Friday, February 24, 2017

Eurosurveillance: Emergence Of A Novel Subclade Of Seasonal A/H3N2 - London

Credit NIAID













#12,259


Twice each year (February & September) influenza experts from around the world meet (often electronically) to discuss recent developments in human and animal influenza viruses, and to decide on the composition of the next influenza season’s flu vaccine.  Vaccine strains must be selected for two A strains (H1N1 & H3N2) and two B strains (Victoria & Yamagata Lineage)

NIAID has a terrific 3-minute video that shows how influenza viruses drift over time, and why the flu shot must be frequently updated, which you can view at this link.

Due to the time it takes to manufacture and distribute a vaccine, these decisions must be made six months in advance, so the composition of next fall's flu vaccine is expected soon.

While we talk about 2 primary influenza A subtypes (H1N1 & H3N2) - in truth there are multiple variations of each subtype in circulation at any given time. Usually, one of these versions is dominant, but these evolving strains are constantly playing a viral game of `king of the mountain’, and the balance of power can shift quickly.

In the fall of 2014, a late arriving `drifted' H3N2 virus practically negated that year's flu vaccine's effectiveness (see CDC HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus).

Since 2009 seven distinct genetic groups have been defined for H3N2While all belong to clade 3C, they are divided into three subdivisions; 3C.1 , 3C.2, and 3C.3, with last November's ECDC Influenza Virus Characterization Report stating:

In 2014 three new subclades emerged, one in subdivision 3C.2, 3C.2a, and two in 3C.3, 3C.3a and 3C.3b , with subclade 3C.2a viruses dominating in recent months.

Yesterday's edition of  the Journal Eurosurveillance adds yet another layer of complexity to this already diverse field of H3N2 viruses. A new subclade of H3N2 - proposed as 3C.2a2 - has recently appeared in London. 

While more studies are needed - and the future spread or dominance of subclade 3C.2a2 is far from assured  - there are concerns that the current H3N2 vaccine may offer sub-optimal protection against this new strain.


Eurosurveillance, Volume 22, Issue 8, 23 February 2017
Rapid communication
Emergence of a novel subclade of influenza A(H3N2) virus in London, December 2016 to January 2017

H Harvala 1 2 , D Frampton 2 , P Grant 1 , J Raffle 2 , RB Ferns 2 3 , Z Kozlakidis 2 , P Kellam 4 , D Pillay 2 , A Hayward 5 , E Nastouli 1 3 6 , For the ICONIC Consortium 7


Correspondence: Eleni Nastouli (e.nastouli@ucl.ac.uk), Heli Harvala (heli.harvala@uclh.nhs.uk)

Citation style for this article: Harvala H, Frampton D, Grant P, Raffle J, Ferns RB, Kozlakidis Z, Kellam P, Pillay D, Hayward A, Nastouli E, For the ICONIC Consortium. Emergence of a novel subclade of influenza A(H3N2) virus in London, December 2016 to January 2017. Euro Surveill. 2017;22(8):pii=30466. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.8.30466
Received:13 February 2017; Accepted:23 February 2017

We report the molecular investigations of a large influenza A(H3N2) outbreak, in a season characterised by sharp increase in influenza admissions since December 2016. Analysis of haemagglutinin (HA) sequences demonstrated co-circulation of multiple clades (3C.3a, 3C.2a and 3C.2a1). Most variants fell into a novel subclade (proposed as 3C.2a2); they possessed four unique amino acid substitutions in the HA protein and loss of a potential glycosylation site. These changes potentially modify the H3N2 strain antigenicity.

The ongoing influenza season started early in eleven European Union countries, including England, on week 46 of 2016 [1]. The majority of reported infections have been caused by clade 3C.2a or 3C.2a1 influenza A(H3N2) viruses. The clade 3C.2a contains the current vaccine strain A/Hong Kong/4801/2014, and the first few viruses within the more recently emerged subclade 3C.2a1 were earlier shown to be antigenically matched with the vaccine component [2]. However, evidence for suboptimal vaccine effectiveness (VE) against laboratory-confirmed influenza A infection in people over 65 years-old was obtained in the first studies from Finland [3] and Sweden [4].

An outbreak of influenza A(H3N2) was first notified in our London centre on 30 December 2016. The outbreak coincided with unusually high ongoing circulation of respiratory syncytial virus (RSV) (Figure 1), and affected both patients and staff in the acute medical unit (AMU).

While infection control precautions were intensified, it resulted in multiple bay closures. We suspected that the sharp increase in the number of influenza A(H3N2) infections may have been caused by the emergence of a new genetic variant of H3N2, a hypothesis investigated through next generation sequencing (NGS) of influenza A(H3N2) strains.


(SNIP)


Discussion

In our centre in London, the early start and higher intensity of the 2016/17 influenza A(H3N2) virus epidemic mirrored that of the season 2014/15 where the subtype H3N2 also predominated. During the 2014/15 season, most influenza A(H3N2) infections in Europe were shown to be caused by antigenically drifted virus variants within the new genetic subgroup 3C.2a [8]. Our genetic analysis of London A(H3N2) viruses demonstrates ongoing co-circulation of drifted variants from multiple subclades (3C.3a, 3C.2a1 and proposed 3C.2a2). 

Four or more substitutions in two or more antibody binding sites are predicted to give an antigenically different virus [9] as in our case. Although we did not observe mutations in the seven positions suggested as being responsible for major transition clusters [10], position 144 is at the flank of the RBS, and additionally recognised as antigenic [11].

Although not necessarily determining major antigenic drift, the alterations of N-linked glycosylation sites are likely to contribute to more complex conformational changes in the HA due to gain or loss of glycosylation and can thus facilitate immune escape [12]. Furthermore, any amino acid changes in the 140–146 region of HA have been shown to be characteristic for antigenically distinct viruses of epidemic significance [9,13,14]. The amino acid substitution S144K in the emerging subclade 3C.2a2 viruses together with the loss of an N-linked glycosylation site (N122D) shows potential for antigenic drift that warrants further monitoring during this ongoing season. A limitation of our study was the lack of detailed vaccination data.

Our findings in London of the rapid emergence of genetically drifted influenza A(H3N2) viruses underscore the potential for such strains to spread rapidly in hospital environments among patients and staff. Characterising emerging strains of influenza by next generation sequencing adds to the local and national monitoring of influenza trends. Further studies are needed to investigate the antigenic effects of substitutions occurring within the newly described subclade.

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