#16,195
The only constant with viruses is that they are constantly evolving. Most viruses do so through minute replication errors, that slowly accrue, causing antigenic drift.
Influenza viruses mutate slowly through antigenic drift, but they have an even more powerful evolutionary pathway; multiple flu strains can infect a single host and swap or share entire gene segments - a process called reassortment or `antigenic shift' - which can quickly, and sometimes radically, change their abilities.
And as any virologist will tell you, `Shift happens'.
Broadly speaking, antigenic drift is why influenza vaccines must be updated every year or so, while antigenic shift is the abrupt evolutionary mechanism behind most influenza pandemics. Of course it's never quite that simple, as most reassortments turn out to be evolutionary failures, and novel subtypes are always the product of both antigenic drift and shift.
In the summer of 2017, China - fearing a growing H7N9 epidemic and a rise in H5N6 human infections - rolled out a new, and remarkably effective, H5+H7 poultry vaccine, that quickly subdued both viruses in poultry, and human infections (see OFID: Avian H5, H7 & H9 Contamination Before & After China's Massive Poultry Vaccination Campaign).
Despite its initial success, influenza viruses constantly change, and vaccines must be updated regularly to deal with those changes. In the past, we've seen poultry vaccination programs loose effectiveness over time (see Egypt: A Paltry Poultry Vaccine and The HPAI Poultry Vaccine Dilemma).
Poor vaccine matches can sometimes 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: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
While H7N9 remains highly suppressed in China, over the past year we've seen a resurgence in human infections with avian H5N6 - even while reports of outbreaks in poultry remain rare - suggesting that H5N6 viruses are evolving away from the vaccine's protection.
Yesterday we saw China's 19th H5N6 case since late last fall, with the pace of infections picking up over the summer, a time when transmission should be at its lowest.
It should be noted that there are numerous iterations of the H5N6 virus circulating in the wild (see J. Virology: Molecular Evolution and Emergence of Avian H5N6) - spanning multiple clades and subclades - and that some are invariably going be more virulent, more transmissible, more biologically `fit', and more dangerous than others.
None of this has escaped the notice of the Chinese CDC. Two weeks ago, in CCDC Weekly: Outbreak Report - Five Independent Cases of Human Infection With HPAI H5N6 — Sichuan Province, they published in their MMWR-clone, they warned:. . . . recent serological studies have found that the vaccine strains recommended by WHO cannot fully cover the emerging strains in these clades (15). Thus, the balance between viral evolution and the capacity of the candidate vaccine protection needs to be timely updated which will reduce infection events and mortality in humans and animals.
Yesterday the CCDC Weekly published a new study, this time looking at two human H5N6 infections this year in Guangxi Zhuang Autonomous Region, which occurred 6 months apart (Feb. & July).
Both viruses were of different subclades (2.3.4.4h & 2.3.4.4b), were the product of recent (and different) ressortments, and showed worrisome mutations which could increase their threat.
I've only included the abstract and some excerpts from the discussion section, so you'll want to follow the link to read the (English language) report in its entirety. I'll have a brief postscript when you return.
Fuyin Bi1,&; Lili Jiang2,&; Lihua Huang3; Jingguang Wei3; Xiaowen Pan2; Yu Ju1; Jianjun Mo1; Minmei Chen1; Ning Kang1; Yi Tan1; Yonghong Li1; Jing Wang1, ,
What is known about this topic?
H5N6 has replaced H5N1 as a dominant avian influenza virus (AIV) subtype in southern China. The increasing genetic diversity and geographical distribution of H5N6 pose a serious threat to the poultry industry and human health.What is added by this report?
A total of 2 cases of H5N6 that occurred from February 2021 to July 2021 in Guangxi, China were reported in this study. Phylogenetic analysis of gene was constructed, and some mutations of HA gene, PB2 gene, PA gene, M1 gene, NS1 gene, the receptor-binding site were detected. The evolutionary origins of the internal genes were different.What are the implications for public health practice?
As a multi-source reassortant virus, the H5N6 highly pathogenic AIV is continuously evolving. There is an urgent need to strengthen the surveillance of drug-resistant strains and novel variants.
Since the first human infections with highly pathogenic avian influenza (HPAI) H5N6 virus was detected in Sichuan Province of China in April 2014, a total of 38 human cases and 21 deaths due to H5N6 infection have been reported as of August 6, 2021 in the Western Pacific Region (1).
However, the newly emergent HPAI H5N6 virus belonging to the genetic clade 2.3.4.4 of H5 virus subtypes has possessed the capability for binding human-origin SA-α, 6 Gal-linked receptor and has demonstrated more transmissibility than H5N1 virus in a ferret model (2), suggesting that this subtype virus may be of high public health risk.
Guangxi Zhuang Autonomous Region in southern China has a history of human infection with avian influenza virus (AIV). H7N9 virus emerged here (3) and HPAI H7N9 virus hit this region in 2017, with 27 infections and 14 deaths (4).
(SNIP)
DISCUSSION
The previous study showed H5N6 has replaced H5N1 as one of the dominant AV subtypes in southern China (9). The avian influenza A (H5N6) virus continues to threaten human life and health. From January to July 2021, 2 cases were reported in Guangxi zhuang autonomous region. Compared with 4 H5N6 infections reported from 2016 to 2019, and the number of infections cases was slightly higher than that in previous years. It is necessary to sequence and analyze the virus.The case infected with GX01 had obvious clinical symptoms and a history of exposure to dead poultry. Homology analysis showed that GX01 virus was a recombinant virus of H5N6 and H9N2, while GX11151 was a recombinant virus of H5N8, H5N6, and H9N2. Previous study showed H5N6 lineage have been co-circulating in different region in China (10-11).The mutations in the important sites of proteins of avian influenza virus may change the adaptivity, virulence, tissue tropism, and infectivity. The cleavage between HA1 and HA2 proteins of HA gene of these two viruses were multiple continuous basic amino acids motif (RERRRKR), indicating that they possessed potentially high pathogenicity in chickens. The 222-224 receptor binding site of HA gene suggested that the viruses were avian-like receptors (α 2,3 SA). Studies have shown that the sensitivity of viruses carrying H274Y mutation in NA protein to oseltamivir decreased 1,000 times. In addition, when the NA protein of the virus carries E119A/D/V, A247V, R293K, and R372K mutations, it will cause different degrees of resistance to oseltamivir and zanamivir (12-13). Fortunately, these mutations were not found in our virus. Therefore, using NA inhibitors to treat the 2 cases infected with avian influenza A (H5N6) was still a good choice.
The median age of the two cases was over 50 years old. Like other studies previously reported, the elderly people may be more vulnerable to avian influenza (3). One case was reported through ILI surveillance system (14), indicating that the ILI system was beneficial for the detection of avian influenza cases to a certain extent. However, this may be just the tip of the iceberg, and perhaps many mild cases have not been detected.
This study has certain limitations. Sampling of the environment exposed by the cases, and poultry around the living environment were missing, resulting in lacking of laboratory tests. One reason was that the period from onset to reporting was too long for sampling, in spite of dead poultry found in epidemiology survey, and another reason was that patient B had no clear history of exposure to poultry.
At present, coronavirus disease (COVID-19) has caused a worldwide pandemic (15), and over 200 million people have been infected. Meanwhile, the increasing trend of human infection with avian influenza virus has become an important public health issue that cannot be ignored, alerting us that COVID-19 and avian influenza may be simultaneously prevalent in some regions.
Acknowledgments
Dr. Yu Lan and Dr. William J. Liu.
In the spring of 2017 there were grave concerns that China's avian H7N9 epidemic was on the verge of spiralling out of control, and possibly sparking a pandemic (see NPR: A Pessimistic Guan Yi On H7N9's Evolution).
China's gamble on a new, experimental H5+H7 poultry vaccine not only subdued the H7N9 threat, it greatly reduced the threat from HPAI H5 viruses as well. At least, temporarily.
But the H5 virus lived on in wild birds, and in unvaccinated ducks and geese, and over time appears to have evolved away from the vaccine. Vaccination may still protect gallinaceous poultry from illness or death, but may not prevent the virus from spreading (and evolving) asymptomatically in flocks.
As the diversity and complexity of HPAI H5 viruses increases in China - and around the world - the risks of one of these avian viruses finding the right genetic combination to do us real harm increases.
Now that H5N8 has been declared zoonotic (see CDC Adds Zoonotic Avian A/H5N8 To IRAT List) the stakes have raised even higher.
While it may never happen - or it may take years before HPAI H5 becomes a legitimate public health threat - another pandemic is inevitable (see PNAS Research: Intensity and Frequency of Extreme Novel Epidemics), and it could easily be worse than COVID.
All reasons why we should be preparing seriously now, else we risk being caught flat footed and unprepared. Again.
