Frontiers Cell. & Infect. Microb.: Pandemic Potential Of H7N9 In Humans

Credit FAO - Dec 5th Update

#13,723

Although you'd scarcely know it by its recent lack of activity (see FAO chart above), China's complex array of avian H7N9 viruses continue to occupy the top spot of our pandemic flu watch list.  

Not only due to its high mortality rate (30%+ among hospitalized patients) and the record number of cases during wave 5, but because of its incredible (and growing) diversity.   

During wave 5 (2016/17) 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).

We've seen literally scores of H7N9 genotypes created by the prolific reassortment between H7N9, H9N2, H6Nx and H7Nx viruses (see below). 

Add in the emergence of mammalian adapted amino acid substitutions (eg. PB2 E627K and HA G186V and Q226L/I ) and we end up with dozens of viruses with varying  degree of pandemic potential, all on their own evolutionary paths. 

Some past studies & blogs on these changes include:

Arch. Virology: Co-circulation Of Multiple Genotypes of H7N9 in Eastern China, 2016-2017

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

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

PLoS Pathogens: Three Mutations Switch H7N9 To Human-type Receptor Specificity

The dramatic and welcomed drop in H7N9 activity over the past 18 months has been credited to a last-ditch and highly successful nationwide H5+H7 poultry vaccination program over the summer of 2017, which has - at least temporarily - suppressed the virus in poultry. 

The concern is that the effectiveness of this vaccination program may diminish over time as the various strains of H7N9 evolves away from the vaccine.  We've already noted a bit of an uptick in H5N6 activity (also covered by the vaccine) over the past 4 months.

As noted yesterday, in EID Journal: Two H9N2 Studies Of Note, and previously in Vet. Sci.: The Multifaceted Zoonotic Risk of H9N2 Avian Influenza and in PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9 (among others), the continued evolution of and genetic diversity of H7N9 has been heavily intertwined with the evolution of LPAI H9N2. 

As H9N2 gains new mammalian adaptations (see Genomic Characteristics Of 2 A(H9N2) Virus Isolates From Humans In Anhui Province - 2015) it has shared them (via reassortment) with multiple strains of the H7N9 virus.  

All of which brings us to a new, open-access study, appearing in Frontiers of Cellular & Infection Microbiology, that looks at H7N9's remarkable evolution - due in large part to H9N2's genetic contributions - towards a more `humanized' virus. 

While the virus isn't quite ready for prime time, the authors warn that a failure to continue to control the virus in poultry could potentially lead to a human pandemic down the road.

Due to its length, I've only posted a few excerpts (bolding mine), so follow the link to read the report in its entirety.

Potential Pandemic of H7N9 Avian Influenza A Virus in Human 

Zhiqing Pu1, Dan Xiang2, Xiaobing Li1, Tingting Luo1, Xuejuan Shen1, Robert W. Murphy3, Ming Liao1,4 and Yongyi Shen1,4* 
 
1College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
2Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College, Shantou, China
3Centre for Biodiversity and Conservation Biology, Royal Ontario Museum, Toronto, ON, Canada
4Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, China

Since 2013, the H7N9 avian influenza A virus (AIV) has caused human infections and to the extent of now surpassing H5N1. This raises an alarm about the potential of H7N9 to become a pandemic problem. 

Our compilation of the amino acid changes required for AIVs to cross the species-barrier discovers 58 that have very high proportions in both the human- and avian-isolated H7N9 viruses. These changes correspond with sporadic human infections that continue to occur in regions of avian infections. 

Among the six internal viral genes, amino acid changes do not differ significantly between H9N2 and H7N9, except for V100A in PA, and K526R, D627K, and D701N in PB2. H9N2 AIVs provide internal genes to H7N9. Most of the amino acid changes in H7N9 appear to come directly from H9N2. Seventeen amino acid substitutions appear to have fixed quickly by the 5th wave. Among these, six amino acid sites in HA1 are receptor binding sites, and PB2-A588V was shown to promote the adaptation of AIVs to mammals. 

The accelerated fixation of mutations may promote the adaptation of H7N9 to human, but need further functional evidence. Although H7N9 AIVs still cannot efficiently transmit between humans, they have the genetic makeup associated with human infections. These viruses must be controlled in poultry to remove the threat of it becoming a human pandemic event.

(SNIP)

Discussion

Recent research on gain-of-function has identified genetic changes required for AIVs to cross the species-barrier and adapt to replication and transmission in mammals. Our compilation of these genetic changes (Supplementary Table 1) and surveillance data serve to predict that H7N9 poses a great threat to humans.

AIVs must adapt to their new host (humans) to infect successfully. To initiate infection, hemagglutinin (HA), which is the major surface glycoprotein of influenza viruses, binds to host cell surface complex glycans via a terminal sialic acid. The switch of the preference from avian- to human-type sialic acid receptors (α-2,6 sialo-saccharides) is a key element necessary for AIVs to cause human pandemics (Matrosovich et al., 2000).

Amino acid changes S155N, T156A, G182V, S205Y, and Q222L (H5 numbering) in HA increase virus-binding to human α-2,6 sialo-saccharides (Suzuki et al., 1989; Yamada et al., 2006; Wang et al., 2010; Herfst et al., 2012; Imai et al., 2012). These changes occur in very high proportions in both human- and avian-isolated H7N9 viruses (Figure 1). This suggests that H7N9 viruses have an ability to bind to human-type receptors because receptor-binding specificity assays have shown that the human-isolated H7N9 viruses can bind to both avian-type (α2,3-linked sialic acid) and human-type (α2,6-linked sialic acid) receptors (Zhou et al., 2013). 

(SNIP)

The 5th wave of human infection saw a rapid growth in the number of cases (Wang et al., 2017). Have H7N9 AIVs experienced an accelerated fixation of beneficial adaptations to the environmental of human? In addition to the known amino acid mutations associated with changes in host tropism or increased pathogenicity in mammals, our analyses detect a trend for the fixation of 17 amino acid changes in the 5th wave (Figure 3). Among these, six amino acids sites substituted in HA1 locate at receptor binding region (Figure 4). Amino acid change PB2-A588V which showed much higher proportion in human-isolated than avian-isolated H7N9 in the 5th wave, was proved to promote the adaptation of H7N9 to mammals (Xiao et al., 2016). This might explain the increased number of human infection cases in the 5th wave. The function of other sites needs further experimental study.

H7N9 AIVs have continuously evolved since 2013. Although they have triggered five epidemics of human infections, they still do not have efficient human-human transmission, and only fix to avian. Our analyses identify a series of amino acid changes that associate with cross-species transmission from avian to human in high proportions in both human- and avian-isolated H7N9 AIVs. Avian-isolated H7N9 viruses have the genetic makeup associated with human infections and this suggests that if we cannot control this subtype in poultry, an impending human pandemic is still on the doorstep.

Author Contributions

YS conceived, designed, and supervised the study. ZP, DX, XL, TL, and XS collected and analyzed the data. YS and RM wrote the drafts of the manuscript. ML commented on and revised drafts of the manuscript. All authors read and approved the final report.

        (Continue . . . .)

One of the reasons we spend so much time looking at H9N2 (and other, lesser avian flu threats like H6N1, and H4N6, etc.) is that influenza viruses are a promiscuous lot, and none of them circulate in a vacuum. 

They interact readily, share genetic information, and continually  reinvent themselves into new genotypes - and occasionally - new subtypes. 

And while China's introduction of a new H5+H7 vaccine in poultry has been a great success, these avian flu viruses persist in unvaccinated ducks and other wild birds, and are capable of staging a comeback at any time.