Friday, March 22, 2019

WHO Selects Fall H3N2 Flu Shot Component: Clade 3C.3a

Recent FluView H3N2 Clade Charts


The chart above shows the rapid rise in the detection of the 3C.3a clade of the H3N2 virus in the United States since the first of January - rising from an 18% share to nearly 60% in a matter of a couple of months.
In light of this rapidly evolving fluscape, a month ago in WHO: (Partial) Recommended Composition Of 2019-2020 Northern Hemisphere Flu Vaccine, the World Health Organization made the unusual decision to delay selection of the H3N2 component for next fall's flu vaccine for 30 days to further evaluate the recent rise of this new, antigenically distinct strain (clade 3C.3a).

They wrote:
The majority of A(H3N2) viruses collected from September 2018 to January 2019 belonged to the phylogenetic subclade 3C.2a1b; however, the number of clade 3C.3a viruses has increased substantially since November 2018 in several geographic regions.

There has continued to be considerable genetic diversification of the HA and NA genes, but viruses in subclade 3C.2a2 were much less prevalent than in the previous reporting period.
Yesterday the WHO announced their decision on the H3N2 strain for this fall's vaccine - selecting a 3C.3a clade virus - based on its recent and very rapid rise in the United States, Israel, and and parts of Europe.
It is, admittedly, a gamble. There is no guarantee clade 3C.3a will be the dominant global clade six months from now, as H3N2 viruses continue to change and evolve at a rapid and unpredictable rate.
But since the VE (Vaccine Effectiveness) of the last several H3N2 flu components haven't been anything to brag about (see ECDC: H3N2 Flu Vaccine Component Likely `Suboptimal'), right now rolling the dice on this up and coming clade makes sense.

First, some excerpts from yesterday's announcement, then I'll return with a brief postscript.
Addendum to the recommended composition of influenza virus vaccines for use in the 2019–2020 northern hemisphere influenza season
21 March 2019
On 21 February 2019 WHO announced a recommendation on the composition of three of the four components of influenza vaccines for use in the 2019-2020 northern hemisphere influenza season (
The decision on the A(H3N2) component was postponed to allow more time to better understand the distribution and proportions of recently circulating antigenically and genetically  diverse A(H3N2) viruses and to develop and fully characterize appropriate candidate vaccine viruses. This addendum provides the recommendation and supporting data for the A(H3N2) component of 2019-2020 northern hemisphere influenza vaccines.
Additional data obtained in recent weeks has confirmed the wide regional differences in the relative proportion of A(H3N2) viruses belonging to the phylogenetic subclade 3C.2a1b and clade 3C.3a.
The majority of A(H3N2) viruses collected and genetically characterised from September 2018 to February 2019 belonged to the phylogenetic subclade 3C.2a1b; however, the proportion of viruses falling into clade 3C.3a has increased substantially since November 2018 in several countries in western Europe, Israel and especially in the United States of America.
HI and virus neutralisation assays with ferret antiserum panels showed that viruses from subclade 3C.2a1b and clade 3C.3a were antigenically distinct. The majority of recent viruses from subclade 3C.2a1b were inhibited well by post-infection ferret antisera raised against cell culture-propagated A/Singapore/INFIMH-16-0019/2016-like viruses of subclade 3C.2a1 (Table 1).
In contrast, ferret antisera raised against egg-propagated A/Singapore/INFIMH-16-0019/2016-like and egg-propagated A/Switzerland/8060/2017-like viruses of subclade 3C.2a2 inhibited a much smaller proportion of recently circulating viruses (Table 2). Viruses from clade 3C.3a were poorly inhibited by post-infection ferret antisera raised against cell culture-propagated A/Singapore/INFIMH-16-0019/2016-like viruses, but were well inhibited by ferret antisera raised against recent 3C.3a cell culture-propagated reference viruses such as A/Kansas/14/2017 (Table 1).
Ferret antisera raised against egg-propagated A/Kansas/14/2017 inhibited recent viruses from clade 3C.3a but showed little inhibition against viruses from clade 3C2a1b. Current vaccines containing A/Singapore/INFIMH-16-0019/2016-like antigens induced antibodies in humans that cross-reacted with recent 3C.2a1b viruses but reacted poorly with clade 3C.3a viruses.
Accordingly, it is recommended quadrivalent vaccines for use in the 2019-2020 northern hemisphere influenza season contain the following:
- an A/Brisbane/02/2018 (H1N1)pdm09-like virus;
- an A/Kansas/14/2017 (H3N2)-like virus;
- a B/Colorado/06/2017-like virus B/Victoria/2/87 lineage); and
- a B/Phuket/3073/2013-like virus (B/Yamagata/16/88 lineage).
It is recommended that the influenza B virus component of trivalent vaccines for use in the 2019-2020 northern hemisphere influenza season be a B/Colorado/06/2017-like virus.
Lists of egg- or cell culture-propagated candidate vaccine viruses (CVVs) suitable for use in human vaccine production are available on  the WHO website 1 . Lists of reagents for vaccine standardisation, including those for this recommendation, can be found on the same WHO website 1 . 

The 4 week delay in deciding on the H3N2 component may result in a 2-4 week delay in vaccine deliveries in the fall, according to the WHO, but they are working on minimizing those impacts. 
The H3N2 virus emerged as a pandemic strain in 1968 (supplanting  a short 11 year run of seasonal  H2N2), settling in the following year as a seasonal flu strain and remained the sole human influenza A strain until 1977, when H1N1 mysteriously reappeared after a 20 year absence.
That makes it the longest-continuously-circulating Influenza A subtype on record by a wide margin.  In order to survive and thrive for half a century, it has to be very good at changing up its game, and avoiding acquired community immunity.

All of which means, unless and until it is supplanted by a new pandemic strain, H3N2 is likely to remain the bane of flu experts, flu victims, and vaccine manufacturers for years to come.

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