Tuesday, October 15, 2019

ECDC: Influenza Virus Characterisation, September 2019



The only real constant with influenza strains is that they are constantly evolving. As viruses, they leave behind (varying degrees) of immunity in every host they infect, so were they not to change over time, they would eventually run out of susceptible hosts. 
While we talk about the four main strains of influenza that currently circulate in humans (A/H1N1(pdm), A/H3N2, B Victoria, B Yamagata) as if they were single entities - in reality – within each strain, you will find a good deal of diversity.
New `prototypes’ from  these strains are constantly being generated (mostly via  antigenic drift) and `field tested’ for biological fitness and transmissibility.
Most are evolutionary failures, and go nowhere.
But some will have what it takes to compete with its parental strains, manage to spread widely, and perhaps even become the dominant strain for awhile.  But dominance rarely lasts for very long, as new contenders are always in the viral queue.

Younger influenza subtypes - like H1N1, which has been in circulation for only a decade - seem to have less diversity and evolutionary pressure than older subtypes. Indeed, for the first six years following the 2009 pandemic, the H1N1 component of the flu vaccine remained unchanged.  
By contrast, H3N2 - which emerged more than 50 years ago (1968) as a pandemic strain - shows far more genetic diversity and rapid and erratic evolution, making vaccine strain selection 6 months in advance increasingly problematic.
This chaotic H3N2 strain - which also tends to produce the most severe flu seasons,.particularly in the elderly - makes the development of a`universal' flu vaccine (see J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine) of greater importance than ever.
Credit NIAID
While progress is being made, it may be 5 years (or more) before we see a commercially available universal flu vaccine. Until then, we have to work with what we've got.

Last February - when the WHO normally decides on which strains to put in next fall's vaccine - they opted to delay their decision on the H3N2 component for 30 days (see WHO: (Partial) Recommended Composition Of 2019-2020 Northern Hemisphere Flu Vaccine).
At issue was the sudden rise of H3N2 clade 3C.3a reported in the United States (and other places), which had started last fall's season as a minor component of what appeared on track to being a relatively mild H1N1 season.
By early 2019 we'd switched into a moderately severe H3N2 season with clade 3C.3a leading the pack (see CDC HAN #0418: Influenza Season Continues with an Increase in Influenza A(H3N2) Activity).

In late March the WHO decided to switch to the surging Clade 3C.3a H3N2  virus, betting that it would become the dominant H3 strain worldwide by this fall. But over the summer, we've seen signs that clade 3C.3a may already be losing momentum, and another clade -  3C.2a1b - appears to be on the ascendant. 
This trend convinced the WHO to switch next year's Southern Hemisphere vaccine recommendations to an entirely different strain (A/South Australia/34/2019 (H3N2)-like virus), raising concerns over this fall's Northern Hemisphere's vaccine effectiveness.
In truth, we won't know how good of a match this year's 2019-2020 flu vaccine will be until the season ends.  Clade 3C.3a could stage a comeback later this fall, or we could see an H1N1 or influenza B dominated season. 
At this point, we have the vaccine that we have, and will have to deal with whatever comes.
We should start getting virus characterization reports from the CDC for North American flu viruses in the coming weeks, but in the meantime the ECDC publishes - roughly once a month - a review of recently isolated seasonal flu viruses collected across the EU in their Influenza Virus Characterization Report.

These (highly technical) reports help us track the evolutionary changes that are occurring in seasonal flu strains - at least in those regions submitting samples - and hopefully provide early warning of any major antigenic variances with this year's vaccine.  
I've reproduced the executive summary and provided a link to the full 29-page report.  I'll have a postscript when you return.

Executive summary

Since the July 2019 characterisation report1, a further three shipments of influenza-positive specimens from EU/EEA countries were received at the London WHO CC, the Francis Crick Worldwide Influenza Centre (WIC). A total of 1 511 virus specimens, with collection dates after 31 August 2018, have been received.

The 85 A(H1N1)pdm09 test viruses characterised antigenically since the last report showed equivalent good reactivity with antisera raised against both the A/Michigan/45/2015 2018–19 vaccine virus and the A/Brisbane/02/2018 2019–20 vaccine virus. The 613 test viruses with collection dates from week 40/2018 genetically characterised at the WIC, including two H1N2 reassortants, have all fallen in subclade 6B.1A, defined by S74R, S164T and I295V HA1 substitutions; 564 of these viruses also have HA1 S183P substitution, often with additional substitutions in HA1 and/or HA2. 

Since the last report, 37 A(H3N2) viruses successfully recovered had sufficient HA titre to allow antigenic characterisation by HI assay in the presence of oseltamivir; all were poorly recognised by antisera raised against the vaccine virus, eggpropagated A/Singapore/INFIMH-16-0019/2016. Of the 505 viruses with collection dates from week 40/2018 genetically characterised at the WIC, 399 were clade 3C.2a (with 43 3C.2a2, 17 3C.2a3, eight 3C.2a4 and 331 3C.2a1b); 106 were clade 3C.3a.

Ten B/Victoria-lineage viruses have been characterised in this reporting period. All recent viruses have HA1 amino acid substitutions of I117V, N129D, and V146I compared to B/Brisbane/60/2008 (clade 1A), a previous vaccine virus. Groups of viruses defined by deletions of two (Δ162-163, 1A(Δ2)) or three (Δ162-164, 1A(Δ3)) amino acids in HA1 have emerged, with the Δ162-164 group having subgroups of Asian and African origin. These virus groups are antigenically distinguishable by HI assay. Of 20 viruses from EU/EEA countries this season that have been characterised genetically, one has been clade 1A, two 1A(Δ2) and 17 1A(Δ3) (16 African and one Asian subgroup).

Nine B/Yamagata-lineage viruses have been characterised antigenically in this reporting period, giving a total to 23 for the 2018–19 season. All have HA genes that encode HA1 amino acid substitutions of L172Q and M251V compared to, but remain antigenically similar to, the vaccine virus B/Phuket/3073/2013 (clade 3) recommended for use in quadrivalent vaccines for the next northern hemisphere influenza season.

Influenza virus characterisation, September 2019 EN - [PDF-2.85 MB]
The good news from this report is that the H1N1 component to this year's flu vaccine still appears to be a good match to over 90% of the H1N1 viruses tested. The influenza B/Yamagata-lineage vaccine appears to be a decent match as well. 
Things are less certain for how well the Influenza B/Victoria-lineage and A/H3N2 components will fare this winter, and both have been changed for next year's Southern Hemisphere vaccine.
While there are legitimate questions over how effective this year's flu vaccine will be, the global fluscape is rarely consistent. Often North America will see a different dominant subtype than does Europe, or Asia, or at least a different clade.
And last year proved that the flu subtype we start off with may not carry sway throughout the entire season. 
All of which makes getting the flu shot a good insurance policy, even if one or two of the vaccine strains don't appear to be a great match. Like wearing a seat belt in a car crash, getting the vaccine doesn't guarantee you'll walk away unscathed . . . but it does increase your chances.