Saturday, April 20, 2024

Two Recent Papers On The Evolution of H7N9 in China

H7N9 Epidemic Waves - June 14th 2017 - Credit FAO


Seven years ago - long before COVID emerged and at a time when HPAI H5N1 had all but disappeared from the map - the world held its breath and watched as China's 5th, and largest, wave of H7N9 raised pandemic concerns around the globe.   

LPAI H7N9, which had emerged in the spring of 2013, was virtually asymptomatic in poultry, but could be deadly in humans, and over 5 years had infected at least 1,500 people in China, killing roughly 40% of them.  

In late 2016, an HPAI version emerged, which threatened China's poultry industry as well as public health. Fearing the worst, China embarked on a national emergency poultry vaccination campaign with a new H5+H7 vaccine (see EID Journal: China's H5+H7 Poultry Vaccination Program, Guangdong 2017-18).

Within months human infections fell dramatically, with the last one reported in 2019.  Poultry losses plummeted, and in a 2019 report (see OFID: Avian H5, H7 & H9 Contamination Before & After China's Massive Poultry Vaccination Campaign) the authors reported:

The vaccine was associated with a 92% reduction in H7 positivity rates among poultry and a 98% reduction in human H7N9 cases.

While previous poultry vaccination programs around the world have yielded varying levels of success, China's H5+H7 poultry vaccination campaign exceeded all expectations. It even reduced the number of H5N1 & H5N6 spillovers, although China saw a rebound in H5N6 starting in late 2020. 

H7N9 remains largely suppressed in China, but it has not been eradicated, and so we check in on its continued evolution from time to time:

EID Journal: Antigenic Variant of Highly Pathogenic Avian Influenza A(H7N9) Virus, China, 2019

EID Journal: Evolution and Antigenic Drift of Influenza A (H7N9) Viruses, China, 2017–2019

This week we've seen 2 new studies published in major journals (EID & Emerging Microbes & Inf.) by Chinese researchers on the recent evolution of H7N9.  Both credit China's H5+H7 vaccination program's success, but caution that the virus continues to evolve, and that the vaccine needs to keep up.

I've only post excerpts from both studies, so follow the links to read them in their entirety. I'll have a postscript after the break. 

Evolution and Antigenic Differentiation of Avian Influenza A(H7N9) Virus, China
Yang Liu1, Yuhua Chen1, Zhiyi Yang, Yaozhong Lin, Siyuan Fu, Junhong Chen, Lingyu Xu, Tengfei Liu, Beibei Niu, Qiuhong Huang, Haixia Liu, Chaofeng Zheng, Ming Liao , and Weixin Jia


We characterized the evolution and molecular characteristics of avian influenza A(H7N9) viruses isolated in China during 2021–2023. We systematically analyzed the 10-year evolution of the hemagglutinin gene to determine the evolutionary branch. Our results showed recent antigenic drift, providing crucial clues for updating the H7N9 vaccine and disease prevention and control.

From early 2013 through October 2017, a total of 5 outbreaks of avian influenza A(H7N9) virus infection occurred, resulting in 616 human deaths (1). In particular, the fifth wave of the epidemic saw a substantial increase in human fatalities. By late 2017, a total of 1,568 laboratory-confirmed cases of H7N9 virus infection in humans had been reported according to International Health Regulations guidelines (External Link). The rapid emergence, prevalence, and pandemic potential of H7N9 virus were suddenly of great concern. Since 2017, low-pathogenicity avian influenza H7N9 virus transformed into the highly pathogenic avian influenza (HPAI) A(H7N9) virus (25). 

In response, China initiated a large-scale vaccination program in the poultry industry, effectively limiting the H7N9 epidemic. Although no human H7N9 infections have been reported since February 2019, the virus is still circulating in poultry, particularly in laying hens, and remains a potential threat to poultry industry and public health (68).
Furthermore, since 2017, the H7N9 virus has undergone multiple instances of antigenic drift to evade immune pressure from vaccines (911). We investigated the genetic evolution and antigenic differentiation of the H7N9 virus in China to provide information to better control the epidemic, ensure the safety of the poultry industry, and protect public health.

This study explored the evolution and antigenic differentiation characteristics of H7N9 virus over the past decade through continuous monitoring and selection of representative sequences from all publicly available H7N9 virus sequences. However, our research still had certain limitations, and further investigation is needed to understand the relationship between the evolution of viruses under positive selection pressure and the underlying cause of antigenic variation.

In summary, influenza A viruses are highly prone to mutation and evolution, making the H7N9 virus epidemic more complex and challenging to control. This study offers vital insights into the genetic evolutionary branches and recent antigenic drift, providing crucial clues for updating the H7N9 vaccine seed virus and for disease prevention and control.     

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While the first dispatch was more cautionary, this second report is more upbeat, describing a greatly attenuated threat from the H7N9 virus. 

Evolution of H7N9 highly pathogenic avian influenza virus in the context of vaccination

Yujie HouGuohua DengPengfei CuiXianying ZengBin LiDongxue Wang


Human infections with the H7N9 influenza virus have been eliminated in China through vaccination of poultry; however, the H7N9 virus has not yet been eradicated from poultry. Carefully analysis of H7N9 viruses in poultry that have sub-optimal immunity may provide a unique opportunity to witness the evolution of highly pathogenic avian influenza virus in the context of vaccination. Between January 2020 and June 2023, we isolated 16 H7N9 viruses from samples we collected during surveillance and samples that were sent to us for disease diagnosis.
Genetic analysis indicated that these viruses belonged to a single genotype previously detected in poultry. Antigenic analysis indicated that 12 of the 16 viruses were antigenically close to the H7-Re4 vaccine virus that has been used since January 2022, and the other four viruses showed reduced reactivity with the vaccine.
Animal studies indicated that all 16 viruses were nonlethal in mice, and four of six viruses showed reduced virulence in chickens upon intranasally inoculation. Importantly, the H7N9 viruses detected in this study exclusively bound to the avian-type receptors, having lost the capacity to bind to human-type receptors. Our study shows that vaccination slows the evolution of H7N9 virus by preventing its reassortment with other viruses and eliminates a harmful characteristic of H7N9 virus, namely its ability to bind to human-type receptors.

The early H7N9 viruses bound to human-type receptors with high affinity and to avian-type receptors with low affinity [5,47,48], which is a major reason why these viruses easily infected humans. However, since 2018, the receptor-binding preference of the H7N9 viruses we detected from poultry gradually changed: their affinity for avian-type receptors has gradually increased, and their affinity for human-type receptors has gradually declined [32].

The viruses detected in this study exclusively bound to avian-type receptors. Although the underlying mechanism that has driven this receptor-binding change remains to be investigated, the fact that the surviving H7N9 viruses in vaccinated poultry have lost a key harmful trait indicates that vaccination does not cause the highly pathogenic avian influenza virus to become more dangerous to humans.

In conclusion, our study reveals the genetic evolution and biological properties of the H7N9 highly pathogenic avian influenza virus detected in recent years in China. Although antigenic differences could be easily detected between the surviving viruses and the vaccine seed strain, the lack of reassortment with other viruses and the loss of human-type receptor binding ability of existing H7N9 viruses strongly suggest that although vaccination alone cannot eradicate highly pathogenic H7N9 influenza viruses from poultry in a short time, surviving H7N9 viruses are not evolving faster or becoming more dangerous to humans.

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Although the evolutionary trend of H7N9 appears to be away from posing a public health threat, one lucky reassortment, or a handful of of the `right' amino acid changes, could change that trajectory overnight.  

All of which makes it important that researchers in China continue to study the virus, and update the poultry vaccine. 

While H7N9 isn't anywhere near the top of my pandemic concerns today, we've seen how swiftly things can change.  And with influenza viruses, it is wise never to say `never'.