Monday, July 02, 2018

ECDC: Influenza Virus Characterisation, May 2018


Every month or so the ECDC  publishes a review of recently isolated seasonal flu viruses collected in the EU they call an Influenza Virus Characterization Report.  Today they have published their 5th review of the 2017-18 influenza season, with data as of May of this year.
There are currently 4 main categories of seasonal flu viruses (A/H1N1, A/H3N2, B/Yamagata and  B/Victoria), but within each of these subtype/lineages there can be multiple variants and/or clades.
While influenza viruses are always evolving, in recent years - particularly with H3N2 subtype - we've seen the emergence of a number of new subclades, and (often subtle) amino acid changes that can make antigenic changes in the virus.

This not only complicates future vaccine virus selection - it can lower the effectiveness of the current vaccine - an all too familiar outcome over the past few years (see last October's ECDC: H3N2 Flu Vaccine Component Likely `Suboptimal').

H1N1, on the other hand, has remained remarkably stable since it emerged 9 years ago, requiring only one vaccine virus change since the 2009 pandemic. Influenza B viruses are typically slower to evolve than influenza A viruses, but must still be monitored for signs of antigenic changes.

Executive summary

This is the fifth report of the 2017–18 influenza season. As of week 20/2018, nearly 240 000 influenza detections across the WHO Europe region have been reported. Types A and B viruses have been detected in the proportions 44% and 56%, respectively, with A(H1N1)pdm09 viruses being slightly more prevalent than A(H3N2) (1:0.98) and B/Yamagata being significantly more prevalent than B/Victoria viruses (52.5:1).

Twenty-nine EU/EEA countries have shared influenza-positive specimens with the London WHO CC, Crick Worldwide Influenza Centre (WIC), since week 40/2017, with 1 281 specimens having collection dates after August 2017.  

The 49 A(H1N1)pdm09 test viruses characterised antigenically showed good reactivity with antiserum raised against the 2017–18 vaccine virus, A/Michigan/45/2015. The 210 test viruses with collection dates from week 40/2017 genetically characterised at the WIC, as others from the European Region recently deposited in the GISAID EpiFlu database, have all fallen in subclade 6B.1, defined by HA1 amino acid substitutions S162N and I216T, the great majority with additional substitutions of S74R, S164T and I295V.

Of 215 A(H3N2) viruses successfully recovered to date, only 44 (20%) had sufficient HA titre to allow antigenic characterisation by HI assay in the presence of oseltamivir, of which seven were tested since the last report. The majority of these 44 viruses were poorly recognised by antisera raised against the currently used vaccine virus, egg propagated A/Hong Kong/4801/2014, in HI assays.
Of the 251 viruses with collection dates from week 40/2017 genetically characterised at the WIC, 247 were clade 3C.2a (with 144 3C.2a2, 78 3C.2a1, 21 3C.2a3 and four 3C.2a4 subclade viruses) and four were clade 3C.3a. Of the 78 subclade 3C.2a1 viruses 73 and 3, respectively, fell in subgroups 3C.2a1b and 3C.2a1a.

Nine B/Victoria-lineage viruses were tested by HI, and eight reacted well only with post-infection ferret antisera raised against tissue culture-propagated cultivars of B/Norway/2409/2017 and B/Colorado/06/2017, viruses with a deletion of two amino acids in HA1 (Δ162-163). Of the 41 viruses characterised genetically at the WIC with a collection date after week 40/2017, 11 fell within clade 1A and 30 fell within the subgroup (1A(Δ2)) carrying the HA1 double amino acid deletion.  

A total of 58 B/Yamagata viruses were characterised antigenically and all reacted well (within fourfold of the homologous titre) with post-infection ferret antiserum raised against egg-propagated B/Phuket/3073/2013, the recommended vaccine virus for use in quadrivalent vaccines for the northern hemisphere 2017–18 and 2018–2018–19 seasons and for trivalent vaccines in the southern hemisphere 2018 season. The 298 viruses with collection dates from week 40/2017 genetically characterised at the WIC, as others recently circulating in the European region and reported to the GISAID EpiFlu database, fall within genetic clade 3.
Influenza virus characterisation, Summary Europe, May 2018

Below you'll find the list of growing number of  clades, subclades, and subgroups of seasonal H3N2 collected in the EU from this month's report.
Phylogenetic analysis of the HA genes of representative A(H3N2) viruses from Europe with recent collection dates, after 31 August 2017 as available in the GISAID EpiFlu database, is shown in Figure 2. Viruses in clades 3C.2a and 3C.3a have been in circulation since the 2013–14 northern hemisphere influenza season, with clade 3C.2a viruses predominating since the 2014–15 influenza season and continuing to predominate in recent months (Figure 2), but the HA gene sequences continue to diverge. 

New subclades and new genetic subgroups have been adopted. Amino acid substitutions that define these subclades and subgroups are:

Clade 3C.2a: L3I, N144S (resulting in the loss of a potential glycosylation site), F159Y, K160T (in the majority of viruses, resulting in the gain of a potential glycosylation site) and Q311H in HA1, and D160N in HA2, e.g. A/Hong Kong/4801/2014.

Subclade 3C.2a1: Those in clade 3C.2a plus: N171K in HA1 and I77V and G155E in HA2, most also carry N121K in HA1, e.g. A/Singapore/INFIMH-16-0019/2016.
Subgroup 3C.2a1a: Those in subclade 3C.2a1 plus T135K in HA1, resulting in the loss of a potential glycosylation site, and also G150E in HA2, e.g. A/Greece/4/2017.
Subgroup 3C.2a1b: Those in subclade 3C.2a1 plus K92R and H311K in HA1, e.g. A/England/74560298/2017.
Subclade 3C.2a2: Those in clade 3C.2a plus T131K, R142K and R261Q in HA1, e.g. A/Norway/4465/2016.
Subclade 3C.2a3: Those in clade 3C.2a plus N121K and S144K in HA1, e.g. A/Norway/4849/2016.

Subclade 3C.2a4: Those in clade 3C.2a plus N31S, D53N, R142G, S144R, N171K, I192T, Q197H and A304T in HA1 and S113A in HA2, e.g. A/Valladolid/182/2017.
Clade 3C.3a: T128A (resulting in the loss of a potential glycosylation site), R142G and N145S in HA1 which defined clade 3C.3 plus A138S, F159S and N225D in HA1, many with K326R, e.g. A/Switzerland/9715293/2013.
The great majority of recently circulating viruses have HA genes that fall into genetic groups within clade 3C.2a, with a low number of viruses falling in clade 3C.3a. Within EU/EEA countries recently circulating viruses have fallen in approximately equal proportions into subclades 3C.2a2 and 3C.2a1, with the majority of viruses in thelatter subclade having HA genes that fell into genetic subgroup 3C.2a1b (Figure 2).
The location of A/Singapore/INFIMH-16-0019/2016 (3C.2a1), the A(H3N2) virus recommended for inclusion in vaccines for the southern hemisphere 2018 [2] and the northern hemisphere 2018–2019 influenza seasons [3], is indicated in Figure 2.

This fall's Northern Hemisphere H3N2 component (A/Singapore/INFIMH-16-0019/2016 (H3N2)-like) is the same that is currently being used in the Southern Hemisphere flu vaccine. This should give us some idea of how well it works. 
Hopefully it will improve upon last year's sub-par VE (Vaccine Effectiveness) against H3N2, but concerns remain over the impact of egg-propagated flu vaccines (see PNAS: Egg-Passaged Flu Vaccine Antibodies Poorly Neutralize Recent H3N2 Viruses).
The continued evolution and growing diversification of seasonal H3N2 - which has helped contribute to underwhelming flu vaccine performance (at least against H3N2 viruses) the past several years - makes the development of a `universal flu shot' an increasingly important goal.

For more on the challenges involved, you may wish to revisit J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine.

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