate viruses for reassortment –Keep vaccine manufacturers informed of the TC outcome, provided potential candidate vaccine viruses WHO Consultations with an advisory group –Review and analyse: accumulative antigenic and genetic data from CCs Serological data from CCs and ERLs A broader lab-based epidemiology context from WHO based on GISRS reporting Additional data from NICs –In recent years, antigenic cartography to collate and statistically visualize antigenic variations –Based on all considerations, the advisory group advise WHO the recommendation Current process WHO recommendations

11. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Announcement of WHO recommendation: –An Information Meeting the next day with manufacturers and regulatory agencies –WHO recommendation with a detailed technical report published on WHO web the following day, in WER in 2 weeks Since 2004, vaccine virus selection and development for H5N1, H9N2 and possible other subtypes is one item on the Consultation agenda. –Outcome announced and published at the same time as vaccine composition recommendation Current process WHO recommendations

12. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Tight timelines Egg isolates Growth property Potency reagents Regulatory authorization Current process vaccine development considerations

13. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Retrospective studies shown WHO recommendations closely matched the viruses that have circulated during the targeted season. –with very few exceptions e.g. the emergence of "Fujian"-like virus in spring 2003 Rapid response to the out-of-season emergence of pandemic A(H1N1) 2009 –Demonstrated the solid yet resilient ability of the system, the GISRS and the process Current process performance

14. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Improving the process

15. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Since 2004, successful efforts at national, regional and global levels –Network coverage, quality, facilities, expertise and experiences Limitations revealed by the pandemic response –Analysis and integration of epidemiological surveillance data –Early seroprevalence surveys to assess extent and impact of pandemic –Lab infrastructure, personnel and funding, in particular in developing countries Research priorities –Evaluation of temporal and geographical circulation of viruses and of the burden of influenza Improving surveillance and virus sharing GISRS capacity

16. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Predominant use of PCR should not adversely affect the isolation and forwarding of viruses WHO shipment fund project: instrumental for virus sharing More-systematic approach engaging NICs –More web-based tools for additional data from NICs Virus characterization, serological studies –NIC summary report complementary to CC packages in WHO Consultations Active communications among the GISRS members: formal and informal Improving surveillance and virus sharing virus and information sharing

17. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Collaboration with OFFLU –Some joint initiatives conducted –Areas for improvement: Collection and analysis of antigenic and genetic data Timely exchange of representative viruses and reference reagents A more formal collaborative mechanism –Animal virus data to the WHO consultation on vaccine composition Efforts being made to establish triggers for initiating enhanced surveillance beyond notification –Constraints: economic consequences for livestock industries and potentially impacts on human food supplies Constraints of collaboration between animal and human sectors –Practical, funding, regulatory and policy issues Improving surveillance and virus sharing animal viruses

18. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting HAI, surrogate for virus neutralization - widely used –Sensitivity and utility influenced: RBC from different species Difference in receptor-binding properties –Standardization between labs difficult –Not suitable for full automation HAI refinements –Synthetic RBC: unsuccessfully so far –Recombinant HA being used: to assess antibody specificity and inhibition Expensive Potentially suitable for automation Potentially may reduce the need of virus isolates Currently being validated using ferret and human antisera Improving vaccine virus selection assays

19. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Neuraminidase-focused More understanding of antigenic evaluation of NA and NA antibodies contribution to immunity – will have significant impact –Studies of NA antigenic evolution limited –NA content of influenza vaccines not standardized currently NAI assays –Cumbersome in general Low antibody level in ferret antisera Interference from homologous antibodies against HA –Some different NAI assay being developed Improving vaccine virus selection assays

20. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting MN assays – an important adjunct to HAI –More sensitive and measure a broader repertoire of functional antibodies –Consistent degree of correlation with HAI MN assays under development –Being Simplified  routine use –Use MN for H1 and B viruses –Use pseudotype viruses: offering advantages for highly pathogenic viruses –Efforts being made on automation Epitope mapping using genome fragment phage display libraries –Further dissect the fine specificity of antibody responses to vaccination and infection Improving vaccine virus selection assays

21. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Improving vaccine virus selection serological studies To assess impact of influenza, countries encouraged to –Establish serum banks of age-stratifies representative sera –Perform seroepidemiological surveys Current serological studies by CCs and ERLs, valuable to the process –Advantages: shared sera and common antigens –Limitations: variety of HI data, need for MN or other assays to resolve inconsistencies. Need for antibody standards Increasing interest to vaccine effective studies –More real-time data: clinical benefit vs. antigenic relatedness of vaccine and circulating viruses –Consistent such studies: better understanding of the effect of small antigenic differences on clinical outcomes

22. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Improving vaccine virus selection technology development High-throughput genetic sequencing –Improve understanding of genetic changes and evolutionary interactions between co-circulating viruses –Help reveal broader genetic changes underlying antigenic variation X-ray crystallography on structural features of HA, together with computer modelling –Assist in attempts to predict influence on AA substitution on antigenic and receptor-binding properties High-throughput laboratory system – integrated and automated genetic and phenotypic analysis – from initial to data management –Intriguing prospect of a futuristic network –Broad implications – vaccine virus selection, organizing of global surveillance –Suggested application closely integrated with GISRS activities

23. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Improving vaccine virus selection mathematical modelling Numerous models being developed to gain insight into mechanisms underlying evolution and epidemiology of influenza viruses Exploratory models –Generate and test various hypotheses to explain relatively restricted diversity of antigenic repertoire –Explain underlying nature of immunity –Understand the extent of between-subtype/type competition, and its consequences for trends of seasonal viruses

24. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Improving vaccine virus selection mathematical modelling Phylogenetic models –Understanding of selective constraints related to antigenic drift and inter- species transmission –Phylodynamic modelling based on sequences data, supplemented with antigenic data  already used to trace emergence of new variants and their geographical spread Capacity of modelling to predict virus changes limited –Little understanding of underlying evolutionary and biological mechanisms –Stochastic nature of virus evolution making predictive modelling extremely challenging Simpler non-mechanistic statistical algorithms e.g. antigenic cartography –Likely more useful in facilitating the vaccine virus selection process

25. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Impact of new vaccine technologies

26. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Impact of new vaccine technologies All such new technologies have impact vaccine virus selection, regulatory and manufacturing process –Unlikely a crucial issue for vaccine virus selection: on the contrary, greater flexibility in the timing Live attenuated vaccines –Same process followed –Issue: antibody response is not a good correlate of protection; true correlate might affect composition Quadrivalent vaccines – affect vaccine supply Adjuvanted vaccines: broader spectrum of immunity –Less likely for GISRS to provide product-specific recommendations

27. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Impact of new vaccine technologies Non-HA based vaccines –Might impact current process, depending on their type and mechanism of protection –NA: included as part of vaccine virus selected, based on sequencing, not antigenicity Standardizing NA requires antigenic characterization Cell-culture vaccines –CRADA project to provide a universal qualified cell culture system to derive isolates for vaccine development –Rigorous regulatory evaluation needed High-growth reassortant –Associated genetic mechanism little known Potency assays –Pandemic experience –Alternative assays to SRID, e.g. HPLC, mass spectrometry – being evaluated

28. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting Brief summary GISRS vaccine virus selection process lies at heart of global efforts against influenza The process –Highly technical, complex and collaborative –Successful for decades, value proved by the response to pandemic 2009 –Being improved in the past dozen of years –Opportunity for improvement with new technologies and new knoledges WHO will continue to work with GISRS and its partners to identify improvements, harness new technologies, strengthen and sustain collaboration –Next informal consultation in Dec 2011 WHO will continue its central role of coordinating worldwide expertise to meet increasing public health needs

29. Vaccine Virus Selection W. Zhang 10 Jun 2011 Vientiane WHO WPR and SEAR NIC Meeting