Upload
lauren-lawrence
View
214
Download
0
Embed Size (px)
Citation preview
Vaccine Virus Selection • W. Zhang10 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
5th WPR and SEAR NIC Meeting 7 – 10 June 2011 • Vientiane
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
ContextContext
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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Scope and objectivesScope 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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Review of current process
Improving the process
Impact of new vaccine technologies
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Current processhighlights
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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Current processrole of NICs
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
Vaccine Virus Selection • W. Zhang10 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 processrole of WHO CCs
Current processrole of WHO CCs
Vaccine Virus Selection • W. Zhang10 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 processrole of WHO CCs
Current processrole of WHO CCs
Vaccine Virus Selection • W. Zhang10 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 processWHO recommendationsCurrent processWHO recommendations
Vaccine Virus Selection • W. Zhang10 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 processWHO recommendationsCurrent processWHO recommendations
Vaccine Virus Selection • W. Zhang10 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 processWHO recommendationsCurrent processWHO recommendations
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Tight timelines
Egg isolates
Growth property
Potency reagents
Regulatory authorization
Current processvaccine development considerations
Current processvaccine development considerations
Vaccine Virus Selection • W. Zhang10 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 processperformance
Current processperformance
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Improving the processImproving the process
Vaccine Virus Selection • W. Zhang10 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 sharingGISRS capacity
Improving surveillance and virus sharingGISRS capacity
Vaccine Virus Selection • W. Zhang10 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 sharingvirus and information sharing
Improving surveillance and virus sharingvirus and information sharing
Vaccine Virus Selection • W. Zhang10 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 sharinganimal viruses
Improving surveillance and virus sharinganimal viruses
Vaccine Virus Selection • W. Zhang10 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 selectionassays
Improving vaccine virus selectionassays
Vaccine Virus Selection • W. Zhang10 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 selectionassays
Improving vaccine virus selectionassays
Vaccine Virus Selection • W. Zhang10 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 selectionassays
Improving vaccine virus selectionassays
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Improving vaccine virus selectionserological studies
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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Improving vaccine virus selectiontechnology development
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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Improving vaccine virus selectionmathematical modelling
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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Improving vaccine virus selectionmathematical modelling
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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Impact of new vaccine technologiesImpact of new vaccine technologies
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Impact of new vaccine technologiesImpact 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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Impact of new vaccine technologiesImpact 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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting
Brief summaryBrief 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
Vaccine Virus Selection • W. Zhang10 Jun 2011 • Vientiane • WHO WPR and SEAR NIC Meeting