Monday, March 26, 2018

J. Virol.: Spread & Evolution of HPAI & LPAI H7N9 During 5th Wave - China

Wave 5 As of Sept 2017 -  Credit FAO


Despite its unexpected disappearing act this winter, H7N9 remains the novel flu virus that is viewed as our greatest pandemic threat.  Not only due to its high mortality rate (30%+ among hospitalized patients) and the record number of cases last year, but because of its incredible (and continually growing) diversity.  
Last year a new LPAI Yangtze River Delta lineage emerged as dominant - dethroning the original Pearl River Delta lineage - and an HPAI variant surfaced in Guangdong Province and began to spread (see MMWR: Increase in Human Infections with Avian Influenza A(H7N9).
Add to this literally dozens of genotypes created by freewheeling reassortment between H7N9, H9N2, H6Nx and H7Nx viruses (see below), and the emergence of mammalian adapted amino acid substitutions (eg. E627K and A588V in PB2) and we end up with not one - or even ten - competent H7N9 viruses in circulation - but dozens. 

Just last week, in Arch. Virology: Co-circulation Of Multiple Genotypes of H7N9 in Eastern China, 2016-2017, we looked at a study that identified 18 different H7N9 genotypes out of just 41 samples collected in Jiangsu Province.
All 41 samples carried the HA G186V and Q226L/I amino acid substitutions, which are linked to switching the virus from binding preferentially to avian (a2,3) receptor cells to mammalian (a2,6) receptor cells.
Today's report, from the Journal of Virology, doubles the number of genotypes (n=36), and importantly, describes amino acid (aa) mutations that promote both NAI resistance and mammalian adaptations in some isolates collected from non-human hosts.

It isn't unheard of to find these aa changes in a human host (particularly one receiving antivirals), but it becomes more significant to find them circulating in the wild. The full study is behind a pay wall, but we get the gist from the abstract below. I'll return with a bit more when you are done.

New threats of H7N9 influenza virus: the spread and evolution of highly and low pathogenic variants with high genomic diversity in Wave Five
Chuansong Quana,b,Weifeng Shic,Yang Yangd,Yongchun Yange,Xiaoqing Liuf,Wen Xug,Hong Lig,Juan Lic,Qianli Wangh,Zhou Tongb,Gary Wongb,d,Cheng Zhangb,Sufang Mab,Zhenghai Mai,Guanghua Fuj,Zewu Zhangk,Yu Huangj,Houhui Songe,Liuqing Yangd,William J. Liua,Yingxia Liuc,Wenjun Liub,George F. Gaoa,b,d andYuhai Bib,d

H7N9 virus has caused five infection waves since it emerged in 2013. The highest number of human cases was seen in Wave Five; however, the underlying reasons have not been thoroughly elucidated. In this study, the geographical distribution, phylogeny and genetic evolution of 240 H7N9 viruses in Wave Five, including 35 new isolates from patients and poultry in nine provinces, were comprehensively analyzed together with strains from first four waves.
Geographical distribution analysis displayed the newly-emerging highly pathogenic (HP) and low pathogenic (LP) H7N9 viruses were co-circulating, causing human and poultry infections across China.
Genetic analysis indicated that dynamic reassortment of the internal genes among LP-H7N9/H9N2/H6Ny and HP-H7N9, as well as the surface genes between Yangtze and Pearl River Delta lineages resulted in at least 36 genotypes, with three major genotypes (G1, A/chicken/Jiangsu/SC537/2013-like, G3, A/Chicken/Zhongshan/ZS/2017-like and G11, A/Anhui/40094/2015-like).
The HP-H7N9 likely evolved from G1 LP-H7N9 by the insertion of a “KRTA” motif at the cleavage site (CS), then evolved into fifteen genotypes with four different CS motifs including PKGKRTAR/G, PKGKRIAR/G, PKRKRAAR/G and PKRKRTAR/G. Approximately 46% (28/61) of HP strains belonged to G3.
Importantly, neuraminidase (NA) inhibitor resistance (R292K in NA) and mammalian adaptation (eg. E627K and A588V in PB2) mutations were found in a few non-human-derived HP-H7N9 strains.
In summary, the enhanced prevalence and diverse genetic characteristics with mammalian-adapted and NAI-resistant mutations may have contributed towards increased numbers of human infections in Wave Five. 


The highest numbers of human H7N9 infections were observed during Wave Five from October 2016 to September 2017. Our results showed that HP-H7N9 and LP-H7N9 has spread virtually throughout China and underwent dynamic reassortment with different subtypes (H7N9/H9N2 and H6Ny) and lineages (Yangtze and Pearl River Delta lineages), resulting in a total of 36 and three major genotypes.
Notably, the NAI drug-resistant (R292K in NA) and mammalian-adapted (eg. E627K in PB2) mutations were found in HP-H7N9 not only from humans, but also from poultry and environmental isolates, indicating increased risks for human infections.
The broad dissemination of LP- and HP-H7N9 with high genetic diversity, host adaptation and drug-resistant mutations likely accounted for the sharp increases in the number of human infections during Wave Five.
Therefore, more strategies are needed against the further spread and damage of H7N9 in the world.

While welcome, the present lull in H7N9 activity in China is not guaranteed to last forever.
Last summer's massive H7+H5 poultry vaccination campaign, combined with two back-to-back seasonal flu epidemics (last summer's H3N2 and this winter's Influenza B) have likely helped  to suppress its spread. 
But the use of poultry vaccinations against AI - in China, and around the world -  has produced mixed results.
While vaccines can often protect poultry against illness -  they don't necessarily prevent infection - which can allow subclinical `stealth' infections to spread unnoticed (see PLoS One: Effectiveness of HPAI H5N1 Vaccination in Poultry - Indonesia).
Poorly matched or improperly administered vaccines can even help drive the evolution of `vaccine escape' variants, which can increase viral diversity and further diminishes the vaccines effectiveness (see Study: Recombinant H5N2 Avian Influenza Virus Strains In Vaccinated Chickens).

Which is why, despite it's no-show this winter, H7N9 remains atop the CDC's Influenza Risk Assessment Tool (IRAT) ranking list of 14 novel flu subtypes/strains that circulate in non-human hosts and are believed to possess some degree of pandemic potential.

While we wait for H7N9's next move, you may wish to revisit:
The Long Road To An H7N9 (or Any Other Pandemic) Vaccine
EID Journal: Changing Geographic Patterns/Risk Factors For H7N9 In China
J. Virology: Genesis and Spread of Newly Emerged HPAI H7N9 In China

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