Giuseppe
Emeritus
[From ECDC Influenza News - Excerpts - http://www.ecdc.europa.eu/ ]
1d) SCIENTIFIC ADVANCES -SEASONAL INFLUENZA- EPIDEMIOLOGY - Where do new human flu viruses come from?
? The global circulation of seasonal influenza A (H3N2) viruses. Russell CA, Jones TC, Barr IG, et al. Science 2008; 320:340-6.
? The genomic and epidemiological dynamics of human influenza A virus. Rambaut A, Pybus OG, Nelson MI, Viboud C, Taubenberger JK, Holmes EC. Nature 2008; advance online publication 16 April
Description :
These two papers describe the application of sophisticated antigenic and genetic analysis to study variation, change and evolution of human influenza A viruses, specifically the haemagglutinin (HA) surface glycoprotein, in the most virulent circulating influenza sub-type at present A/H3N2.
Haemagglutinin (HA) surface glycoprotein is the part of the virus which, along with the neuraminidase surface glycoprotein (NA) varies the most and these two glycoproteins are the primary target of protective responses by the human immune system.
Unlike most of the rest of the influenza virus these surface proteins have not been preserved over time but have varied and are responsible for the way that these viruses constantly change and evade the human immune system which with a constant supply of new susceptibles causes annual epidemics and occasional pandemics.
The first paper in Science is more comprehensive as it studies the haemagglutinin (HA) surface glycoprotein derived from more than 13,000 influenza A/H3N2 viruses obtained through the WHO Global Influenza Surveillance Network, its component WHO Collaborating Centres and National Influenza Centres over the period 2002 to 2007.
The second paper in Nature examines the evolution of haemagglutinins in a more limited set of viruses (around 1300 in number) obtained from the Northern and Southern hemispheres but looking at both A/H3N2 and A/H1N1.
As well as studying the process of change and evolution in itself what the researchers were doing was trying to answer the question of where new seasonal influenza A viruses come from.
The Russell paper in particular examines the different theories on this and supports an attractive model that new influenza A/H3N2 viruses emerge from influenza evolution in East and South East Asia and then spread without much further antigenic / genetic change to the rest of the world along the routes of human travel.
There is an eye-catching diagram illustrating this mechanism on page 345 of the Russell article which will probably be reproduced widely.
The Science researchers conclude that epidemics in regions like Europe are seeded from the Asian network each year and they point out that if the trends observed during this period are an accurate representation of overall patterns of spread, then the characteristics of A (H3N2) viruses in Europe might be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine strain selection.(1)
ECDC Comment (30/04/08):
So called human seasonal influenza occurs each year in the winter in Europe.
Transmission almost ceases in the spring and summer though sporadic cases continue to be detected.(2)
The behaviour much less well studied in the equatorial regions (where the term ?seasonal? influenza is misleading) but what studies there are indicate a more constant circulation among humans with intensifying transmission and epidemics at predictable times of year, perhaps associated with the wetter months.(2-5)
For many years there has been discussion and debate over the origins of annual epidemics in the temperate regions like Europe and the competing hypotheses are well summarised in the Russell paper.(1)
Do they come from low-level persisting transmission in Europe itself, movement to and fro between the epidemics in the temperate zones in the Northern and Southern Hemispheres, emergence of novel strains from China alone or from all part of the Tropics?
The conclusion of Russell et al is ?none of the above? but rather that in this period of study new strains of A/H3N2 emerged from a network of transmission in Southern China and South East-Asia and then these viruses spread, without much further change across the rest of the globe to Oceania and Australasia, the Rest of Asia, Europe and Africa arriving last in South America because its human links with the China / South East hub are the weakest and longest.(1)
What neither paper could investigate is what actually is happening inside that network of transmission in Southern China and South East-Asia and how the new viruses are generated (influenza surveillance is relatively weak in that zone).
Pandemics are thought to emerge through the insertion of novel antigens from animal viruses (5) but the process described here may not involve animal viruses at all as the changes are quite minor and could arise from genetic exchange when a human is infected by two different human viruses or even simple mutations.(1,2)
An issue that deserves attention now is whether the recently emerged influenza A/H1N1 viruses highly resistant detected first in Europe also originated in the East / South East Asian network.(6)
These viruses do not look like a single clade and were not in Europe before the 2007-8 season (6) thus suggesting they emerged elsewhere.
However to date few have been detected in East Asia and they represent far lower proportions of all A/H1N1 viruses than seen in Europe though the global table shows the usual story of little surveillance outside centres in Hong Kong and Thailand.(7,8)
These findings are not just of scientific interest.
Each year WHO convenes a meeting at which the influenza vaccines in use in the Northern and Southern hemispheres are compared with the circulating strains and the selections recommended for use by industry are changed if the match is considered less than the best than could be achieved with what strains are available and growing well.(9)
However this process is always one of playing catch-up against the virus.
The scientists have to look back and see how good the match was in the season that have just passed using virological and now occasionally epidemiological studies.
The attraction of the hypothesis supported by these papers and especially that by Russell is that it might be possible to predict from surveillance in the East/South East Asian Hub what new antigens should be inserted into the selection ahead of a European Season.(1)
One problem with this suggestion are the current difficulties over virus sharing, notably the understandable concern that surveillance in East and South East Asia may be of little benefit for those parts of the world, simply because very few influenza vaccines are used and even less are produced in that Region.(10)
This leads to understandable regional feelings that work done in East and South East Asia is mostly benefiting other, better off parts of the world.
WHO has since 2006 had a global programme working to greatly expand the use and production of influenza vaccines in the middle and low income parts of the world.(4,11)
These two important papers by Russell and Rambaut et al point to a scientific need for better influenza surveillance in East and South East Asia.
There are public health justifications for that as well but they will be made stronger if influenza vaccines are also made available in those localities though the joint efforts of national governments and the international community.
References:
1 - Russell C, Jones T, Barr I et al The global circulation of seasonal influenza A (H3N2) viruses Science 2008; 320 340-6. http://www.sciencemag.org/cgi/content/abstract/sci;320/5874/340
2 - Cox N, Subbaro K. Global epidemiology of influenza. Past and Present. Ann Rev med 2000; 51: 407-21
3 - Viboud C, Alonso W, Simonson Influenza in tropical regions. PloS medicine 2006; 3 (4) e89 http://medicine.plosjournals.org/archive/1549-1676/3/4/pdf/10.1371_journal.pmed.0030089-L.pdf
4 - Simmerman J, Thawawsupha P, Kingnate D, Fukuda K, Cahising A, Dowell SF. Influenza in Thailand: a case study for middle income countries. Vaccine 2004; 23: 182-7.
5 - Alonso W, Viboud L, Hirano E, Daufenbach L, Miller M. Seasonality of influenza in Brazil.: a travelling wave from the Amazon to the aub-tropics. Amer J Epidemiol 2007; 165: 1434-1442
6 - Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, Zambon MC. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill. 2008;13(5)
ii=8026. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8026
7 - WHO Influenza A(H1N1) virus resistance to oseltamivir http://www.who.int/csr/disease/influenza/h1n1_table/en/index.html
8 - ECDC Antivirals and Antiviral Resistance - Influenza http://ecdc.europa.eu/Health_topics/influenza/antivirals.html
9 - Gerdil C. The annual production cycle for influenza vaccine. Vaccine 2003; 21: 1776-9.
10 - European Centre for Disease Prevention and Control. Interim ECDC Scientific and Public Health Briefing: Sharing influenza Virus Samples ? Version November 2007. Available from: http://ecdc.europa.eu/pdf/ECDC_influenza_briefing.pdf
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. http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_2006_1/en/index.html
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1d) SCIENTIFIC ADVANCES -SEASONAL INFLUENZA- EPIDEMIOLOGY - Where do new human flu viruses come from?
? The global circulation of seasonal influenza A (H3N2) viruses. Russell CA, Jones TC, Barr IG, et al. Science 2008; 320:340-6.
? The genomic and epidemiological dynamics of human influenza A virus. Rambaut A, Pybus OG, Nelson MI, Viboud C, Taubenberger JK, Holmes EC. Nature 2008; advance online publication 16 April
Description :
These two papers describe the application of sophisticated antigenic and genetic analysis to study variation, change and evolution of human influenza A viruses, specifically the haemagglutinin (HA) surface glycoprotein, in the most virulent circulating influenza sub-type at present A/H3N2.
Haemagglutinin (HA) surface glycoprotein is the part of the virus which, along with the neuraminidase surface glycoprotein (NA) varies the most and these two glycoproteins are the primary target of protective responses by the human immune system.
Unlike most of the rest of the influenza virus these surface proteins have not been preserved over time but have varied and are responsible for the way that these viruses constantly change and evade the human immune system which with a constant supply of new susceptibles causes annual epidemics and occasional pandemics.
The first paper in Science is more comprehensive as it studies the haemagglutinin (HA) surface glycoprotein derived from more than 13,000 influenza A/H3N2 viruses obtained through the WHO Global Influenza Surveillance Network, its component WHO Collaborating Centres and National Influenza Centres over the period 2002 to 2007.
The second paper in Nature examines the evolution of haemagglutinins in a more limited set of viruses (around 1300 in number) obtained from the Northern and Southern hemispheres but looking at both A/H3N2 and A/H1N1.
As well as studying the process of change and evolution in itself what the researchers were doing was trying to answer the question of where new seasonal influenza A viruses come from.
The Russell paper in particular examines the different theories on this and supports an attractive model that new influenza A/H3N2 viruses emerge from influenza evolution in East and South East Asia and then spread without much further antigenic / genetic change to the rest of the world along the routes of human travel.
There is an eye-catching diagram illustrating this mechanism on page 345 of the Russell article which will probably be reproduced widely.
The Science researchers conclude that epidemics in regions like Europe are seeded from the Asian network each year and they point out that if the trends observed during this period are an accurate representation of overall patterns of spread, then the characteristics of A (H3N2) viruses in Europe might be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine strain selection.(1)
ECDC Comment (30/04/08):
So called human seasonal influenza occurs each year in the winter in Europe.
Transmission almost ceases in the spring and summer though sporadic cases continue to be detected.(2)
The behaviour much less well studied in the equatorial regions (where the term ?seasonal? influenza is misleading) but what studies there are indicate a more constant circulation among humans with intensifying transmission and epidemics at predictable times of year, perhaps associated with the wetter months.(2-5)
For many years there has been discussion and debate over the origins of annual epidemics in the temperate regions like Europe and the competing hypotheses are well summarised in the Russell paper.(1)
Do they come from low-level persisting transmission in Europe itself, movement to and fro between the epidemics in the temperate zones in the Northern and Southern Hemispheres, emergence of novel strains from China alone or from all part of the Tropics?
The conclusion of Russell et al is ?none of the above? but rather that in this period of study new strains of A/H3N2 emerged from a network of transmission in Southern China and South East-Asia and then these viruses spread, without much further change across the rest of the globe to Oceania and Australasia, the Rest of Asia, Europe and Africa arriving last in South America because its human links with the China / South East hub are the weakest and longest.(1)
What neither paper could investigate is what actually is happening inside that network of transmission in Southern China and South East-Asia and how the new viruses are generated (influenza surveillance is relatively weak in that zone).
Pandemics are thought to emerge through the insertion of novel antigens from animal viruses (5) but the process described here may not involve animal viruses at all as the changes are quite minor and could arise from genetic exchange when a human is infected by two different human viruses or even simple mutations.(1,2)
An issue that deserves attention now is whether the recently emerged influenza A/H1N1 viruses highly resistant detected first in Europe also originated in the East / South East Asian network.(6)
These viruses do not look like a single clade and were not in Europe before the 2007-8 season (6) thus suggesting they emerged elsewhere.
However to date few have been detected in East Asia and they represent far lower proportions of all A/H1N1 viruses than seen in Europe though the global table shows the usual story of little surveillance outside centres in Hong Kong and Thailand.(7,8)
These findings are not just of scientific interest.
Each year WHO convenes a meeting at which the influenza vaccines in use in the Northern and Southern hemispheres are compared with the circulating strains and the selections recommended for use by industry are changed if the match is considered less than the best than could be achieved with what strains are available and growing well.(9)
However this process is always one of playing catch-up against the virus.
The scientists have to look back and see how good the match was in the season that have just passed using virological and now occasionally epidemiological studies.
The attraction of the hypothesis supported by these papers and especially that by Russell is that it might be possible to predict from surveillance in the East/South East Asian Hub what new antigens should be inserted into the selection ahead of a European Season.(1)
One problem with this suggestion are the current difficulties over virus sharing, notably the understandable concern that surveillance in East and South East Asia may be of little benefit for those parts of the world, simply because very few influenza vaccines are used and even less are produced in that Region.(10)
This leads to understandable regional feelings that work done in East and South East Asia is mostly benefiting other, better off parts of the world.
WHO has since 2006 had a global programme working to greatly expand the use and production of influenza vaccines in the middle and low income parts of the world.(4,11)
These two important papers by Russell and Rambaut et al point to a scientific need for better influenza surveillance in East and South East Asia.
There are public health justifications for that as well but they will be made stronger if influenza vaccines are also made available in those localities though the joint efforts of national governments and the international community.
References:
1 - Russell C, Jones T, Barr I et al The global circulation of seasonal influenza A (H3N2) viruses Science 2008; 320 340-6. http://www.sciencemag.org/cgi/content/abstract/sci;320/5874/340
2 - Cox N, Subbaro K. Global epidemiology of influenza. Past and Present. Ann Rev med 2000; 51: 407-21
3 - Viboud C, Alonso W, Simonson Influenza in tropical regions. PloS medicine 2006; 3 (4) e89 http://medicine.plosjournals.org/archive/1549-1676/3/4/pdf/10.1371_journal.pmed.0030089-L.pdf
4 - Simmerman J, Thawawsupha P, Kingnate D, Fukuda K, Cahising A, Dowell SF. Influenza in Thailand: a case study for middle income countries. Vaccine 2004; 23: 182-7.
5 - Alonso W, Viboud L, Hirano E, Daufenbach L, Miller M. Seasonality of influenza in Brazil.: a travelling wave from the Amazon to the aub-tropics. Amer J Epidemiol 2007; 165: 1434-1442
6 - Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, Zambon MC. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill. 2008;13(5)
ii=8026. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=80267 - WHO Influenza A(H1N1) virus resistance to oseltamivir http://www.who.int/csr/disease/influenza/h1n1_table/en/index.html
8 - ECDC Antivirals and Antiviral Resistance - Influenza http://ecdc.europa.eu/Health_topics/influenza/antivirals.html
9 - Gerdil C. The annual production cycle for influenza vaccine. Vaccine 2003; 21: 1776-9.
10 - European Centre for Disease Prevention and Control. Interim ECDC Scientific and Public Health Briefing: Sharing influenza Virus Samples ? Version November 2007. Available from: http://ecdc.europa.eu/pdf/ECDC_influenza_briefing.pdf
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. http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_2006_1/en/index.html
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