Re: Seasonal Flu 2008 - 2009
[ECDC] The science and practicalities of making recommendations for the composition of influenza vaccines.
The contents of the syringe - Salzberg S. - Nature 2008. 454, 160-161 (09 Jul 2008)
Description:
In this commentary the author argues that the influenza vaccination essentially failed in the USA in the 2007-8 season and that public confidence fell.(1)
He notes that vaccine effectiveness in the field was estimated to be only 44% (2) and he suggests that as a consequence the influenza season was especially bad last year in the USA, noting in passing that for this coming 2008/9 season WHO has recommended changing all three of components of vaccines: A(H3N2), A(H1N1) and influenza B compared to what was recommended for 2007/8 (Table).(3,4,5)
He goes on to criticise the WHO and others for holding closed meetings where recommendations on vaccination are made, not allowing debate and not publishing the data on which the decisions are based.
He argues that those like himself who make available sequence data publicly available could especially contribute to the process and improve strain selection (1,4)
He also recommends moving to producing influenza vaccines by cell-culture rather than the predominant technology which uses embryonated (fertilised) chicken eggs.(1)
Table: Comparing Influenza Vaccine Strain Recommendations for 2007/8 and 2008/9 Northern Hemisphere Influenza Seasons
WHO Northern Hemisphere 2007/8 season recommendation (February 2007)(3)
-- an A/Solomon Islands/3/2006(H1N1)-like virus;
-- an A/Wisconsin/67/2005 (H3N2)-like virus;
-- a B/Malaysia/2506/2004-like virus
WHO Northern Hemisphere 2008/9 season recommendations (February 2008)(4)
-- an A/Brisbane/59/2007 (H1N1)-like virus;
-- an A/Brisbane/10/2007 (H3N2)-like virus;+
-- a B/Florida/4/2006-like virus.#
+) A/Brisbane/10/2007 is a current southern hemisphere vaccine virus.
#) B/Florida/4/2006 and B/Brisbane/3/2007 (a B/Florida/4/2006-like virus) are current southern hemisphere vaccine viruses.
ECDC Comment (21/08/08):
The 2007/8 winter influenza season in the United States (US) was interesting and instructive for at least two reasons.
Firstly it was one of the few areas of the world there was significant circulation of influenza A(H3N2) viruses.(4)
In most other parts of the world where surveillance took place (including Europe) the season was dominated by A(H1N1) and influenza B viruses.(4)
Secondly for the first time ever CDC and its collaborator the Marshfield clinic in Wisconsin successfully produced interim in-season estimates of vaccine effectiveness.
However it would be wrong to characterise the 2007/8 influenza vaccine as having failed in the USA, or elsewhere.
In controlled trials among health adults it has been found that vaccines well-matched to the circulating strains often give between 70% and 90% protection against laboratory confirmed infection.
However what is observed in the field against clinical disease, hospitalisation and deaths is often lower.(2,5)
This is partially because of methodological issues (using less precise end-points than in trials) and also because the elderly and those with chronic medical conditions have the highest rates of severe outcomes from infection but often respond less well to immunisation.
Nevertheless because the prevalence of influenza infections in the population is high the protection afforded remains invaluable preventing much illness and saving many lives.(2,5)
Salzberg argues that there is a need to publish more of the data on which the recommendations are made, and to have some more debate.(1)
But WHO does publish the data quickly, and in some detail.(3,4,6)
Also in Europe and the USA, after the global recommendations are made, both the European Medicines Agency and the US Food and Drug Administration rapidly hold further discussions and debates.
However it is crucial to set this decision-making in the context of the industrial, scientific and public health process of vaccine production.
This works extraordinarily well despite its complexity with virological surveillance data well-linked to public health action.(7,8)
In order to have millions of doses available for the early autumn in the Northern Hemisphere the manufacturers have to have recommendations on vaccine composition as early as possible in the calendar year.
Then the best-growing strains have to selected and there also has to be time to for specialist laboratories (for Europe the National Institute for Biological Standards and Controls) to produce essential reagents for measuring vaccine potency before the vaccines are released.(7,8)
Running in completely the opposite direction is the need to wait as late as possible to get a good idea of what viruses are circulating in the current season, characterised not only by sequence analysis (as implied by Salzberg) but also be antigenicity, which requires growth and titration with appropriate antisera.
This is difficult especially since epidemics in the Northern Hemisphere have moved forward in recent years so that they are only become established in January or even February.
Usually the specialists have to meet in a short window in February which means intense pressure to get the most recent isolates in and generate the large amounts of data needed to make judgements.
This is why referral of specimens to National Influenza Centres (NICs) is so important, especially early each influenza season.
Again this works surprisingly well despite the testing, isolating and forwarding of viruses by primary laboratories is financially unsupported in many countries.
There can be no time for more public debate and peer-review before the decisions are made.
Salzberg suggests that more use should be made of sequence data in the decisions. That may be true but the decisions do not depend on structure and sequence data alone but also the antigenic similarity between vaccine candidate and the circulating wild-type viruses.
Classically this is judged not by sequencing but by seeing how the new season?s predominant isolates react in haemagglutination inhibition tests against post-infection ferret sera. (3,4,6)
Antigenic cartography (looking at where new strains are emerging in other parts of the world) is now starting to be added to the decision making.(9)
After the decisions are made at there is then always an element of chance.
Whether or not decisions that had to be made for the northern hemisphere in February based on last season?s data will hold ten to twelve months later in the next season. I.e. How much will the viruses alter before the next winter?
Even with hindsight it is difficult to see that the changes that were considered necessary for 2008/9 could have been anticipated in February 2007 (as they were by the time of the Southern Hemisphere discussion in the Summer of 2007)(6).
Though it may be desirable to see more data being published and there being an invitation for debate after the event it will be interesting to see whether this improves the decision after the event.
Finally of course the manufacturers still need to act on the February recommendation and having them second-guessed later may not be helpful, not inspire confidence in the public.
Salzberg?s recommendation to grasp the new technologies like cell-culture vaccine production is correct but as a statement it is out-dated.(1) The cutting edge of industry is already looking past animal cells to other growth systems. This kind of forward look is already part of WHO?s programme to expand global vaccine production and use where ECDC acts as an observer.(10)
However these new processes are expensive and potentially hazardous processes requiring high levels of biosafety. Though they are not dependent on the supply of special eggs switching manufacturing plants from egg-based technologies to cell culture will not be accomplished overnight. They will also not necessarily be much quicker in production where the rate-limiting steps are quality control, formulation and packaging irrespective of the use of cell culture or egg-based vaccines.(6,7)
What is interesting and important for the future is investing in virological and epidemiological surveillance in the tropical Far-East which seems to be the engine-room for production at least of new A(H3N2) influenza viruses which then disseminate out to the temperate zones.(9)
This may give better indication on what is coming to the Northern and Southern Hemispheres.
1) Salzberg S. The Contents of the syringe Nature 2008 Nature 454, 160 - 161 (09 Jul 2008), doi: 10.1038/454160a
2) Centers for Disease Control and Prevention. Interim within-season estimate of the effectiveness of trivalent inactivated influenza vaccine. 2007-8 Influenza Season. MMWR 2008; 57:393-398
3) WHO Recommended composition of influenza virus vaccines for use in the 2007-2008 (northern hemisphere) influenza season. WER 2007; 82: 69-76 (March 2nd)
4) WHO Recommended composition of influenza virus vaccines for use in the 2008-2009 (northern hemisphere) influenza season. WER 2008 83: 81-87(February 29th)
5) Mangtani P, Cumberland P, Hodgson CR, Roberts JA, Cutts FT, Hall AJ. A cohort study of the effectiveness of influenza vaccine in older people using the United Kingdom General Practice Research Database. JID 2004; 190:1-10.
6) WHO Recommended composition of influenza virus vaccines for use in the 2007 southern hemisphere influenza season. WER 2007, 82: 345?356 (October 5th)
7) Gerdil C. The annual production cycle for influenza vaccine. Vaccine 2003; 21: 1776-9.
8) Inglis S, Wood J, Minor P. Making flu vaccines is a race against time in an uncertain world (correspondence). Nature 2008, 454, 939 (21 August 2008) | doi:10.1038/454939c
9) Russell C, Jones T, Barr I et al The global circulation of seasonal influenza A (H3N2) viruses Science 2008; 320 340-6.
10) WHO Global pandemic influenza action plan to increase vaccine supply. WHO Geneva Immunization, Vaccine and Biologicals. Epidemic and Pandemic Alert and Response. September 2006.
ECDC would like to thank a number of specialists who assisted in producing this text
Comments are invited to
influenza@ecdc.europa.eu
ECDC discussed this earlier in the year in ECDC Influenza News Scientific Advances May 8th 2008. It should be noted that final vaccine effectiveness results from the 2007/8 season are pending and that the observed vaccine effectiveness against the most dangerous viruses, the A(H3N2) group was 58%.(2)
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http://www.ecdc.europa.eu/Health_topics/influenza/news/news_Influenza_080821.html
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