Molecular Genetics of Influenza haemagglutinin production: Developing a rational basis for optimising vaccine yield

Lead Research Organisation: Nat Inst for Bio Standards and Control
Department Name: Division of Virology

Abstract

Pandemic influenza presents a major threat to global public health. The ideal approach to countering this threat would be to develop a vaccine to prevent the disease. Unfortunately, however, because there are so many different types of influenza virus constantly circulating in humans and animals, and because the virus can mutate easily and quickly, scientists can?t predict exactly what the next pandemic virus will look like. It is not currently possible, therefore, to prepare in advance a vaccine that is guaranteed to work against any pandemic threat. For this reason, research scientists are trying to find ways of speeding up the process of developing and producing a vaccine once a pandemic has begun. An important part of this is maximising vaccine production capacity since during an outbreak, tens of millions of vaccine doses would need to be produced each week to have an impact on the first wave of disease. Influenza virus vaccines are produced in eggs and so the number of vaccine doses that can be produced from a given number of eggs is crucial. We know that this yield is quite variable depending on the particular virus strain that is used for vaccine production, but we don?t know why. This research project aims to understand the reasons behind this variable yield and to use this knowledge to find ways of developing high yielding vaccine strains that will help manufacturers produce the maximum possible number of vaccine doses in the shortest possible time when a pandemic strikes.

Technical Summary

Vaccine production against pandemic strains of influenza virus depends crucially on rapid development of attenuated virus strains which are safe to put into large scale production but that also produce good yields of vaccine antigen in eggs, the principal basis for influenza vaccine production. Recent work at NIBSC and other laboratories has revealed that properties apparently inherent in the haemagglutinin and/or neuraminidase genes of currently circulating avian H5N1 strains result in low yields of antigen during production, in spite of the fact that these strains grow to high titres in eggs. Since global influenza vaccine manufacturing capacity is already well short of that needed to deal with a pandemic, any reduction in yield will have a huge public health impact. The research programme aims to investigate the genetic basis for the low yield phenomenon in current H5 strains and to provide a basis for rapidly creating robust, high yielding vaccine strains in the event of future pandemic emergencies.
 
Title Modified SDS PAGE analysis including deglycosylation 
Description A deglycosylation step was optimized and added to the SDS - PAGE analysis of whole virus concentrates to quantitate the proportion of HA as a percentage of total protein. 
Type Of Material Data analysis technique 
Year Produced 2008 
Provided To Others? Yes  
Impact An international collaboration has been set up to assess the method, and in future it could have an impact on the assignment of values to antigen standards for vaccine production. 
 
Description Collaborative study to assess modified method for Quantitation of HA 
Organisation Food and Drug Administration (FDA)
Department Centre for Biologics Evaluation and Research
Country United States 
Sector Academic/University 
PI Contribution We set up and co-ordinated the collaborative study to assess the reproducibility of the modified method developed during this project. The method was assessed alongside the standard in-house method in each centre for quantitation of HA as a potential part of annual assignment of values to HA antigen reagent.
Collaborator Contribution My collaborators took part in a multi centre study to assess the accuracy and reproducibility of the modified procedure for the Quantitation of HA developed during this study.My collaborators took part in a multi centre study to assess the accuracy and reproducibility of the modified procedure for the Quantitation of HA developed during this study.
Impact A manuscript from this collaboration is currently in preparation.
Start Year 2007
 
Description Collaborative study to assess modified method for Quantitation of HA 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution We set up and co-ordinated the collaborative study to assess the reproducibility of the modified method developed during this project. The method was assessed alongside the standard in-house method in each centre for quantitation of HA as a potential part of annual assignment of values to HA antigen reagent.
Collaborator Contribution My collaborators took part in a multi centre study to assess the accuracy and reproducibility of the modified procedure for the Quantitation of HA developed during this study.My collaborators took part in a multi centre study to assess the accuracy and reproducibility of the modified procedure for the Quantitation of HA developed during this study.
Impact A manuscript from this collaboration is currently in preparation.
Start Year 2007
 
Description Poster presentation - London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact A poster was prepared for the one day symposium 'Medical, Scientific and Historical Lessons from the Great Avian (H1N1) "Spanish" Influenza Pandemic of 1918: The 90th Anniversary

None that we are aware of
Year(s) Of Engagement Activity 2008