Improving influenza vaccine virus selection process

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

2. Context • 1971 - 1st 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. 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. Review of current process • Improving the process • Impact of new vaccine technologies

5. Current processhighlights • 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. Current processrole 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. Current processrole of WHO CCs • 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

8. Current processrole of WHO CCs • 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

9. Current processWHO recommendations • 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

10. Current processWHO recommendations • 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

11. Current processWHO recommendations • 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

12. Current processvaccine development considerations • Tight timelines • Egg isolates • Growth property • Potency reagents • Regulatory authorization

13. Current processperformance • 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

14. Improving the process

15. Improving surveillance and virus sharingGISRS capacity • 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

16. Improving surveillance and virus sharingvirus and information sharing • 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

17. Improving surveillance and virus sharinganimal viruses • 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

18. Improving vaccine virus selectionassays • 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

19. Improving vaccine virus selectionassays 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

20. Improving vaccine virus selectionassays • 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

21. Improving vaccine virus selectionserological 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. Improving vaccine virus selectiontechnology 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. Improving vaccine virus selectionmathematical 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. Improving vaccine virus selectionmathematical 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. Impact of new vaccine technologies

26. 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. 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. 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