vaccine virus selection w. zhang 10 jun 2011 vientiane who wpr and sear nic meeting improving...

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


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


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


Review of current process

Improving the process

Impact of new vaccine technologies


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


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


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



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




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


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



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



Tight timelines

Egg isolates

Growth property

Potency reagents

Regulatory authorization

Current processvaccine development considerations

Current processvaccine development considerations


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


Improving the processImproving the process


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


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


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


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



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




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 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


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


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




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


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



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


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. zhang 10 jun 2011 vientiane who wpr and sear nic meeting improving...

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