Covering Pandemic and Seasonal Flu, H5N1 `Bird Flu, Emerging Infectious Diseases, public health, community & Individual preparedness, and anything else that piques my admittedly eclectic interests
Today the journal Nature has published a study which looked at the characteristics of the first H5N1 virus isolated in Texas from a dairy worker (huTX37-H5N1) which carried a worrisome mutation(PB2-E627K), but produced only mild symptoms in the index case.
In contrast to its mild presentation in the human, it proved lethal in both ferrets and mice, and it transmitted - with limited efficiency - via respiratory droplets to nearby ferrets.
The study, which is behind a subscription paywall, can be accessed at the following link. Luckily, however, we have an excellent overview published today from the NIH.
From this NIH review, we learn that this virus may be more formidable than previously thought, and that our mainstay influenza antiviral - oseltamivir (aka `Tamiflu') - may not be as effective as some newer options (i.e. favapirivir and baloxavir).
The `money quote' from these researchers is `. . . based in these observations, every effort should be made to contain HPAI H5N1 outbreaks in dairy cattle to limit the possibility of further human infections.”
A goal which, right now, we seem to be falling well short of.
Some antiviral drugs highly effective against bovine H5N1
What
A highly pathogenic avian influenza (HPAI) H5N1 virus, isolated from the eye of a farm worker who became infected through contact with dairy cows, was lethal in mice and ferrets infected in a high-containment laboratory environment, according to a new study in Nature. The study investigators also found that the virus isolated from the worker, who experienced mild inflammation of the cornea (conjunctivitis), could be transmitted through the air between separated ferrets and might be capable of binding to and replicating in human respiratory tract cells.
The virus isolated from the worker is called huTX37-H5N1 and has a mutation (PB2-E627K) frequently seen in avian influenza viruses that replicate in mammal
“based in these observations, every effort should be made to contain HPAI H5N1 outbreaks in dairy cattle to limit the possibility of further human infections.”
s, typically making virus replication more efficient. These mutations underscore the need for continued monitoring and evaluation of viruses from the current H5N1 outbreak.
The study also showed that a bovine H5N1 virus is susceptible to the antiviral drugs favipiravir and baloxavir marboxil (brand name Xofluza) of the polymerase inhibitor class, as well as the neuraminidase inhibitor zanamivir. The virus is less sensitive to oseltamivir (Tamiflu), another neuraminidase inhibitor.
In laboratory experiments, huTX37-H5N1 replicated in human cornea and lung cells. The scientists determined the lethal dose of huTX37-H5N1 as less than 1 plaque-forming unit (PFU) in mice, compared to 31.6 PFU as the lethal dose of a bovine H5N1 virus isolated from the milk of a lactating cow. The huTX37-H5N1 virus also infected each of 15 different mouse tissues tested, with the highest virus levels found in respiratory tissues.
Researchers also infected ferrets with a high dose of huTX37-H5N1. Flu infections in ferrets more closely resemble human flu infections than those in mice. All infected ferrets died within 5 days and scientists found huTX37-H5N1 virus in all the tissues sampled, with high levels in the respiratory system.In a prior study, the researchers had infected ferrets with a bovine H5N1 virus and, although it caused severe disease, lethality was limited.
To evaluate respiratory transmission, the scientists placed healthy ferrets in cages about 5 centimeters away from ferrets infected one day earlier with one of four decreasing doses of huTX37-H5N1. All directly infected ferrets died within 6 days and, depending on the exposure dose, between 17% and 33% of the nearby animals became infected via respiratory droplet transmission. These results indicate that a bovine HPAI H5 virus isolated from an infected person can transmit among mammals via respiratory droplets, though with limited efficiency.
The authors note that the person infected with the huTX37-H5N1 virus did not develop severe illness. In fact, human cases reported from the current outbreak have mostly experienced conjunctivitis and/or mild respiratory symptoms. The researchers speculate that eye infection with a low dose of bovine H5N1 virus might result in localized conjunctivitis without severe disease in humans. Multiple exposures to seasonal human influenza viruses, they say, might provide people with low levels of protection against currently circulating HPAI H5N1 viruses—though additional study is needed.
In summary, this study characterizes the huTX37-H5N1 isolate, finding that it may be capable of replicating in cells of the respiratory tract in humans, that it is pathogenic in mice and ferrets, and that it is capable of being transmitted by the respiratory route in ferrets.
“based in these observations, every effort should be made to contain HPAI H5N1 outbreaks in dairy cattle to limit the possibility of further human infections.”
Scientists from the University of Wisconsin at Madison led the research with collaborators from Shizuoka and Tokyo Universities and the Research Center for Global Viral Diseases in Japan. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded much of the work through its Centers of Excellence for Influenza Research and Response program.
Articles
C Gu et al. A human isolate of bovine H5N1 is transmissible and lethal in animal models. Nature DOI: 10.1038/s41586-024-08254-7 (2024).
A Eisfeld et al. Pathogenicity and transmissibility of bovine H5N1 influenza virus in mice and ferrets. Nature DOI: 10.1038/s41586-024-07766-6 (2024).
Last Thursday, the California Department of Food an Agriculture reported a total of 137 confirmed H5N1 infected dairy herds in that state, which is more than double that of the next largest affected state (Colorado at 64).
Reportedly, many of these herds have been identified by bulk testing of milk, and not because they were symptomatic. But bulk testing in California has been limited to those herds in close proximity to known outbreaks.
The decision not to require weekly bulk testing of milk in every state of the nation continues to obscure the true scope of this epizootic. Instead, states and the dairy industry appear to be hoping that HPAI H5 will eventually burn itself out in cattle, and that human infections will remain sporadic and mild.
And while that could happen, it is far from guaranteed.
Although numbers are incomplete due to a lack of testing and reporting, the number of confirmed cases in Africa has risen sharply over the past 2 months. The WHO estimates that only about 20% of suspected cases in Africa are laboratory confirmed, making it difficult to accurately gauge the size of the outbreak.
Nearly every WHO DON or diseaseSituation Report contains diplomatic reminders to member nations of their `duty to report' these cases under the IHR 2005 agreement, but compliance remains spotty at best.
The global expansion of Clade II, and recent inroads made by Clade I are shown in the map below.
Over the weekend the WHO has published their 41st Mpox External Situation Report. I've posted some of the highlights from this 25 page update, but you'll want to follow the link to read it in its entirety.
• In September 2024, the last month for which complete global surveillance data is available, 2763 confirmed
mpox cases were reported. This is the highest number of cases since November 2022 and marks an
increasing trend in the number of reported confirmed mpox cases globally, driven by the increase in the
African Region, followed by the Western Pacific Region.
• Outside Africa, the highest number of confirmed cases in September 2024 was reported by Australia. The
country is currently experiencing an increasing outbreak of clade IIb MPXV, affecting mainly men who have
sex with men and are infected through sexual contact.
• The rise in mpox cases in Africa is driven by the Democratic Republic of the Congo, Burundi, and an
expanding outbreak in Uganda.
• As of 20 September 2024, Clade Ib monkeypox virus (MPXV) has been detected in six provinces in the
Democratic Republic of the Congo: South Kivu, North Kivu, Kinshasa, Kasai, Tshopo and Tanganyika.
• In the Democratic Republic of the Congo, the number of new mpox cases continues to rise in South Kivu
province, where clade Ib is spreading and making it the most affected province in the country. The spread
is driven by close interpersonal human-to-human contact, including sexual contact and direct close contact
in households and communities. The increase in cases is uneven within the province, with a few hotspots
driving transmission. While the initial phase of the clade Ib epidemic in eastern Democratic Republic of the
Congo was mostly affecting adults, as clusters expand in the community, the epidemic is affecting both
adults and children, reflecting wider community transmission through close contact.
• In Kinshasa, the capital of the Democratic Republic of the Congo, where both clade Ia and clade Ib are cocirculating, the epidemic is expanding too. Adults are disproportionally affected, although there are reports
of infections across all age groups.
• Further details about the epidemic dynamics in the Democratic Republic of the Congo can be found in the
WHO mpox surveillance report, now displaying subnational level trends for the country.
• In neighbouring Burundi, where the epidemic is also presumed to be driven by clade Ib, 182 cases were
reported last week, compared to 134 the previous week and 157 the week before. The epidemic remains
largely concentrated in- and around Bujumbura, with two main age groups being affected, similar to what
is observed overall in South Kivu (young children <5 years and young and middle-aged adults), suggesting
similar epidemic dynamics.
• The epidemic in Uganda is expanding. It is presumed to be driven by clade Ib predominantly affecting adults
and there is documented transmission that involved sexual contact and sex workers.
• Zimbabwe reported its first two mpox cases, in a person with travel history to South Africa and in a person
with travel history to Tanzania. Clade information is not yet available for these cases.
• The first mpox deaths were reported in Kenya (one) and in Uganda (one). Both cases were adults living
with HIV, and although clade information for the specific cases is not yet available, they are likely to be
clade Ib MPXV.
• Germany reported the first mpox case due to clade Ib MPXV in a person with travel history to an affected
African country.
• A rise in reported cases has also been observed in Côte d’Ivoire, where only clade IIa MPXV was detected
in 2024.
• This report includes the description of the mpox literature repository and the summary of the latest WHO
interim guidance for mpox in school settings.
Since the eradication of smallpox in the 1970s, there has been a general feeling that poxviruses are a thing of the past, a relic of the 20th century. But as our collective immunity from thesmallpox vaccine- which was discontinued in the late 1970s - wanes, there are increased opportunities for pox viruses to make a comeback.
The Mpox virus is continually evolving, and we now have at least 4 clades of Mpox in circulation (I, Ib, II, IIb), with Clade I and Ib considered the most severe.
While we may be somewhat comforted by the fact that of the 34+ H5N1 cases reported in the United States in 2024 have all been mild, in many other parts of the world different incarnations of the HPAI H5 virus have not been so benign.
In Cambodia, we've seen 18 human H5N1 infections (clade 2.3.2.1c) reported since early 2023, with nearly a 40% fatality rate. And as we've seen previously with other incarnations of HPAI H5N1, Children and adolescents have been the hardest hit.
In Asia, several clades continue to circulate, including A(H5N1) 2.3.4.4b, 2.3.2.1c and others, which can lead to reassortment and the appearance of viruses with new characteristics. A novel reassortant influenza A(H5N1) virus has been detected across the Greater Mekong Subregion (GMS), causing infections in both humans and poultry since mid- 2022.
This virus has recently caused human outbreaks in Cambodia early this year. This virus contains the surface proteins from clade 2.3.2.1c that has circulated locally, but internal genes from a more recent clade 2.3.4.4b virus.
The introduction and widespread circulation of this reassortant influenza A(H5N1) virus into the GMS poses a significant risk to both animal and human health, given the historical impact of HPAI outbreaks in the region. Further, this reassortment event indicates not only the adaptive capacity of the virus but also the ever-present risk of the emergence of new, potentially more virulent strains.
Meanwhile, in China, we've been watching the spread and evolution of H5N6 since the spring of 2014, and among the 92 reported cases out of China(likely an undercount), its fatality rate has been running in excess of 50%.
The concern is that - like with the recent changes we've seen in Cambodia's H5N1 virus - the H5N6 virus may be evolving towards becoming a more mobile threat. All of which brings us to a new report out of China of the the detection of H5N6 in wild birds, and signs of continued reassortment with other viruses.
The highly pathogenic avian influenza 2.3.4.4b H5 viruses have been a cause for concern recently, as they have been responsible for continuous outbreaks since 2021. In China, the H5N6 subtype has been predominantly circulating in domestic poultry but has rarely been detected in wild birds over the past 3 years.
In December 2023, novel reassortant 2.3.4.4b H5N6 viruses were resurgent in wild birds and domestic ducks in Eastern Asia. The viruses were reassorted with those of currently prevalent 2.3.4.4b H5N1 viruses of wild bird origin worldwide, as well as the H5N6 viruses that caused human infections in 2022 and low pathogenic avian influenza viruses, such as the H9N2 virus, which also contributed internal gene to the novel H5N6 viruses.
Based on the phylogenetic analyses, we inferred that this recombination process occurred in migratory breeding sites in early 2023. Given the rapid transmission and high mutation capacity of currently circulating H5N1 viruses, as well as the strong pathogenicity of H5N6 viruses to humans, the novel recombinant viruses may continue to evolve and pose new threats to human health. Therefore, continuous surveillance of H5N6 viruses in wild birds and domestic poultry should be strengthened.
(SNIP)
The concurrent detection of this novel 2.3.4.4b H5N6 viruses in Eastern Asia implies that the viruses seemed to be well-adapted in migratory wild birds, thereby raising concerns regarding their potential ability to asymptomatically spread viral pathogens over long distances. On the one hand, the cross-regional transmission of the virus is facilitated by migratory movements of wild birds, while on the other hand, the cross-species transmission is also increased through poultry being exposed to viruses due to their shared habitats with wild birds. Furthermore, the novel 2.3.4.4b H5N6 viruses can infect domestic duck in Korea, and our findings indicate that the 23997-H5N6 has undergone multiple mutations at antigenic sites B (185, 192, and 193) and C (276) when compared to the vaccine strain Re-14 [15, 16] (Table S2), highlighting the potential risk of an outbreak in poultry and the subsequent spillover to humans due to possible inadequacy of current commercial vaccines in providing complete protection.
The prevalence of H5N1 AIVs is currently increasing in Europe and America, and they have infected multiple wild mammals and farm animals [17]. Furthermore, the H5N6 virus is widespread among domestic poultry in China, and human infection with the H5N6 viruses has shown even higher mortality rates than those caused by the H5N1 viruses based on current clinical statistics [18]. It is noteworthy that a recent rise in the frequency of 2.3.4.4b clade H5N1 and H5N6 cases has been observed.
The cocirculation of H5N6 and H5N1 viruses in migratory birds may accelerate the evolution of novel variants, increasing their ability for recombination, pathogenicity, and dissemination. Eastern Asia has been a host spot for the emergence of novel genetic reassortments. Therefore, increased surveillance is needed in these regions to further elucidate the origin and evolution of these viruses, thereby providing crucial early warning that could potentially prevent an influenza epidemic in humans.
4. Conclusions
In this study, we identified a novel influenza A (H5N6) virus in wild waterfowl in Shanghai in 2023. These findings provide evidence of H5N6 virus recombination, highlighting the role of wild waterfowl for virus cross-region and cross-species transmission. We also demonstrated that this recombinant H5N6 virus may acquire the escalated transmission of 2.3.4.4b H5N1 viruses and the high pathogenicity of H5N6 viruses in domestic poultry and humans, pausing great threats to the poultry industry and human health. Thus, we called for continued attention and monitoring of this novel H5N6 virus worldwide.
We've been extraordinarily lucky that the H5N6 virus hasn't demonstrated the same ability to hitch transoceanic rides on migratory birds the way that clade 2.3.4.4b H5N1 viruses have.
But now that we are seeing reassortments between the deadlier H5N6 virus and the more mobile H5N1 virus, the concern is our luck could change. Earlier this year the FAO warned that reassortments between H5N1 clade 2.3.2.1c and 2.3.4.4b in Cambodia pose similar risks.
While we are understandably focused on HPAI H5 in our own backyard, the world is a very big place - and if a pandemic virus emerges anywhere - it will very quickly become a problem everywhere.
Late yesterday the CDC published their weekly H5 update, which added 3 more poultry-related human infections in Washington State (n=5), bringing the total number of human cases in 2024 to 34 across 6 states.
Given that only one U.S. case had been reported prior to April of this year (in Apr 2022), this is a significant departure from what we've seen in the past. Not only are these numbers are likely to rise, they also likely under represent the true number of cases.
We've seen multiple anecdotal reports indicating that some (perhaps many) symptomatic farm workers have refused to be tested for the virus (see EID Journal: Avian Influenza A(H5N1) Virus among Dairy Cattle, Texas, USA), and that describe a general reluctance of many farm owners to cooperate with investigators.
This week KFF Health News published an eye-opening report (link below) on the obstacles that local health departments are facing identifying cases. Highly recommended.
Despite that fact that better testing in California and Colorado have turned up many more (previously unsuspected) infected farms, testing for the virus in cattle (and bulk milk) remains sporadic - and largely voluntary - across the country.
`Don't test, don't tell'may serve the short-term interests of the dairy industry - but it only hides the problem - it doesn't solve it.
The good news is that there is still no sign of human-to-human transmission of the virus, although the regrettable lack of testing limits our ability to make definitive statements. This remains an evolving situation.
Some excerpts from last night's CDC update, after which I'll have a postscript.
H5 bird flu is widespread in wild birds worldwide and is causing outbreaks in poultry and U.S. dairy cows with several recent human cases in U.S. dairy and poultry workers.
While the current public health risk is low, CDC is watching the situation carefully and working with states to monitor people with animal exposures.
CDC is using its flu surveillance systems to monitor for H5 bird flu activity in people.
10,458wild birds detected as of 10/22/2024 | Full Report
51 jurisdictions with bird flu in wild birds
103,620,541poultry affected as of 10/25/2024 | Full Report
48 states with outbreaks in poultry
338 dairy herds affected as of 10/24/2024 | Full Report
14 states with outbreaks in dairy cows
These data will be updated daily, Monday through Friday, after 4 p.m. to reflect any new data.
Cumulative data on wild birds have been collected since January 20, 2022. Cumulative data on poultry have been collected since February 8, 2022. Cumulative data on humans in the U.S. have been collected since April 28, 2022. Cumulative data on dairy cattle have been collected since March 25, 2024.
With practically every infectious disease you can name, surveillance and testing only picks up a fraction of the total number of cases. The proverbial `tip of the iceberg’ or in the case of the CDC graphic below, the `top of the pyramid’.
Sentinel surveillance systems are important for the monitoring of respiratory viruses in the EU/EEA, but these systems are not designed and are not sufficiently sensitive to identify a newly emerging virus such as avian influenza in the general population early enough for the purpose of implementing control measures in a timely way.
Similarly, in 2023's analysis from the UKHSA (see TTD (Time to Detect): Revisited), there could be dozensor even hundreds of undetected human H5N1 infections before public health surveillance would likely detect them, potentially over a period of weeks or months.
While great emphasis is placed on the latest official numbers of people, or cattle herds, or other animals infected by the virus, the reality is - without better testing and reporting - we are only seeing a small part of a much larger picture.
And while that may be reassuring, it can lull us into dangerous complacency.
