Thursday, July 05, 2018

JID: Antigenic Drift of H7N9 Viral Hemagglutinin


Anyone who as been following seasonal flu the past few years is aware that the H3N2 strain has become the problem child of the flu world, as it continues to evolve rapidly, and has diversified into numerous co-circulating subclades.
As a result, vaccine candidate virus selection for the seasonal flu vaccine has been greatly complicated, and VE (Vaccine Effectiveness) against H3N2 has been `suboptimal' at best.
While all influenza viruses evolve incrementally via antigenic drift (or abruptly, via reassortment), the H3N2 subtype has been an over-achiever for the past 4 or 5 years.  Today we learn, via a report in the Journal of Infectious Diseases, that H3N2 isn't alone.  

The authors report that H7N9 - which is ranked by the CDC as having the highest pandemic potential of the currently circulating novel flu viruses - is mutating at a rate comparable to H3N2.
While H7N9 activity has been dramatically dampened down over the past 12 months following China's roll-out of an experimental poultry vaccine, today's study raises new questions over how long that vaccine formula will remain effective.
First the abstract, and a couple of small snippets from the body of the study, then I'll return with a bit more.

Antigenic Drift of H7N9 Viral Hemagglutinin

The Journal of Infectious Diseases, jiy408,
Published: 05 July 2018


Since its emergence in 2013, there have been five H7N9 influenza epidemic waves in China. However, evolution of the hemagglutinin (HA) antigenicity has not been systematically investigated.
To better understand how antigenic drift in HA proteins of H7N9 occurs, 902 H7N9 HA sequences from public database were retrieved and analyzed. 53 mutants with single amino acid substitutions in HA were introduced into pseudoviruses and their antigenic characteristics were analyzed using pseudovirus-based assays.


Nine mutations incrementally increased over the past 5 years, with mutations identified at multiple sites. While mean neutralization titers of most variants remain unchanged, three mutations, A143V, A143T and R148K displayed a median 4-fold lower susceptibility to neutralization by antisera against A/Anhui/1/2013(H7N9) (A/Anhui).

Notably, A143V and A143T were located outside the previously reported antigenic sites. The most dominant variant (A143V/R148K) in the most recent season constitutes 74.11% of all mutations and demonstrated a 10-fold reduction in its reactivity to A/Anhui antisera.

Importantly, compared to DNA construct without the corresponding HA mutation, DNA vaccine encoding A143V/R148K mutant induced a 5-fold increase in the neutralizing activity against this circulating virus.

Appropriate vaccine strain should be considered in response to increasing antigenic drift in H7N9 HA.


Since H7N9 emerged, the outbreak of this virus in human has occurred in 5 epidemic waves. Through analysis, we found that the H7N9 HA protein is mutating with a high rate of about 1.79×10 -3 amino acid substitutions per site per year, which was similar to H3N2 virus HA, whose overall rate for replacement substitutions is 10.8 × 10 codons/year[26].


These findings, if substantiated by future studies using sera against other H7N9 candidate vaccine strains, may have important implications for the future selection of vaccine strain. In addition, the A143T mutation has been reported as a molecular marker for mammalian adaptation and virulence in H10N8 virus.[32]. Therefore, enhanced surveillance of antigenic change of H7N9 is still urgently needed and the combination of A143V and R148K along with A143T
should be closely monitored.

(Continue . . . )

Not all mutations in the flu virus are bad, in fact, most either prove benign or actually detrimental to the virus's overall biological fitness.  
Our understanding of exactly what amino acid substitutions (or, more likely what combination of substitutions) really matter is still fairly limited, a topic that is addressed in a review of the above study, appearing in the same issue of the JID.
Both articles are available for download as `accepted manuscripts' in PDF format.

Influenza A (H7N9) virus evolution: Which genetic mutations are antigenically important?
Joshua G Petrie Adam S Lauring

The Journal of Infectious Diseases, jiy409,

Published: 05 July 2018


Not unexpectedly, influenza A (H7N9) viruses have continued to evolve since they first began infecting humans. This has resulted in antigenic changes in the viruses that infect humans and increased virulence in avian species.
The degree to which poultry vaccination has limited recent human infection and how the vaccination program will further shape the genetic and antigenic characteristics of these viruses remain open questions.
Therefore, integrated genetic and antigenic monitoring of these viruses in humans and birds remains essential for informing public health interventions, human vaccine development, and pandemic preparedness.
        (Continue . . . )

As we've discussed previously (see Sci. Reports: Efficacy Of AI Vaccines Against The H5N8 Virus in Egypt), well matched poultry vaccines can be very effective in preventing morbidity and mortality, and reducing viral shedding, in infected poultry.
But as avian viruses evolve, existing poultry vaccines become increasingly less effective (see Egypt: A Paltry Poultry Vaccine). and history has shown many countries continue to use outdated vaccines.
Poor vaccine matches can then allow AI viruses to spread silently among flocks, to continue to reassort and evolve, and potentially lead to the emergence new subtypes of avian flu.

All of which means that the welcomed lull in H7N9 activity in China today may not last forever, and that China's MOA must be prepared to continually refine their poultry vaccine to deal with a rapidly changing virus-scape, if it is to remain effective.

And of course, vaccine candidates for humans will need to be updated frequently as well, which means that stockpiling large quantities of any H7N9 pandemic vaccine in advance is likely futile.  

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