Nature: Virus Diversity, Wildlife-Domestic Animal Circulation and Potential Zoonotic Viruses of Small Mammals, Pangolins and Zoo Animals

 

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While historically influenza viruses - and more recently coronaviruses - have dominated discussions of potential pandemic pathogens, there is ample evidence throughout history that other diseases can be contenders. 

The Black Death (bubonic plague), Cholera, HIV, and even mosquito borne illnesses like Malaria, Yellow Fever,  and Dengue have all produced pandemics or widespread epidemics causing severe morbidity and mortality.

And there are numerous reports of mysterious, still unidentified diseases in the past, including:

• the English Sweats of the 1500s

• febris comatosa which sparked a severe epidemic in London between 1673 and 1675

• in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

• and Encephalitis Lethargica which killed millions in the 10 years following the Great Influenza pandemic of 1918

While we may not know the etiology of these disease outbreaks, it is probably safe to say most were zoonotic in origin, and that there are probably a lot more out there in the wild like them that we have yet to identify. 

A decade ago, in mBio: A Strategy To Estimate The Number Of Undiscovered Viruses, we saw an estimate that there were at least 320,000 unidentified mammalian viruses awaiting discovery.  Most are benign or of little consequence, but among them are probably scores of high consequence pathogens. 

In 2018 the World Health Organization released their second update of their WHO List Of Blueprint Priority Diseases, which listed 8 priority diseases and pathogens to prioritize for research and development.

• Crimean-Congo haemorrhagic fever (CCHF)
• Ebola virus disease and Marburg virus disease
• Lassa fever
• Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS)
• Nipah and henipaviral diseases
• Rift Valley fever (RVF)
• Zika
• Disease X

Disease X being the catch-all name for the pathogens out there with pandemic potential that we have yet to identify.  Most of them - like SARS-CoV-2 - are destined to fly below the radar until they evolve (as did  COVID) into a public health threat. 

Every few months we learn about new or expanding threats in the wild (see UK HAIRS Timeline below), and there are no signs this trend is slowing down.

All of which brings us to a lengthy, detailed, and at times technical review of zoonotic viruses detected across more than 2,000 animals collected in South China between 2015 and 2022.  

Due to its length, I've only posted the link, abstract, and some brief excerpts. Those interested in taking a deep dive will want to follow the link to read it in its entirety. 

I'll have a brief postscript after the break. 

Virus diversity, wildlife-domestic animal circulation and potential zoonotic viruses of small mammals, pangolins and zoo animals

Xinyuan Cui, Kewei Fan, Xianghui Liang, Wenjie Gong, Wu Chen, Biao He, Xiaoyuan Chen, Hai Wang, Xiao Wang, Ping Zhang, Xingbang Lu, Rujian Chen, Kaixiong Lin, Jiameng Liu, Junqiong Zhai, Ding Xiang Liu, Fen Shan, Yuqi Li, Rui Ai Chen, Huifang Meng, Xiaobing Li, Shijiang Mi, Jianfeng Jiang, Niu Zhou,… Yongyi Shen Show authors

Nature Communications volume 14, Article number: 2488 (2023) Cite this article

Abstract

Wildlife is reservoir of emerging viruses. Here we identified 27 families of mammalian viruses from 1981 wild animals and 194 zoo animals collected from south China between 2015 and 2022, isolated and characterized the pathogenicity of eight viruses. Bats harbor high diversity of coronaviruses, picornaviruses and astroviruses, and a potentially novel genus of Bornaviridae. 

In addition to the reported SARSr-CoV-2 and HKU4-CoV-like viruses, picornavirus and respiroviruses also likely circulate between bats and pangolins. Pikas harbor a new clade of Embecovirus and a new genus of arenaviruses. Further, the potential cross-species transmission of RNA viruses (paramyxovirus and astrovirus) and DNA viruses (pseudorabies virus, porcine circovirus 2, porcine circovirus 3 and parvovirus) between wildlife and domestic animals was identified, complicating wildlife protection and the prevention and control of these diseases in domestic animals. 

This study provides a nuanced view of the frequency of host-jumping events, as well as assessments of zoonotic risk.

(SNIP)

Herein, we used meta-transcriptomic sequencing to determine the viromes in small mammals (bats, rodents, insectivores, and pikas), pangolins and zoo animals collected in South and Southwest China (Supplementary Data 1), and from this determine the extent and pattern of cross-species virus transmission. We also isolated some of the viruses identified and performed experimental infection studies. This work documents virus diversity and identifies viruses in wildlife with zoonotic potential.

(SNIP)

 

Overview of animal viromes

A total of 503 libraries representing 2175 individual animals that were collected between 2015 and 2022 were sequenced (Supplementary Data 1). In brief, there were 214, 123, 18, 21, 56, and 71 libraries from bats, rodents, pikas, insectivores, pangolins and zoo animals, respectively. An average of 12 Gb of sequence data was obtained for each library. We focus only on the viruses that are able to infect vertebrates, while those infecting archaea, bacteria, fungi, invertebrates, and plants were excluded. An overview of the reads for the mammalian viruses is presented in Fig. 1, Supplementary Fig. 1, and Supplementary Data 2. A total of 328 viruses were identified through phylogenetic analyses, with 171 of them having near-complete genomes, and 167 of them were unreported (Supplementary Data 3 and Supplementary Table 1).

Rodents had 20 virus families, followed by bats, insectivores and zoo animals (with 19, 15, and 14 virus families, respectively), whereas pikas and pangolins showed the presence of the fewest number of viral families (nine each). Viral reads from the families Arenaviridae, Arteriviridae, Astroviridae, Caliciviridae, Circoviridae, Coronaviridae, Flaviviridae, Hantaviridae, Hepeviridae, Herpesviridae, Paramyxoviridae, Parvoviridae, Picornaviridae, and Reoviridae were widely distributed in these animals. These viruses were further confirmed by RT-PCR (RNA viruses) and PCR (DNA viruses), with the details shown in Supplementary Data 4. The reads of Retroviridae and Herpesviridae derived from the host genomes could not be excluded since the genomes of most of the tested animals are not available. Therefore, the abundance of Retroviridae and Herpesviridae in the heatmap might be overestimated.

(SNIP)

Conclusion

(excerpt)

The continual outbreaks caused by emerging and reemerging viruses raises considerable concern over the roles of wildlife, especially in those species that frequently contact humans and domestic animals. This study has revealed the diversity of mammalian viruses in some important mammals, and identified a series of novel genera and species of viruses with some of them having potential for cross-species transmission. More surveillance of wildlife-borne viruses, particularly at the wildlife-domestic animal-human interface, is needed to prevent outbreaks of emerging and reemerging viral diseases.

          (Continue . . . )

 

Suffice to say, when it comes to identifying zoonotic disease threats, we are barely scratching the surface of what is out there.  

Eighteen months ago, in PNAS Research: Intensity and Frequency of Extreme Novel Epidemics, researchers suggested that the probability of novel disease outbreaks will likely grow three-fold in the next few decades. 

Looking at the plethora of pathogens in the wild, its hard not to consider that an optimistic assessment. 

The `Other Mixing Vessel' For Pandemic Influenza

Just a few of many scenarios  

#17,430

Since zoonotic influenza viruses - like H5N1, H3N8, or H9N2 - circulate in non-human hosts, we focus on ways these viruses could evolve into human adapted viruses.  Usually that involves a series of reassortment events (`antigenic shift') - the combining of two or more flu viruses in a single host - aided and abetted by `antigenic drift'. 

NIAID, the National Institute of Allergy and Infectious Diseases, has a pair of short (3 minute) videos on YouTube ( How Influenza Pandemics Occur and Influenza: Antigenic Drift) that illustrate both in action. 

Swine served as reassortment hosts for the 2009 H1N1 pandemic virus, but the origins of the 1968 (H3N2) and 1957 (H2N2) pandemic viruses are still murky. Both involved a reassortment of a novel flu virus (avian H2 in 1957 and avian H3 in 1968) with the current human seasonal flu virus (H1N1 in 1957, H2N2 in 1968), producing a novel virus. 

Even though both of these pandemics occurred in the `modern era' of virology, we don't know with certainty in what host these reassortments occurred.  But since it involved the then circulating seasonal flu, and an avian strain, a human host seems likely. 

One of the things we've learned in the past couple of decades about influenza is that humans - much like birds and pigs - can be co-infected with 2 or more flu viruses simultaneously. Up until 2009, human co-infection with influenza A had only rarely been reported. 

Dual infections had been noted, but usually with an `A’ and a `B’ virus. 

In 2008, we saw a report of an Indonesian teenager who tested positive both H5N1 and the seasonal flu strain H3N2 (see CIDRAP report Avian, human flu coinfection reported in Indonesian teen), demonstrating that co-infection with Influenza A was possible.

 

But the big breakthrough came in 2009 when the pandemic H1N1 virus emerged and co-circulated for a time with the old seasonal H1N1 virus, allowing scientists in New Zealand to isolate and document 11 cases of Influenza A co-infection (see EID Journal: Co-Infection By Influenza Strains for the full story).

Since then we've seen a growing number of documented human co-infections, and more importantly, the detection of novel flu reassortants originating from them.  A few (of many) examples include:

(2019) Eurosurveillance: Novel influenza A(H1N2) Seasonal Reassortant - Sweden, January 2019

(2019) Denmark Reports Novel H1N2 Flu Infection

(2016) J Clin Virol: Influenza Co-Infection Leading To A Reassortant Virus

(2014) EID Journal: Human Co-Infection with Avian and Seasonal Influenza Viruses, China

(2013) Lancet: Coinfection With H7N9 & H3N2

(2011) Webinar: pH1N1 – H3N2 A Novel Influenza Reassortment

Luckily, most reassortant viruses aren't biologically `fit' enough to compete with more established strains, and quickly fade away, often without ever being noticed.  If creating a pandemic virus were easy, we'd be hip deep in them all the time. 

But with record levels of avian H5N1 being reported globally, the opportunities for it to meet up with a better adapted seasonal virus in a human host are increasing. And that raises the likelihood that an H5N1/H1N1 or H5N1/H3N2 reassortant could emerge. 

After three years of the COVID pandemic, and round-after-round of COVID shots, many people are weary of getting vaccines, including for seasonal flu. While understandable, not vaccinating against seasonal flu provides additional opportunities for H5N1 (or H5N6, H3N8, H9N2, etc.) to reassort in a human host. 

Granted, there are other pathways that these viruses could take to become a pandemic. But the most straightforward way is by reassorting with an already `humanized' flu virus. 

It is for this reason (and concerns over reverse zoonosis) that the CDC, and other health agencies around the world, recommend that poultry and swine workers get vaccinated against seasonal flu every year (see The Importance of Including Swine and Poultry Workers in Influenza Vaccination Programs).

Up until fairly recently, H5N1 exposure was pretty much limited to poultry workers, but with the virus rapidly becoming endemic in wild birds (and increasingly spilling over into mammals) around the world, the risks of exposure - while still low - are increasing for other cohorts. 

While there are plenty of other good reasons to get the flu shot every year (see here, here, and here), if you are still on the fence and need more motivation, then maybe lowering the opportunities for  H5N1 to reassort in a human host will suffice. 

Granted, it is a bit of a long-shot.  But it beats doing nothing. 

CDC Nowcast: Recombinants Rule

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During the opening year of the COVID pandemic, recombination was rarely mentioned as driving the evolution of the virus. SARS-CoV-2 was considered relatively `stable', and genetic changes were chalked up to antigenic drift, caused by random replication errors. 

Recombination is the sharing of genetic material between similar genomes that simultaneously infect a single host.  The resultant hybrid is called a recombinant.   

It wasn't until the summer of 2021 that we learned of a`documented' dual infection with two COVID variants (Alpha & Beta), which was presented initially at the 31st ECCMID Conference.

Around the same time, a study called SARS-CoV-2: Possible recombination and emergence of potentially more virulent strains, was published in PloS One.  But actual evidence of recombination of the virus was scant. 

The emergence of recombinant variants was still considered mostly a theoretical concern, but that summer the UK's SAGE publicly discussed the possible emergence of a more severe COVID variant via recombination  (see UK SAGE: Can We Predict the Limits of SARS-CoV-2 Variants and their Phenotypic Consequences?).

By early 2022, we were beginning to see scattered reports of `likely' recombinant variants, although none had managed make much of an impact. In February 2022 the UKHSA made headlines when they announced that they were monitoring a recombinant virus (see A COVID Recombination Review).

It wasn't until last fall, however, that we finally saw the rise and rapid spread of a recombinant virus (XBB), which the CDC began tracking in the United States in late November.  A month later, the writing was on the wall (see CDC Nowcast: A New Dominant Variant (XBB.1.5) For A New Year).

Four months later, six XBB*.* variants make up roughly 98% of the COVID viruses in this week's CDC Nowcast, and about 75% of viruses globally according to the WHO. 

While XBB.1.5 remains hugely dominant in the United States, it continues to lose ground to newcomers XBB.1.16, XBB.1.9.1, and XBB.1.9.2.  

So far, we've not seen any evidence that these XBB recombinant variants pose any greater health risks than their Omicron ancestors, but they still appear to be gaining in transmissibility and immune evasion over time. 

Whether this dramatic shift to recombination as the driving force behind COVID's evolution makes any tangible difference to how the pandemic plays out is unknown.  We are literally less than six months into this new phase of COVID's evolution, and the virus continues to explore new trajectories.  

But it is a reminder that COVID in particular - and viruses in general - can still find ways to surprise us, and that we shouldn't get too attached to our current expectations. 

OpenWHO: Online Learning Courses On Epidemics, Pandemics & Health Emergencies

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Earlier this week I ran across an article in the BMC journal Archives of Public Health called Online learning for WHO priority diseases with pandemic potential: evidence from existing courses and preparing for Disease X by Heini Utunen, Anna Tokar, Mafalda Dancante & Corentin Piroux, that reminded me of a blog I wrote long ago (in 2017) on the opening of the WHO's online learning center (see below). 

OpenWHO: Preparedness Training For Epidemics, Pandemics & Health Emergencies

At that time, course offerings were quite limited (only 10 ), but more were promised.  I fully planned to go back and explore further, but life got in the way, and so it sat on a back burner.  

That is, until this week, when I returned to the OpenWHO site, registered (free, but requires answering a small questionnaire), and found over 200 English language courses offered (more in other languages). 

I decided to take their basic course on avian influenza (see below) and then review it here. 

Overview: Avian influenza is an acute viral disease of the respiratory tract. It is one of several severe zoonotic diseases with pandemic potential in the presence of sustained human-to-human transmission. This course provides a general introduction to the disease through a short video lecture and quizzes to test your knowledge. It targets personnel involved in avian and other zoonotic influenza outbreak preparedness and response, including medical professionals, public health officials, incident managers and risk communication experts.

Learning objectives: By the end of this course, participants should be able to:describe transmission, symptoms and treatment for zoonotic influenza;

• describe why zoonotic influenza viruses are of potential concern to public health;
• describe the role of public health authorities in reducing the risk of human infections with zoonotic influenza viruses; and list key preventive strategies.

Course duration: Approximately 1 hour.

This one-hour course consisted of a pre-test (9 multiple choice questions) - followed by a 35 minute video lecture - and ended with a post-test (same questions, but answers in a different order). 

I spent about 45 minutes in total. 

Although I aced the pre-test (9 out of 9 correct) it wasn't quite as easy as I expected.  While most of the questions were fairly basic - there were a couple I actually had to think about. It genuinely helps to read the questions carefully.

The video - presented by Dr. Aspen Hammond - was detailed enough to be interesting, yet short enough not to wear out its welcome. A 35-slide PDF presentation was also available for download, along with the video, and audio files. 

Based on this favorable first experience, I plan to explore further. 

Currently there are 11 courses available dealing with influenza, 5 on Ebola, and 2 on MERS-CoV.  Dozens of other topics are available, meaning you will probably find at least a few that will pique your interest.

EID Dispatch: Replication of Novel Zoonotic-Like Influenza A(H3N8) Virus in Ex Vivo Human Bronchus and Lung

#17,427

With China last month reporting their third human infection with avian H3N8, and recent studies suggesting that this avian virus continues to accrue mammalian adaptations (see EID Journal: Evolution of Avian Influenza Virus (H3) with Spillover into Humans, China), there is a good deal of concern over its future trajectory. 

Last week the above mentioned study identified 4 sublineages of H3 AIVs and 126 distinct genotypes, of which the H3N2 G23 genotype has recently predominated in China. The study found:

• After reassortment with 6 internal genes of H9N2, current H3N8 AIVs seem to have the advantage of infecting humans (42). Ongoing adaptation in mammals after continuous human infections may underlie emergence of pandemic strains.

• H3 AIV has shown the potential for cross-species transmission and was the origin of other animal influenza viruses, which caused epidemics in horses, dogs, seals, and pigs

• The H3N8 G25 viruses had acquired human-adapted mutations after infecting humans (Appendix Figure 14), such as 228G/S in the HA gene and E627K/V in the PB2 gene, which were also present in 1968 H3N2 pandemic strains (43). This finding indicates the pandemic potential of the newly emerged H3N8 AIVs.

While concerning, the low number of human cases reported so far suggests the virus isn't quite ready for prime time.  Although there may be some cases we are missing, widespread circulation in humans seems doubtful at this point. 

We've another report today from the University of Hong Kong School of Public Health that finds the current H3N8 virus doesn't appear to replicate particularly well in human bronchus and lung cell cultures, suggesting it needs additional adaptations before it can pose a major human health threat. 

Note: This report was written before the recently announced 3rd (and fatal) infection in Guangdong Province, of which we still know little.  Hopefully we'll see a genomic analysis of that isolate in the near future. 

First some excerpts from the EID Dispatch (follow the link to read it in its entirety), after which I'll return with a postscript. 

Dispatch
Replication of Novel Zoonotic-Like Influenza A(H3N8) Virus in Ex Vivo Human Bronchus and Lung

Kenrie P.Y. Hui, John C.W. Ho, Ka-Chun Ng, Samuel M.S. Cheng, Ko-Yung Sit, Timmy W.K. Au, Leo L.M. Poon, John M. Nicholls, Malik Peiris, and Michael C.W. Chan

Abstract

Human infection with avian influenza A(H3N8) virus is uncommon but can lead to acute respiratory distress syndrome. In explant cultures of the human bronchus and lung, novel H3N8 virus showed limited replication efficiency in bronchial and lung tissue but had a higher replication than avian H3N8 virus in lung tissue.


Avian influenza viruses (AIVs) with reassortments between AIVs from domestic poultry and wild birds sporadically cross species barriers, leading to human infections. Viruses with internal genes of H9N2, hemagglutinin, and neuraminidase acquired from wild birds constitute the zoonotic H5N1, H7N9, and H10N8 viruses (1–3) and can lead to severe influenza.

In 2022, two human infections with novel influenza A(H3N8) viruses were reported in Henan and Hunan Province, China (4,5). The first case was identified in a 4-year-old boy with acute respiratory distress syndrome, and the second case occurred in a 5-year-old boy with mild disease. Phylogenetic analysis revealed that the novel H3N8 viruses were triple reassortments containing the Eurasian avian H3 gene of wild-bird origin, the North American avian N8 gene derived from the wild bird AIV, and G57 genotype H9N2 internal genes from AIVs found in poultry in China (6,7).

H3N8 viruses that are genetically similar to the zoonotic H3N8 viruses reported in China (4,5) have been isolated in poultry markets in Hong Kong, China (8). Those novel avian H3N8 viruses are antigenically distant from contemporary human influenza A(H3N2) viruses, and little cross-reactive immunity to these chicken H3N8 viruses exists in the human population (8). We assessed the replication of the novel influenza A(H3N8) virus in human ex vivo bronchus and lung tissues (Appendix).

The Study

The viruses used in this study were H9N2/Y280, pH1N1, avH3N8/MP16, novel H3N8, and H5N1/483 (Appendix Table 1). The novel H3N8 virus was isolated from chickens and is genetically closely related to the virus causing zoonotic human disease in China (A/Henan/4-10CNIC/2022/H3N8) (8). Their hemagglutinin genes share a 99.1% similarity, and the neuraminidase genes share a 98.7% similarity.

The avH3N8 virus was isolated from wild bird droppings in Mai Po, Hong Kong, and is genetically unrelated to the virus causing zoonotic disease in China. The novel H3N8 virus failed to propagate in Madin-Darby canine kidney (MDCK) cells but could be propagated in eggs and titrated in chicken embryo fibroblasts (DF-1), whereas the other strains could be propagated and titrated in MDCK cells. 

(SNIP)

Amino acid comparisons of the novel H3N8 and avH3N8 viruses demonstrated that they shared the same stalk length in the NA gene but did not have the G228S mutation that enhances binding to mammalian receptors (Appendix Table 2). The internal genes of the novel H3N8 virus were reassorted from H9N2 virus, whereas the internal genes of the avH3N8 came from H3N8, H6N1, H6N2, H3N8, H1N1, and H7N1 (Table).  

Neither virus had the E627K mutation in polymerase basic 2 that confers mammal adaptation, virulence, and transmissibility. The novel H3N8 virus had the A588V mutation in polymerase basic 2 that promotes mammal adaptation, but avian H3N8 virus did not have this mutation. This difference might contribute to higher replication of the novel H3N8 virus in human lung tissue. The S31N mutation found in the matrix protein 2 of the novel H3N8 virus provided adamantane resistance.

Conclusions

Although zoonotic H3N8 viruses have a dual receptor-binding affinity of α-2,3 and α-2,6 receptors (7), our findings show that this factor does not confer an advantage for replication in human bronchial tissue. Our findings demonstrated inefficient replication of the novel H3N8 virus in human bronchial tissues, which implies limited efficiency to transmit among humans. This finding is in line with a recent serologic surveillance study in which no poultry workers were positive for antibodies for the novel H3N8 virus (7), and only 2 human cases have been documented since April 2022 (4,5). The moderate replication ability of the novel H3N8 virus in human lung tissue suggests that the virus causes less severe disease than H5N1 virus.

In summary, our findings suggest that the zoonotic-like avian H3N8 virus has limited efficiency for human-to-human transmission and, at present, is unlikely to cause severe disease in humans. However, the limited cross-reactive immunity against this novel H3N8 virus in the human population (8) and the emergence of novel H3N8 viruses by continuous reassortment between AIVs in wild birds and poultry demonstrate that the zoonotic and pandemic potential of avian H3N8 viruses should be closely monitored.

While these findings may dial back some of the concern, they are based on what the virus was, not what it is today, or what it may become tomorrow.  The only real constant about viruses is that they must change in order to survive. 

A little over a month ago we looked at an extensive survey of H3N8 viruses in China (see Emerging Microbes & Inf.: Prevalence, Evolution, Replication and Transmission of H3N8 Avian Influenza Viruses), which described just how diverse and well entrenched this subtype has become in wild birds. 

H3N8 viruses have been detected in at least 64 kinds of wild birds and have evolved into several phylogenetic lineages, whereas only a few strains were detected in chickens in recent years. The H3N8 viruses analyzed in this study shared similar sequence identities and clustered into the same lineages with some strains isolated from Europe, North America and Africa, suggesting that H3N8 viruses can be transmitted globally with the migration of their natural reservoirs. 

We also found that these H3N8 viruses have undergone complicated reassortment with circulating H5N3, H7N4, H9N2, H10N4 and H10N8-like viruses isolated from Yellow River Delta wetlands [Citation21, Citation33, Citation34]. Of note, all the H3N8 viruses detected from chicken and humans in China in 2022 share HA and NA surface genes similar to those of duck- and wild bird-origin strains but bear an internal gene constellation from chicken H9N2 viruses [Citation29, Citation31]. 

While H3N8 may still lack some of the attributes it needs to pose a bigger public health threat, its growing host range, genetic diversity, and potential for international travel via migratory birds, provide it with plenty of opportunities to hone its skills. 

All of which makes H3N8 a virus to keep our eye on.

WHO Novel Flu Summary & Risk Assessment - April 2023

 

#17,426

This week the World Health Organization published their latest novel flu summary, which covers the period from March 4th to April 24th. Of the 7 cases reported in this summary, 6 hail from China, while the 7th is the H5N1 case from Chile. 

Four of the 6 recently confirmed cases from China (2 H9N2 and 2 H1N1v) were `unofficially' reported in last month's update, obtained via unnamed sources at the February WHO Consultation and Information Meeting on the 2023-2024 Northern Hemisphere Influenza vaccine.

A recurring theme in these reports are reminders to all member nations of their obligation - under IHR 2005 regulations - to report in a timely fashion, all human infections with novel flu viruses. In actual practice, cases are sometimes belatedly reported, and often with far less detail than we'd like. 

In this week's report, at least one of China's H9N2 cases goes back to October of 2022, while one of the H1N1v cases occurred last December.  Others occurred in January and February. 

Due to its length, I've only posted some brief excerpts from this summary, so follow the link to read it in its entirety.  I'll return with some background on H1N1v after the break.  

Influenza at the human-animal interface 

Summary and risk assessment, from 4 March to 24 April 2023

• New infections: From 4 March to 24 April 2023, three human cases of infection with influenza A(H9N2) viruses and two human cases of infection with influenza A(H1N1) variant viruses were reported officially. Two of the A(H9N2) cases and both A(H1N1) variant cases were mentioned in the previous risk assessment of 3 March 2023. 3 Additionally, one human case of infection with an influenza A(H3N8) virus and one human case of infection with an A(H5N1) virus were reported. 

• Risk assessment: The overall public health risk from currently known influenza viruses at the human-animal interface has not changed, and the likelihood of sustained human-to-human transmission of these viruses remains low. Human infections with viruses of animal origin are expected at the human-animal interface wherever these viruses circulate in animals. 

• IHR compliance: All human infections caused by a new influenza subtype are required to be reported under the International Health Regulations (IHR, 2005).2F 4 This includes any influenza A virus that has demonstrated the capacity to infect a human and its haemagglutinin gene (or protein) is not a mutated form of those, i.e. A(H1) or A(H3), circulating widely in the human population. Information from these notifications is critical to inform risk assessments for influenza at the human-animal interface.    

The most detailed report comes from Chile, on their 1st H5N1 infection, all of which has been previously discussed (see here, here, and here). Details on China's cases, however, remain sparse. The most verbose report, on their 3rd H3N8 case, tells us little more than the original report from the Guangdong CDC last March.

Avian influenza A(H3N8) viruses 

Since the risk assessment of 3 March 2023, China reported one human infection with an influenza A(H3N8) virus to WHO on 27 March. A 56-year-old female from Guangdong province developed symptoms on 22 February, was hospitalized on 3 March and passed away on 16 March. The patient had multiple underlying conditions. She had a history of exposure to live poultry before the onset of illness and there were wild birds reported near her home. Environmental samples from the live animal market that the patient visited before illness onset tested positive for avian influenza A(H3) viruses. No close contacts of the case developed an infection or symptoms of illness at the time of reporting. 

This is the third human case of infection with an influenza A(H3N8) virus reported to WHO. Two previous cases were reported in April and May 2022 .

China's three H9N2 cases reported are summed by by a single paragraph.

Avian influenza A(H9N2) viruses

Flying Blind In The Viral Storm

Since the last risk assessment on 3 March 2023, three human cases of infection with influenza A(H9N2) viruses were reported from China on 9 March (see Table 1 below). The cases were detected in influenza-like illness surveillance. All were children, had mild illness and were not hospitalized. No suspected cases among family contacts of the cases were reported. Two of the A(H9N2) cases were mentioned in the previous risk assessment of 3 March 2023.10

As are the two H1N1v cases reported by China.

Influenza A(H1N1) variant viruses [A(H1N1)v] 

Since the last risk assessment on 3 March 2023, two human cases of infection with Eurasian avian like swine influenza A(H1N1)v viruses were reported from China on 9 March (see Table 2 below). Both were children, had mild illness and were not hospitalized. No information on the likely source of exposure to the virus was available at the time of reporting and no suspected cases among family contacts of the cases were reported. Both of the A(H1N1)v cases were mentioned in the previous risk assessment of 3 March 2023.11 

Although the following plea to member nations to abide by the 2005 IHR is included in every WHO summary, we continue to see disappointing compliance (see Flying Blind In The Viral Storm) with both the letter and the spirit of the agreement.

• In the current COVID-19 pandemic, vigilance for the emergence of novel influenza viruses of pandemic potential should be maintained. WHO has developed practical guidance for integrated surveillance in the context of the cocirculation of SARS-CoV-2 and influenza viruses. The guidance is available here: https://www.who.int/publications/i/item/WHO-2019-nCoVIntegrated_sentinel_surveillance-2022.

• All human infections caused by a new subtype of influenza virus are notifiable under the International Health Regulations (IHR, 2005). State Parties to the IHR (2005) are required to immediately notify WHO of any laboratory-confirmed case of a recent human infection caused by an influenza A virus with the potential to cause a pandemic. Evidence of illness is not required for this report. 

• It is critical that these influenza viruses from animals or from people are fully characterized in appropriate animal or human health influenza reference laboratories. Under WHO’s Pandemic Influenza Preparedness (PIP) Framework, Member States are expected to share influenza viruses with pandemic potential on a regular and timely basis with the Global Influenza Surveillance and Response System (GISRS), a WHO-coordinated network of public health laboratories. The viruses are used by the public health laboratories to assess the risk of pandemic influenza and to develop candidate vaccine viruses.

(Continue . . . ) 

While few details are offered on the two H1N1v cases, the WHO describes them as Eurasian avian-like swine influenza, which opens the possibility that they may be similar to the EA H1N1 `G4' swine viruses that have raised concerns in China, and globally, over the past 7 years.

How similar?  Based on the limited information provided, we simply can't say.  

There are a lot of variants of H1N1v circulating in swine around the globe, some posing much greater threats than others, and the clade and genotype from these infections are not mentioned in this WHO report.  

In 2015 Chen Hualan, director of China's National Avian Influenza Reference Laboratory, was the lead author on a paper that described a new and rising swine flu threat in China (see PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza).

EAH1N1 is a reassortant virus, with elements from H1N1 avian influenza, human H1N1pdm, and swine-origin influenza viruses.  Despite sharing the same subtype designation as a currently circulating seasonal strain, it is genetically different enough to pose a genuine public health threat. 

In the `Significance' section the authors boiled it down to this:

Here, we found that, after long-term evolution in pigs, the EAH1N1 SIVs have obtained the traits to cause a human influenza pandemic. 

In 2020, another study on EA H1N1 swine influenza virus appeared in PNAS (see Eurasian Avian-like H1N1 Swine Influenza Virus With Pandemic Potential In China) which reported a greater than 10% seroprevalence for the EAH1N1 virus among swine workers tested, suggesting that EAH1N1 is gaining human infectivity.

That sparked a series of high profile risk assessments being published by the CDC, ECDC, WHO and others (here, here, here, and here).

The CDC added this EA H1N1 G4 virus to their IRAT, and put it at the top of their list in 2021. But their list contains several other North American swine viruses with at least some pandemic potential (2 added in 2019). 

Summary: A risk assessment of Eurasian avian-like swine influenza A(H1N1)[A/swine/Shandong/1207/2016] virus, clade 1C.2.3 and genotype 4, was conducted in July 2020. With point scores ranging from 1 to 10, the overall IRAT risk assessment score for this virus falls into the moderate risk category, which ranges from 4.0 to 7.9. The average risk score for potential emergence of the virus to achieve sustained human-to-human transmission was 7.5, within the upper moderate range. The average risk score for the virus to impact public health if it were to achieve sustained human-to-human transmission was 6.9, also in the upper moderate range.

Full report here pdf icon[PDF – 272 KB].

It is entirely possible that the H1N1v cases reported by China are from a less worrisome H1N1 lineage, but without prompt and detailed reporting, we can only guess at their significance.  

While it is easy to single out China for their belated and parsimonious reporting on disease outbreaks, there are plenty of other countries that - for economic, political or societal reasons - either don't test, or don't tell at all. 

A reminder, that when it comes to infectious diseases, that no news isn't always good news.  

V. Evolution: Tracking the Emergence of Antigenic Variants in Influenza A virus Epidemics in Brazil

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While we are understandably concerned about the emergence of new, or exotic, pathogens - like MERS-CoV, Avian H5 viruses,  Swine-Variant flu viruses, or even `Virus X' (the one we don't know about, yet) -  seasonal influenza also has the ability to reinvent itself into a more formidable foe. 

And on rare occasions, the resultant strain can even approach the ferocity of a novel pandemic virus.  

Across large swaths of the globe, however, there is little surveillance or reporting on seasonal flu viruses. Even in North America, Europe, Australia, and Japan - all of which maintain modern surveillance systems - only a small percentage of viral infections are tested and sequenced. 

About a month ago, in UK Novel Flu Surveillance: Quantifying TTD, we looked at an analysis by the UKHSA of their ability to detect community spread of a novel H5N1 virus.  In a country with arguably one of the better surveillance systems in the world, they found:

It would likely take between 3 and 10 weeks before community spread of H5N1 would become apparent to authorities, after anywhere between a few dozen to a few thousand community infections. 

During a swine variant flu outbreak here in the United States a dozen years ago, a study published in 2013 (see CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012) - estimated that during a time when only 13 cases were reported by the CDC - that the actual number of infections was likely 200 times (or more) higher.

In places like Sub-Saharan Africa, South America, and much of Asia, detection would likely take far longer.  

We often hear of outlier `flu epidemics', where some country or region is hit unusually hard by seasonal H1N1 or H3N2, but only rarely do we see a proper analysis of the reasons behind it. 

Sometimes, all it takes is a single mutation to make a `mild' flu virus more deadly, as in the case of D225G, which can increase H1N1's ability to ability to bind deep into the lungs.  

Most of the time, however, we never learn what was behind a severe outbreak. In early 2016, Brazil reported an unusually intense, out-of-season H1N1 epidemic (see below), at a time when the rest of the world was seeing H3N2.  

An Early Start To South America's Flu Season?

Unseasonable Seasonal Flu In São Paulo

Other South American countries, including Bolivia and Argentina, reported similar outbreaks around the same time.  But until now, the reasons behind Brazil's outlier epidemic have been unknown.  

Today we have a report published in the journal Viral Evolution - that looks at 7 year's worth of flu sequences from Brazil, and identifies a new clade of H1N1 (6b1) as having sparked the severe outbreak 7 years ago. 

First the abstract, and a few excerpts, after which I'll return with a postscript. 

Tracking the emergence of antigenic variants in influenza A virus epidemics in Brazil
Tara K Pillai, Katherine E Johnson, Timothy Song, Tatiana Gregianini, Tatiana G Baccin, Guojun Wang, Rafael A Medina, Harm Van Bakel, Adolfo García-Sastre, Martha I Nelson
Virus Evolution, vead027, https://doi.org/10.1093/ve/vead027
Published: 25 April 2023 Article history

PDF
 
Abstract

Influenza A virus circulation patterns differ in North America and South America, with influenza seasons often characterized by different subtypes and strains. However, South America is relatively under sampled considering the size of its population. To address this gap, we sequenced the complete genomes of 220 influenza A viruses collected between 2009 and 2016 from hospitalized patients in southern Brazil. 

New genetic drift variants were introduced into southern Brazil each season from a global gene pool, including four H3N2 clades (3C, 3C2, 3C3, and 3C2a) and five H1N1pdm clades (clades 6, 7, 6b, 6c, and 6b1). 

In 2016, H1N1pdm viruses belonging to a new 6b1 clade caused a severe influenza epidemic in southern Brazil that arrived early and spread rapidly, peaking mid-autumn. Inhibition assays showed that the A/California/07/2009(H1N1) vaccine strain did not protect well against 6b1 viruses. Phylogenetically, most 6b1 sequences that circulated in southern Brazil belong to a single transmission cluster that rapidly diffused across susceptible populations, leading to the highest levels of influenza hospitalization and mortality seen since the 2009 pandemic. 

Continuous genomic surveillance is needed to monitor rapidly evolving influenza A viruses for vaccine strain selection and understand their epidemiological impact in understudied regions.

         (SNIP)

The severe H1N1pdm epidemic in 2016 in RS was unexpected. For one, the H3N2 subtype is more often the cause of severe influenza seasonal epidemics (Thompson, Shay et al. 2003), and H3N2 was the dominant subtype circulating in RS in 2015. 

Little antigenic evolution had been observed in the H1N1pdm virus since the 2009 pandemic, requiring no updates to the H1N1pdm vaccine strain for six years. Presumably, after 5–6 years of H1N1pdm circulation, population immunity had built against H1N1pdm on a global scale, increasing selection pressure for new antigenic variants. 

The severe H1N1pdm epidemic in Brazil was also unexpected given that the United States did not have a severe influenza season in 2015–2016 (the US did have a severe flu season in 2016–2017, but it was dominated by H3N2 viruses). The number of cases and genetic composition of the winter influenza season in North America is not always predictive of what is seen in the Southern hemisphere six months later. Likewise, the subtype that circulates during winter in the Southern hemisphere is not necessarily the same that circulates later on in the Northern hemisphere. 

It remains unclear whether new mutations that occurred in the 6b1 South American viruses had any phenotypic effect. Our antigenic assays confirmed that people infected with 6b1 viruses in RS were poorly protected by the A/California/07/2009(H1N1) vaccine strain, but we did not compare the immunological response to the Brazilian strains against the US strains circulating the prior winter.

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For reasons that are not well understood, this severe H1N1 epidemic did not spread outside of South America. Instead a mutated H3N2 virus dominated both Europe and North America over the 2016-2017 flu season (see The Enigmatic, Problematic H3N2 Influenza Virus). 

Seasonal flu vaccines briefly shifted to an H1N1 A/Michigan/45/2015 subclade 6B.1 component, and that may have helped in subsequent years.

If all of this sound vaguely familiar, in 2018's  Remembering 1951: The Year Seasonal Flu Went Rogue, we looked at another unusually deadly regional wave of influenza during an otherwise mild non-pandemic year. 

The winter of 1950-1951 had been an average flu year, with the dominant flu called the `Scandinavian strain', producing mild illness in most of its victims. In fact, if you look at a graph of flu activity for the United States, running from 1945 to 1956, you'll see nary a blip.

But in December of 1950 a new strain of virulent influenza appeared in Liverpool, England, and by late spring, it had spread across much of England, Wales, and parts of Canada. 

The following comes from an absolutely fascinating EID Journal article: Viboud C, Tam T, Fleming D, Miller MA, Simonsen L. 

1951 influenza epidemic, England and Wales, Canada, and the United States.

The 1951 influenza epidemic (A/H1N1) caused an unusually high death toll in England; in particular, weekly deaths in Liverpool even surpassed those of the 1918 pandemic. . . . . Why this epidemic was so severe in some areas but not others remains unknown and highlights major gaps in our understanding of interpandemic influenza.

According to this study, the effects on the city of origin, Liverpool, were horrendous.

In Liverpool, where the epidemic was said to originate, it was "the cause of the highest weekly death toll, apart from aerial bombardment, in the city's vital statistics records, since the great cholera epidemic of 1849" (5). This weekly death toll even surpassed that of the 1918 influenza pandemic (Figure 1)

For roughly 5 weeks Liverpool saw an incredible spike in deaths due to this new influenza. And it didn’t just affect Liverpool. While it appears not to have spread as easily as the dominant Scandinavian strain, it managed to infect large areas of England, Wales, and Canada over the ensuing months.

Getting started relatively late in the flu season, this new strain never managed to spread much beyond UK and Eastern Canada. Nor did it reappear the following flu season. It simply vanished as mysteriously as it appeared.

While we don't know what made either of these two regional outbreaks so deadly, we do know that seasonal flu can abruptly shift gears, which is why we desperately need better surveillance around the world. 

FEMA: Preparing the Nation for Space Weather Events

Credit FEMA

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Although it may sound like the plot from any of a hundred cheesy-made-for-cable Sci Fi movies - or the hyperbolic content from thousands of `clickbaity' YouTube videos - space weather poses genuine risks for us here on earth (and in space), and has has been a serious concern for FEMA for decades. 

Like great earthquakes (8.0+), and severe pandemics, truly destructive solar flares and CMEs are extremely rare – but they do occur.  

It is a topic that we've revisited a number of times over the years (see below), primarily due to the impacts they could have on our modern electrical infrastructure (see NIAC: Surviving A Catastrophic Power Outage).

USGS: Preparing The Nation For Severe Space Weather

Executive Order: Coordinating Efforts to Prepare the Nation for Space Weather Events

The UK’s Space Weather Preparedness Strategy

NASA: The Solar Super Storm Of 2012

Two days ago the earth was hit by a G4 solar storm due to a (relatively minor) earth-directed filament eruption on the sun. It sparked auroras as far south as the southern United States, but had only limited impacts on the electrical grid. 

The summary from Spaceweather.gov follows:

Starting at 1:37 PM EDT on Sunday, April 23, 2023, Earth was impacted by a Severe Geomagnetic Storm (a level 4 of 5 on NOAA’s space weather G- scale). The most likely areas of impact extend across the northern tier of the United States (north of 45 degrees latitude) and into Canada. These impacts generally include widespread, yet manageable, irregularities to the power grid, spacecraft, global positioning systems, and radio communications. Additionally, if this storm persists into the evening, the Aurora Borealis may be seen as far south as Alabama and northern California. Currently, the Severe Geomagnetic Storm is expected to persist until 2:00 AM EDT on April 24, 2023.

On the afternoon of April 23, 2023, at 2:12 PM EDT, a Moderate Solar Flare (M1.7) erupted from the sun expelling a billion tons of superheated magnetized gas from the sun known as plasma. This ejection, known as a Coronal Mass Ejection (CME),  traveled at nearly two million miles per hour and reached Earth in two days. NOAA’s Space Weather Prediction Center had issued a Minor Geomagnetic Storm (G1) watch for April 23, 2023, and a Moderate Geomagnetic Storm (G2) watch for April 24, 2023, with only a 5% and 30% chance of the storm reaching strong-extreme conditions on the two days. A Strong-Extreme Geomagnetic Storm Warning was issued by SWPC at 3:26 PM EDT on April 23, 2023.  The Geomagnetic Storm arrived earlier and was stronger than expected.

Compared to the great solar storm of 1859 (the Carrington Event), the solar storm of 1989 which brought down Quebec's power grid, and the geomagnetic storm of 2003 which disrupted power in northern Europe and damaged several satellites, this was a fairly minor event. 

NOAA described the impact of the 2004 storm - which pales in comparison to the 1859 Carrington Event  - as `wide ranging', including:

• The Sydkraft utility group in Sweden reported that strong geomagnetically induced currents (GIC) over Northern Europe caused transformer problems and even a system failure and subsequent blackout.

• Radiation storm levels were high enough to prompt NASA officials to issue a flight directive to the ISS astronauts to take precautionary shelter. Airlines took unprecedented actions in their high latitude routes to avoid the high radiation levels and communication blackout areas. Rerouted flights cost airlines $10,000 to $100,000 per flight.

• Numerous anomalies were reported by deep space missions and by satellites at all orbits. GSFC Space Science Mission Operations Team indicated that approximately 59% of the Earth and Space science missions were impacted. The storms are suspected to have caused the loss of the $640 million ADEOS-2 spacecraft. On board the ADEOS-2 was the $150 million NASA SeaWinds instrument.

• Due to the variety and intensity of this solar activity outbreak, most industries vulnerable to space weather experienced some degree of impact to their operations.

In other words, we got lucky.  

Had this been an earth directed storm the size of the 1859 event, we might still be picking up the pieces.  While it has been nearly 20 years since out last major storm, as we learned in 2014 (see NASA: The Solar Super Storm Of 2012), we narrowly escaped being hit again in 2012.

You can view a 4-minute video on our `near-hit' here.

Our sun goes through a roughly 11-year cycle, over which time solar activity (sunspots, flares, Coronal Mass Ejections (CMEs), etc.) build to a maximum, and its magnetic field reverses, and then tapers off to a low activity minimum.  

The following NOAA graphic shows the suns progress over solar cycle 24 between 2010 and 2020. 

The sun hit its last solar maximum peak in 2014, and had been growing quieter with each passing year. That is, until a couple of yeas ago, when we started seeing increased signs of solar activity which is expected to peak in 2025.

Between our growing dependence on highly vulnerable satellites and electrical grids - and reports that our planet's magnetic field continues to weaken (see ESA Swarm probes weakening of Earth’s magnetic field) - there are concerns that we are becoming increasingly vulnerable to the effects of a major solar storm. 

Of course, we could go decades without seeing a major solar storm directly impact earth.  There is no way to predict when the next one will occur, or how damaging it might be.  FEMA is taking the threat seriously, and has recently offered a free online training course - for emergency managers and the general public - on preparing the nation for space weather events. 

FEMA RELEASES SPACE WEATHER TRAINING

published: Monday, April 24, 2023 17:24 UTC

FEMA has developed a training module that introduces both space weather and space weather impacts. It also provides excellent background on the US Government's plan for an extreme space weather storm. This course covers the lessons necessary for a greater understanding of space weather and its impacts, strengthens understanding of space weather events; the potential impacts from those events; and the roles of the Federal Government as well as the local and jurisdictional Emergency Manager in preparing for and mitigating such impacts. It can be found at the FEMA Website(link is external).

The course is interesting, presented in easily digestible snippets, and will take about 2 hours to complete. If you want to take the certification exam, you'll have to register (but anyone can audit the course). 

Either way, I highly recommend the course to anyone interested in learning about the risks posed by extreme space weather, and how our nation is preparing for it.