#14,032
With the 2018-19 Northern Hemisphere just now winding down, we are already looking ahead to what could be a rocky 2019 Southern Hemisphere flu season, and the return of seasonal flu north of the equator next fall.
All flu seasons bring a certain degree uncertainty, but over the past few years the growing diversity of H3N2 viruses has added additional complexity to the twice annual selection of flu vaccine strains.So much so, that last February - when the WHO normally decides on what 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).
Making matters worse, in many other regions of the world, other antigenically distinct H3N2 clades continue strong, making the selection of next fall's H3N2 vaccine component even more difficult.
The most recent ECDC Influenza Characterisation report lists the current H3N2 players on the field:
Viruses in clades 3C.2a and 3C.3a have circulated since the 2013–14 northern hemisphere influenza season, with clade 3C.2a viruses having dominated since the 2014–15 influenza season, notably subclade 3C.2a2 viruses, though subgroup 3C.2a1b viruses have predominated in recent months (Figure 2).
The HA gene sequences of viruses in both clades continue to diverge. Notably, clade 3C.3a viruses have evolved to carry HA1 amino acid substitutions of L3I, S91N, N144K (loss of a N-linked glycosylation motif at residues 144-146), F193S and K326R compared to A/Stockholm/6/2014 and the number of detections in January 2019 has increased in certain WHO European region countries (Belgium, France, Germany, Israel, Netherlands and Spain; Figure 2) and North America. New genetic groups have also emerged among the clade 3C.2a viruses, designated as subclades/subgroups. Amino acid substitutions that define these subclades/subgroups are:
In late March the WHO decided to switch to the surging Clade 3C.3a H3N2 virus, betting that it will become the dominant H3 strain worldwide by next fall. Meanwhile, Australia and New Zealand will face their winter flu season using last year's selected H3N2 vaccine candidate (Subclade 3C.2a2).
- 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/7295/2014 a cell culture-propagated surrogate for A/Hong Kong/4801/2014 (a former vaccine virus).
- 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 (2018–19 northern hemisphere vaccine virus).
- 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 H311Q in HA1, e.g. A/La Rioja/2202/2018, with many viruses in this subgroup carrying additional HA1 amino acid substitutions.
- Subclade 3C.2a2 – those in clade 3C.2a plus T131K, R142K and R261Q in HA1, e.g.• A/Switzerland/8060/2017 (2019 southern hemisphere vaccine virus).
- Subclade 3C.2a3 – those in clade 3C.2a plus N121K and S144K in HA1, e.g. A/Cote d’Ivoire/544/2016
- 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/England/538/2018.
As if things we're complicated enough, for the past 5 years H3N2 viruses have been very difficult to analyze, as explained by the ECDC below:
As described in many previous reports, influenza A(H3N2) viruses have continued to be difficult to characterise antigenically by HI assay due to variable agglutination of red blood cells (RBCs) from guinea pigs, turkeys and humans, often with the loss of ability to agglutinate any of these RBCs. As was first highlighted in the November 2014 report 3 , this is a particular problem for most viruses that fall in genetic clade 3C.2a.All of which brings us to the latest highly detailed ECDC characterization report (PDF File). I've reproduced the summary below, but this is only a small fraction of a much larger report.
As you will see, H1N1 viruses in circulation continue to appear to be a good match to the vaccine strain, but most of the H3N2 viruses that they tested were poorly recognized by the existing flu vaccine.I'll have a bit more after the break.
Summary
This is the fifth report for the 2018–19 influenza season. As of week 14 in 2019, 197 027 influenza detections across the WHO European Region had been reported. Detections were 99.1% type A viruses, with A(H1N1)pdm09 prevailing over A(H3N2), and 0.9% type B viruses, with 72 (67%) of 108 ascribed to a B/Yamagata-lineage.
Since the February 2019 characterisation report 1 , a further five shipments of influenza-positive specimens from EU/EEA countries have been received at the London WHO CC, the Francis Crick Worldwide Influenza Centre (WIC). A total of 1 037 virus specimens, with collection dates after 31 August 2018, have been received.
A total of 103/105 (98.1%) A(H1N1)pdm09 test viruses characterised antigenically since the February 2019 characterisation report showed good reactivity with antiserum raised against the 2018–19 vaccine virus, A/Michigan/45/2015 (clade 6B.1). The 304 test viruses with collection dates from week 40 of 2018 genetically characterised at the WIC, including an H1N2 reassortant, have all fallen in a 6B.1 subclade, designated 6B.1A, defined by HA1 amino acid substitutions of S74R, S164T and I295V. Of these recently circulating viruses, 273 also have HA1 S183P substitution, often with additional substitutions in HA1 and/or HA2.
Since the last report, only 46 A(H3N2) viruses successfully recovered had sufficient HA titre to allow antigenic characterisation by HI assay in the presence of oseltamivir. These viruses were poorly recognised by antisera raised against the currently used vaccine virus, egg-propagated A/Singapore/INFIMH-16- 0019/2016, in HI assays.
Of the 247 viruses with collection dates from week 40 of 2018 genetically characterised at the WIC, 224 were clade 3C.2a (with 29 3C.2a2, nine 3C.2a3, five 3C.2a4 and 181 3C.2a1b) and 23 were clade 3C.3a.
Recent clade 1A B/Victoria-lineage viruses carry HA genes that encode HA1 amino acid substitutions of I117V, N129D and V146I were compared to a previous vaccine virus, B/Brisbane/60/2008. 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 triple deletion group having subgroups of Asian and African origin. HI analyses with panels of post-infection ferret antisera have shown these virus groups to be antigenically distinguishable.
One virus that was characterised since the last report is of the Asian [Δ162–164, 1A(Δ3)] subgroup. Of the five viruses characterised from EU/EEA countries, one was Δ162–163 and four Δ162–164 (three African and one Asian subgroup).
Including the three B/Yamagata-lineage viruses reported here, nine from the 2018–19 season have been characterised. All have HA genes that fall in clade 3 and encode HA1 amino acid substitutions of L172Q and M251V compared to the vaccine virus B/Phuket/3073/2013, but remain antigenically similar to the vaccine virus that is recommended for use in quadrivalent vaccines for current and subsequent northern hemisphere influenza seasons.
In Epi Week 15 Clade 3C.3a comprised roughly 90% of the H3N2 viruses categorized by the CDC in the United States (see CDC FluView) - and while it is gaining ground in Europe - it doesn't yet appear to be dominant.
The ECDC describes the current mix of H3N2 viruses:
Globally, the majority of viruses with collection dates from 1 September 2018 have HA genes that continue to fall into genetic groups within clade 3C.2a, with those in subgroup 3C.2a1b having been more numerous than those in subclade 3C.2a2 from September 2018–February 2019 (Figure 2).
Notably, a significant number of the subgroup 3C.2a1b viruses have fallen in two recently emerged clusters: one defined by amino acid substitutions T131K and K135T (a reversion resulting in re-establishment of the 133-135 glycosylation sequon) in HA1 with V200I in HA2 and the other by T128A substitution in HA1 (resulting in loss of a potential glycosylation sequon).
Furthermore, as indicated above, the number of clade 3C.3a virus detections has increased in recent weeks in a number ofAs the number of viral players increase, so do the number of possible outcomes. Among the known unknowns, we are waiting to see:
countries/regions
- Which H3N2 strain dominates the Southern Hemisphere flu season, and how well the existing vaccine handles it
- Whether clade 3C.3a continues to rise globally, as it has in the United States
- Whether (or how much) the delay in picking a vaccine strain will impact the delivery of flu shots next fall
- If the 2019-2020 flu season is dominated by H3N2 or H1N1
- Whether H3N2 clade 3C.3a persists throughout next year's flu season, or - as we've seen this season - is overtaken by something else
- And finally, how well next fall's vaccine will work against the (then) currently circulating strains
Download
Influenza virus characterisation, March 2019 - EN - [PDF-3.59 MB]
