| The first paper is this one in Nature: The genomic and epidemiological dynamics of human influenza A virus Andrew Rambaut1, Oliver G. Pybus2, Martha I. Nelson3, Cecile Viboud4, Jeffery K. Taubenberger5 & Edward C. Holmes3,4
The authors used a data set of 1,302 A/H3N2 and A/H1N1 isolates sampled over a 12-yr period from NY State and from New Zealand, to measure the genetic diversity of influenza A virus among subtypes, genome segments and geographic locations. Here I'll mostly address the geographic issue.
What they found was in temperate climates in both northern and southern hemispheres, there is a similar pattern, of "annual series of peaks in genetic diversity interspersed by strong genetic bottlenecks at the end of most influenza seasons." What does this mean? The following chart shows the degree of genetic diversity. Notice a couple of things:
- There is generally more genetic diversity for H3N2 than for H1N1
- diversity rises into the flu season, then falls towards the end of it. (the fancy way to describe this fall is to call it "genetic bottleneck").
The question is, if at the end of a flu season there is very little diversity, where does the next season's diversity come from? There are 2 possibilities:
- local low level persistent infections and evolution during the 'off' season
- introduction of new strains from outside
Here's an interesting chart that gives us some clue, from the paper Influenza in Tropical Regions, Viboud et al, PLOS Med 2006. It shows the frequency of virus isolates over different times of the year. Notice the distinct seasonality for the US and Argentina, but for tropical countries there is year-round influenza activity.
In the Holmes paper in Nature, the authors propose a model to explain the global dynamics of influenza evolution. What this 'source-sink' model proposes is that each year, the seasonality in temperate climates means that most of the circulating strains die off, (or reach 'extinction'), but the following season new strains are introduced from tropical countries. Since these countries have a much more extended flu season or year-round activity, the evolution and selection can occur uninterrupted in these populations.
This model is more or less supported by findings from the second paper, published in Science, The Global Circulation of Seasonal Influenza A (H3N2) Viruses Colin A. Russell,1 Terry C. Jones,1,2,3 Ian G. Barr,4 Nancy J. Cox,5 Rebecca J. Garten,5 Vicky Gregory,6 Ian D. Gust,4 Alan W. Hampson,4 Alan J. Hay,6 Aeron C. Hurt,4 Jan C. de Jong,2 Anne Kelso,4 Alexander I. Klimov,5 Tsutomu Kageyama,7 Naomi Komadina,4 Alan S. Lapedes,8 Yi P. Lin,6 Ana Mosterin,1,3 Masatsugu Obuchi,7 Takato Odagiri,7 Albert D. M. E. Osterhaus,2 Guus F. Rimmelzwaan,2 Michael W. Shaw,5 Eugene Skepner,1 Klaus Stohr,9 Masato Tashiro,7 Ron A. M. Fouchier,2 Derek J. Smith1,2*
Smith has made significant contribution to the study of influenza evolution by the use of antigenic maps to illustrate in a 2D manner the antigenic evolution over time. This is particularly useful for the selection of seasonal vaccine strains. Here's an example of antigenic map, from the Holmes paper
Several findings from the Smith paper address the issue of local persistence vs introduction or seeding from outside. They also used a really interesting way to show where the seeding is coming from.
- They compared the inter-epidemic (off season) samples to the previous local epidemic strain and to strains obtained globally. If local persistence is the main mechanism, one should see more similarity with local previous strains, but they found this was not the case. None of the inter-epidemic samples tested were more similar to local previous strain than external strains.
- In general, although there is significant diversity in local strains, the overall global pattern is much more homogeneous, showing migration of viruses over geographical regions to be more important than local persistence and evolution. The following schematic phylogenetic trees illustrate the concept, with different colors representing viruses from different regions. When we look at the phylogenetic tree of sequences collected all over the world (1567 HA1 sequences in total - it's one enormous tree!) if local persistence is the key mechanism, then one would expect the pattern seen in A, whereas seeding from outside would produce B.
Here's the observed result:
smith
- The next question is, where is the seeding coming from, or where is the 'sink' from the Holmes et al 'sink-source' model? Smith and colleagues found that globally, the evolution of the viruses are pretty homogeneous, such that they can actually chart a time-course in the antigenic changes. Using the average global antigenic evolutionary path as the standard (or 'spline') they then mapped the deviation from this standard for each country.
In the following chart, the line down the center represents the global average in antigenic change. Countries with sequences that change ahead of (ie earlier in time than) the global average gets a mark on the right. Those that lag behind are marked to the left. This chart in effect traces the pattern of virus seeding, from one country or region to another.
In general, they found that the earliest antigenic changes occur in populations in E and SE Asia, followed by N America, Europe, Oceania, then S America. This pattern is interesting because if climate is the only determinant, then one should see other tropical or subtropical regions eg in S America being seeded early, in addition to E&SE Asia. But that is not what we are observing - S America is clearly trailing behind.
- They also found that while there is circulation between different countries within Asia, re-seeding from outside rarely occurs, ie the seeding of countries outside of the E&SE Asia network of countries is more-or-less a one-way street. The authors suggest this may be explained by the pattern of global travel.
E-SE Asia's strong travel and trade connections to Oceania, North America, and Europe (14, 37) facilitate the rapid movement of new influenza virus variants into those areas and thus explain the relatively small lag in antigenic and genetic advancement seen in those regions (Fig. 2, A and B). Also, though it is unclear how much travel there must be between two locations for them to be epidemiologically well-connected, South America's 6- to 9-month antigenic lag (Fig. 2A) may be attributable to its paucity of direct connections with E-SE Asia (fig. S5). South America's strong travel connections to Europe and North America, but not to E-SE Asia, could result in a seeding hierarchy where strains are first seeded into North America and Europe and from there to South America (Fig. 5).
If this model is an accurate representation, and antigenic changes consistently occur in E-SE Asia ahead of everywhere else, then seed strain selection for the seasonal flu vaccine may be much improved by using surveillance data from Asia. |
