Cell Reports: A Dominant Gene Constellation Emerged For H7N9 In Wave 5

http://www.cell.com/cell-reports/pdf/S2211-1247(18)30442-X.pdf

#13,277


During the first three waves of H7N9 (which began in the spring of 2013) we saw an explosion in the number of genotypes reported, with literally scores of genetically distinct H7N9 viruses circulating in China.

In the first year alone (Feb 2013 - Feb 2014) researchers identified - out of 146 H7N9 viruses available with full genome sequences - at least 26 different genotypes (see Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission).

Many of these genotypes proved to be flashes in the pan - detected once or twice - and were quickly supplanted by more biologically `fit' variants. A handful of others were more robust, and widespread.

But this illustrates just how volatile H7N9's evolutionary process really was, and why it quickly sparked concerns that the virus was on a path toward becoming a pandemic virus.

After three impressive waves, the 4th wave in China was markedly smaller, raising hopes the virus was losing steam. But the 5th wave was the largest to date; nearly equaling the total of the 4 previous waves (see graphic at top of blog) combined.

The 5th wave was also notable for the emergence of a new, dominant LPAI lineage (Yangtze River Delta) - dethroning the original Pearl River Delta lineage - and an HPAI variant which surfaced in Guangdong Province and began to spread (see MMWR: Increase in Human Infections with Avian Influenza A(H7N9).

We've also seen a number of mammalian adaptations reported (see J. Virol.: Spread & Evolution of HPAI & LPAI H7N9 During 5th Wave - China) which may have contributed to last year's record-setting epidemic. 


Today we've a new research article which appears in Cell Reports that finds the rapid expansion of H7N9 genotypes during the earlier waves appears to have - at least temporarily - slowed dramatically during the 5th wave.

Moreover, a single dominant gene constellation appears to have been responsible for the bulk of the human infections during the 5th wave. 

We've a very long, detailed, open-access report today from Cell Reports that describes this abrupt change in the evolution of H7N9. Due its length, I've only included some excerpts - so you'll want to follow the link to read it in its entirety. 

A Gene Constellation in Avian Influenza A (H7N9) Viruses May Have Facilitated the Fifth Wave Outbreak in China
 
Wenfei Zhu3, Jie Dong3, Ye Zhang3, Lei Yang3, Xiyan Li3, Tao Chen, Xiang Zhao, Hejiang Wei, Hong Bo, Xiaoxu Zeng, Weijuan Huang, Zi Li, Jing Tang, Jianfang Zhou, Rongbao Gao, Li Xin, Jing Yang, Shumei Zou, Wenbing Chen, Jia Liu
, Yuelong Shu4,'Dayan Wang  

Open Access
DOI: https://doi.org/10.1016/j.celrep.2018.03.081 |

Highlights

• H7N9 viruses inherited NP genes from co-circulated H7N9 instead of H9N2 viruses
• H7N9 viruses appear to have entered a relatively stable stage
• One gene constellation is identified as having emerged in H7N9 viruses
• The largest outbreak in wave V may be due to the gene constellation

Summary

The 2016–2017 epidemic of influenza A (H7N9) virus in China prompted concern that a genetic change may underlie increased virulence. Based on an evolutionary analysis of H7N9 viruses from all five outbreak waves, we find that additional subclades of the H7 and N9 genes have emerged.

Our analysis indicates that H7N9 viruses inherited NP genes from co-circulating H7N9 instead of H9N2 viruses. Genotypic diversity among H7N9 viruses increased following wave I, peaked during wave III, and rapidly deceased thereafter with minimal diversity in wave V, suggesting that the viruses entered a relatively stable evolutionary stage.

The ZJ11 genotype caused the majority of human infections in wave V. We suggest that the largest outbreak of wave V may be due to a constellation of genes rather than a single mutation. Therefore, continuous surveillance is necessary to minimize the threat of H7N9 viruses.

(VERY BIG SNIP)


Discussion

The fifth epidemic of H7N9 in China was marked by extensive geographical spread infecting both poultry and humans. The number of human infections reported in the fifth epidemic was almost as many as reported during the previous four epidemics combined.

Epidemiological characteristics, including age, sex distribution, and exposure history of human infections with influenza A (H7N9) virus in China, reported during the fifth wave were similar to those reported for the previous four waves (Xiang et al., 2016). 

This indicates that it may, in fact, be the genetic or antigenic characteristics of the viruses that might have changed. After comprehensive evolutionary analysis of the influenza A (H7N9) viruses from all five waves, we found that viral genetic diversity increased dramatically from wave II to wave IV but significantly decreased in wave V. The reduced genetic diversity in wave V and similar inferred evolutionary change rates in H7 and N9 genes during each wave (Figure S3) may indicate slower adaptation of H7N9 viruses.

Indeed, we found that the ZJ11 genotype viruses were responsible for the majority of human infections in wave V. A gene constellation presented in ZJ11 genotype viruses that we suggest is associated with increased transmission among poultry or from poultry to humans. One of the gene constellation changes, PB2-A588V, had been proven to enhance the pathogenicity of H7N9, H10N8, and H9N2 viruses in mice (Xiao et al., 2016). However, one single mutation was not sufficient to cause the largest outbreak in wave V. 

The rapidly increased number of human infections in wave V would be expected to be associated with a combination of substitutions. Thus, vigilance and further studies of other gene constellation markers are urgently needed to investigate potential links with increased infectivity and transmissibility of the H7N9 viruses.

(SNIP)

In summary, our study indicates that influenza A (H7N9) viruses underwent a period of rapid adaptation via dynamic reassortment and then entered a relatively stable stage of the evolutionary process.

Our findings reveal the emergence of a gene constellation that may have been associated with the largest outbreak of wave V. Other uncertainty could also contribute to the increased number of cases in wave V, including the unknown environmental, behavioral, changes in social factors or the poultry trade, etc. 

While further follow-up on the gene constellation is required, dominant genotype viruses containing the gene constellation found here and the repeated emergence of H7N9 variants may lead to an increased pandemic risk. Field investigations on H7N9 viruses are needed for close monitoring of changes in these viruses. The implementation of effective control measures is also of paramount importance to reduce the opportunity for a pandemic to arise.

(Continue . . . .)

While a reduction in the volatility of H7N9's evolution would seem to be a good thing - this stabilization could also mean the virus has optimized itself into a reasonably  robust genotype, and now only needs to accrue some more mammalian adaptations to become a genuine pandemic threat. 

Another wild card to consider is last summer's introduction of an H5+H7 AI vaccine in China, and their national campaign to inoculate the nation's poultry.

While we've seen a dramatic drop in poultry outbreaks and human infections this winter, as we’ve discussed previously (see  MPR: Poultry AI Vaccines Are Not A `Cure-all’ & The HPAI Poultry Vaccine Dilemma), poultry AI vaccines can have some serious down sides.

They often suppress bird flu, but they don't always eliminate it. 

As avian viruses evolve, poultry vaccines tend to become increasingly less effective; often only masking the symptoms of infection (see Egypt: A Paltry Poultry Vaccine).

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. 

A few earlier blogs on that include:

Virology: Selection Of Antigenic Variants Of An H5N1 HPAI Virus In Vaccinated Chickens

Subclinical Highly Pathogenic Avian Influenza Virus Infection among Vaccinated Chickens, China).

Study: Recombinant H5N2 Avian Influenza Virus Strains In Vaccinated Chickens

EID Journal: Subclinical HPAI In Vaccinated Poultry – China

The bottom line is, despite the welcome drop in H7N9 this winter, there are too many variables in play to even begin to guess where this virus goes from here.  Or what replaces it if it somehow miraculously fades away.

Stay tuned.