Wednesday, July 26, 2017

J. Clin. Vir.: Ιnfluenza A(H3N2) Genetic Variants In Vaccinated Patients In Northern Greece


Last Saturday in The Enigmatic, Problematic H3N2 Influenza Virus we looked at the nearly 50 year history and growing diversity of the H3N2 virus in humans, and recent reports of an emerging subclade 3C.2a1 with amino acid (aa) substitutions (including N121K) that may have adversely affected the influenza Vaccine's Effectiveness (VE) over the last winter's flu season.
Influenza viruses evolve via two well established routes; Antigenic drift & Antigenic Shift (reassortment).
Shift requires the co-infection of a host with two different influenza viruses which then swap chunks of their genetic code, creating a new `reassorted' virus (see NIAID Video: How Influenza Pandemics Occur). 
While viable reassortments are rare, as any virologist will tell you . . . Shift Happens.
Far more common is Antigenic drift, which is driven by replication errors that are common with single-stranded RNA viruses (see NIAID Video: Antigenic Drift).  While most of these biological accidents are evolutionary failures, every once in a while a more biologically `fit' virus is produced, and it is able to compete with its parental viruses.
This is the reason why influenza vaccines must be updated so often. 
Unfortunately, it takes six months to create and produce enough influenza vaccine for each flu season, and during this time the virus continues to evolve. For the northern hemisphere, vaccine strain selections must be made in February (see WHO: Recommended Composition Of 2017-2018 Northern Hemisphere Flu Vaccine).
Despite this production lag, most years the vaccine is still a pretty good match. But as we saw in the 2014-2015 flu season, sometimes the virus is able to evade the vaccine (see CDC HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus).
We never know just how good a match the vaccine will be until well into the flu season. Starting about six months ago we began to get interim reports on last year's vaccine effectiveness (VE). 
But at the same time we've been seeing reports of much lower VE - particularly among those over 65 - who were infected with some recently emerging variants of the H3N2 virus (see Changes in genetically drifted H3N2 influenza A viruses and vaccine effectiveness in adults 65 years and older during the 2016/17 season in Denmark),
Today we've another study, this time from Greece, focusing on genetic variants of the H3N2 virus isolated from both vaccinated  and unvaccinated patients during the last flu season.
Among those who were unvaccinated, H3N2 subclade 3C.2a - which is recognized as a pretty good antigenic match to last year's vaccine - was most commonly detected.  But among those who received the flu vaccine last year, the emerging subclade 3C.2a1 was far most common, suggesting it may be better at evading the vaccine.

Ιnfluenza A(H3N2) genetic variants in vaccinated patients in northern Greece

A. Melidou'Correspondence information about the author A. MelidouEmail the author A. Melidou Email the author A. Melidou , G. Gioula, M. Exindari , E. Ioannou, K. Gkolfinopoulou, T. Georgakopoulou, S. Tsiodras, A. Papa 


    •Common aa substitutions T135K and D122N on viral antigenic and glycosylation sites.
    •These variant strain has been observed in vaccinated patients.
    •Possible antigenic drift in northern Greek A(H3N2) circulating viruses.
    •Continuous monitoring of A(H3N2) evolution and circulation of variant strains is essential to monitor their effect on vaccine effectiveness.



Influenza A(H3N2) viruses predominated during the influenza 2016/2017 season and showed extensive genetic diversification. A high vaccination failure rate was noticed during the 2016/17 season in Greece, especially among the elderly.


The scope of the study was to investigate the genetic characteristics of A(H3N2) circulating viruses and viruses detected in vaccinated patients.

Study design

Virus samples originated from vaccinated and unvaccinated patients, obtained at the National Influenza Centre for northern Greece. Phylogenetic analysis and comparison of the haemagglutinin gene of the viruses to the vaccine virus A/Hong Kong/4801/2014 was performed.


The majority of analysed viruses are clustering in the genetic clade 3C.2a, and in a newly emerged subclade, designated as 3C.2a1. The highest proportion of viruses detected in vaccinated patients fell into a distinct subcluster within the 3C.2a1 subclade, which is characterised by the amino acid substitutions N122D and T135 K in haemagglutinin.


Viruses that belong to the 3C.2a clade are generally considered to resemble antigenically to the northern hemisphere vaccine component A/Hong Kong/4801/2014 that was recommended by WHO to be included also into the 2017/18 vaccine.
However, viruses belonging to a specific 3C.2a1 subcluster was extensively circulating in northern Greece and among vaccinated individuals. Both substitutions carried by this strain were located on antigenic sites and caused losses of N-linked glycosylation sites of the virus, which could potentially affect viral antigenicity. Further studies are needed to determine the antigenicity of this variant strain and its possible implication in vaccine effectiveness.

The 64$ question is which subclade of H3N2 will dominate the northern hemisphere this fall and winter.  Clade 3C.2a should be a pretty good match to this fall's vaccine, while there are nagging questions over the vaccine's effectiveness against some variants of clade 3C.2a1.

The most recent Influenza Virus Characterization from the ECDC  - based on very limited virus sampling this summer - writes:
Genetic characterization

For specimens collected between weeks 21/2017 and 26/2017, genetic characterization of 3 viruses has been reported. Two were B/Yamagata lineage viruses and one fell into the A(H3N2) 3C.2a1 subclade defined by N171K amino acid substitution, often with N121K, in the haemagglutinin.
Viruses in this clade have been antigenically similar to the vaccine component clade (3C.2a), but both clades are evolving rapidly with the emergence of several virus clusters defined by additional amino acid substitutions in the haemagglutinin, thereby requiring continued monitoring of antigenic characteristics. See also the WHO CC London February 2017 report.

As we go into each year’s flu season, we are always presented with a  `Forrest Gump’ moment, as we never really know what we are going to get.  This year appears no different.

Stay tuned.

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