Gain-Of-Function research, involving organizations like the USDA, CAS, and Roslin Institute, may explain the recent jump of bird flu, specifically the H5N1 clade 2.3.4.4b, to cows and humans.
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At least twice in the last six months, experts have been taken aback by avian flu.
Bird flu viruses have long been mostly distributed among birds. In December 2023, an outbreak happened in dairy cows in the United States, even though cattle are normally not vulnerable to the bird flu virus known as avian influenza A.
An H5N1 virus from a cow infected a dairy farm worker in the United States in late March.
A second H5N1 virus case in humans was reported in Michigan on May 22. The patient had previously come into contact with sick dairy cows.
An Australian youngster contracted the H7 strain of influenza A, a different subtype that is known to infect humans, on the same day in May.
Since human cases of avian flu are uncommon, experts are quite concerned about these occurrences.
To what extent should we be concerned, and why is this happening?
This piece seeks to dispel unwarranted anxiety about a possible pandemic in the future. Rather, we urge individuals to exercise reason and make the necessary changes for the future.
Rapid Spread in Birds
The H5N1 virus family was initially identified in a sick goose in the Chinese province of Guangdong in 1996, marking the beginning of its history.
H5N1 has changed throughout time, giving rise to several genetic lineages (clades) as a result of mutations, which is comparable to the usual pattern of behavior for RNA viruses like the constantly resurfacing COVID-19 variations. The H5N1 clade 2.3.4.4b first appeared in 2013. Since then, it has quickly expanded to around 100 nations in Asia, Europe, Africa, and America, where it has taken the lead as the most prevalent clade and severely damaged the chicken business.
This specific clade, 2.3.4.4b, was discovered in American wild birds for the first time in December 2021.
The clade rapidly mingled with other influenza A viruses that were circulating in North American wild birds. As a result, the virus underwent gene recombination and reassortment, displaying a variety of traits. Numerous of these variations seriously impair mammals’ neurological systems and result in severe disorders.
The Jump to Cows
The bird flu virus, often known as the avian influenza virus, is a member of the flu virus family. Natural hosts of flu viruses include pigs, horses, gulls, terns, ducks, geese, and swans.
Some flu viruses normally only infect particular hosts; they do not spread to other hosts.
Bird flu viruses come in many different forms, from H1 to H19, although they have primarily affected animals and birds rather than people.
The H5N1 clade 2.3.4.4b brought forth this modification.
The frequent overflow episodes of this clade become alarming. When a virus spreads to a new or distinct host species—for instance, from a bird to a horse or cattle—it is referred to as a spillover event.
The U.S. Department of Agriculture (USDA) and the Centers for Disease Control indicate that since December 2023, highly pathogenic H5N1 clade 2.3.4.4b viruses have been seen spreading in dairy cows across several U.S. states.
Some cows have been consuming and producing less milk since the beginning of this year. The presence of H5Nx clade 2.3.4.4b viruses in the milk and nasal samples of the cows was subsequently verified. For the first time, the USDA declared an outbreak in this clade of cows.
The same strain of virus was discovered in dairy cows that are not known to be connected to the affected herds, according to the December USDA release. This implies that cows have already begun to silently transmit the disease, and asymptomatic cows most likely contributed to the rapid spread of the virus.
Nine states and 67 herds were infected with the H5N1 influenza as of May 28. This may suggest that host tropism is significantly expanding rather than only being a spillover occurrence, especially in the face of the small number of infected herds. When a widespread outbreak might happen is the cause for alarm.
Moreover, since dairy cows and humans coexist closely, diseases in cows may affect human health.
The Likely Jump to Humans
Human cases of bird flu infections are uncommon, although they do occur.
There have been isolated cases of H5N1 virus infection in humans over the last 20 years. There have been 463 recorded deaths from the 888 affected patients in 23 different countries. Most of the cases have been in Egypt, Vietnam, and Indonesia. Based on statistics gathered by the World Health Organization, these incidents have led to a cumulative case fatality rate of above 50%.
These cases are primarily dispersed around Asia, so until lately, Western nations haven’t paid them any attention.
A Colorado poultry worker was found to have a case in April 2022; the worker has since recovered. This was the first instance of H5N1 infection in the US that was known to have been spread from poultry to people.
It wasn’t until late March that there was the second human case in the United States. The H5N1 clade 2.3.4.4b was identified as the source of the hemorrhagic conjunctivitis symptoms in both eyes of a dairy farm worker in Texas. He healed completely in a matter of days and did not exhibit any respiratory problems.
This individual did, however, claim to have a close touch with sick dairy cows but no contact with dead or sick birds. The cows may have had an H5N1 virus because of their decreased milk production, decreased appetite, fever, and dehydration.
This was the first report of the highly virulent H5N1 avian influenza virus that is thought to have spread from a mammalian animal species to humans in the United States.
Scientists are concerned because these examples raise the possibility that the virus has developed the capacity to transmit between mammals and might infect humans.
Given the high death rate seen in prior outbreaks, a highly pathogenic H5N1 virus might have a substantial effect on the human population if it were to become easily transmissible among people, including through human-to-human transmission.
Since there are only two verified occurrences of cow-to-human transmission in the United States, it is uncertain how widespread these infections are and how high of a death rate they have.
Usually, species-to-species spillover occurs organically via the food chain. For example, it may occur when a different species consumes diseased birds. Unlike the vast occurrences observed in American cattle, these events often take place on a local scale.
Why the current shift to cows of a different species? Like in the past, was it a natural, random occurrence, or were there other elements at play?
Gained the Ability to Spread via Aerosols
The H5N1 viruses that originated in birds were difficult for animals to spread to one another.
Ten years ago, two virologists, Ron Fouchier of Erasmus Medical Center in the Netherlands and Yoshihiro Kawaoka of the University of Wisconsin in Madison, scared the world with their high-risk gain-of-function research on H5N1.
The procedure was intricate. As an illustration, a mutant H5N1 virus was produced with the particular gene mutation PB2 E627K. After that, it was run through ten ferrets. The H5N1 virus underwent five alterations in total before acquiring the capacity to spread through respiratory droplets or aerosols.
Only in nature had these mutations been discovered, and never in the same strain. Furthermore, they have the potential to spread globally due to their lab manipulation and improved aerosol transmission capabilities.
After reading their works, microbial geneticist Paul Keim, the chair of the U.S. National Science Advisory Board for Biosecurity (NSABB), voiced concerns in 2011. He said to Science, “I don’t know of another pathogenic organism that is as scary as this one.” “I don’t think that anthrax is scary at all compared to this,” he continued, having spent many years working on anthrax.
By making these important changes public, the scary H5N1 story begins and others can duplicate the work in their labs.
Discovery of the H5N1 clade 2.3.4.4b occurred in 2013.
Further Manipulation in a Chinese Lab
The USDA, the U.S. National Poultry Research Center, the Southeast Poultry Research Laboratory (SEPRL) in Georgia, the Chinese Academy of Sciences (CAS), and the Roslin Institute in the UK launched a three-party project on April 1, 2021, involving the United States, the United Kingdom, and China.
A $1 million grant is being sponsored by the USDA for this effort. Expertise in viral transcriptomics analysis and avian immunology genomics is offered by the SEPRL and Roslin Institute.
The CAS lab in China is where the real experiments are carried out. This place may have been chosen for a special reason.
The project is also a gain-of-function (GOF) study, as we will clarify later.
Since 2011, GOF studies on the avian flu virus have drawn heavy criticism from the scientific community in the United States. “This work should never have been done,” added Waksman Institute of Microbiology laboratory head and molecular scientist Richard Ebright in a statement to Science. Regarding biosafety, researchers have voiced worries that a novel virus created in the lab would break free or that bioterrorists might use the results of their work to create a bioweapon for nefarious ends.
From October 2014 to December 2017, influenza, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus were prohibited in the United States for use in gain-of-function research. On December 19, 2017, the National Institutes of Health (NIH) removed the moratorium.
Chinese laboratories frequently possess adequate technical capabilities, but they have a significant obstacle because of the country’s lax biosecurity laws.
“Bird flu, I think, is going to be the cause of a great pandemic—where they are teaching these viruses how to be more infectious for humans,” said Dr. Robert Redfield, the former director of the CDC.
A Severe, Rapidly Spreading Virus
Research on bird flu viruses using dangerous gain-of-function techniques is not frowned upon by Chinese scientists.
The three-party collaborative project study design has at least three features that strongly suggest it is a gain-of-function design. But it could be hard to tell without looking between the lines.
The experimental strategy known as “serial passage” is one such problem. Scientists generally agree that serial passage study is a useful technique for gain-of-function investigations.
The process of serial transit entails the virus’s growth and replication from one animal or cell to another. There is a significant chance that the mutations produced by these experiments may increase transmissibility, virulence, and zoonotic transmission. For the following text, the more effective mutants can be chosen.
According to what is stated in their proposal, CAS scientists are in charge of determining “fitness,” which is a proxy for how quickly or slowly a viral infection progresses and whether or not it causes a serious or minor sickness. Before and after every round of passes, samples are taken to determine pathogenicity and patterns of transmission. This raises the possibility of developing mutant H5N1 viruses that can spread more quickly and cause more serious illnesses.
Owing to the bird flu virus’s rapid recombination rate, novel recombinant influenza viruses with erratic host tropism or pathogenicity could result from a genome reassortment between high- and low-pathogenic bird flu viruses.
As a result, there is now even more chance of producing novel gain-of-function mutants.
The H5N1 bird flu virus, which belongs to clade 2.3.4.4b, began spreading rapidly in 2021 among wild birds and domestic poultry in Asia, Europe, and Africa. By the end of that year, the virus had also reached America.
Response to Criticism
The research on gain-of-function has long been criticized. Regarding working with the Chinese on bird flu research, several US Congressmen have likewise voiced grave concerns.
“We are disturbed by recent reports about the U.S. Department of Agriculture’s (USDA) collaboration with the Chinese Communist Party (CCP)-linked Chinese Academy of Sciences (CAS) on bird flu research,” they wrote in an April 12 letter.
“This research, funded by American taxpayers, could potentially generate dangerous new lab-created virus strains that threaten our national security and public health,” they added.
The principal investigator denied that they intended to conduct gain-of-function research in an interview published in the February issue of Science. “In vivo, passage of viruses through mallard ducks and Chinese goose species to predict evolution in natural hosts” is part of the experimental methodology, though.
Wenjun Liu, the principal scientist at CAS who oversaw this work, stressed that stringent rules on lab safety are enforced by the Chinese government. This argument, however, is hardly persuasive because, as the Wuhan Institute of Virology and COVID-19 indicate, major safety compliance problems can arise in even the highest safety level, biosafety level 4 labs.
It is evident from the recent funding suspension for scientist Peter Daszak, head of EcoHealth Alliance, that the public mistrusts virological research associated with Chinese government-run laboratories.
Increased Pathogenicity
It has become more pathogenic for animals to contract H5N1.
Researchers at the University of Pittsburgh and the Vaccination Research Center of the NIH tested the efficacy of the H5N1 vaccination in a 2023 study that was published in Cell using their current model of cynomolgus macaques.
In this study, four out of six macaques died from acute respiratory illness and high fever after inhaling an aerosol dose of 5.1 log10 plaque-forming units (PFU). PFU is a technique for calculating the virus’s concentration.
In contrast, high doses of H5N1 (6.5–7.8 log10 PFU) administered to cynomolgus macaques through mouth, eyes, throat, and nose typically caused mild illness in these monkeys (based on prior reports, 2 out of 49 died from the infection). These studies were carried out between 2001 and 2014.
A far higher percentage (half) of the monkey deaths in the 2023 research were caused by a much lower dose than in the experiments conducted 10 to 23 years ago. This suggests that the pathogenicity of the H5N1 virus has dramatically increased.
History Repeated?
We looked back at the dates of the H5N1 bird flu virus outbreaks in birds and mammals in 2013 and 2021 as well as the GOF investigations in 2012 and 2021, and found a strong temporal correlation between the two.
The present epidemics in birds and cows, along with the studies on bird flu viruses, should serve as a reminder of the hotly contested origin of SARS-CoV-2.
One generally accepted, fact-based theory on the development of the SARS-CoV-2 virus contends that laboratory manipulation gave previously human-immune bat-derived coronaviruses the capacity to infect humans.
It’s especially critical to take into account the current focus of scientific inquiry following an unprecedentedly difficult period brought on by COVID-19. In the name of pandemic preparedness, certain Chinese government-controlled labs are still producing more harmful viruses and facilitating their widespread dissemination. This begs the question of whether they are causing fewer diseases or assisting individuals in need.
These concerning details should lead to rapid, comprehensive investigations of Chinese labs and their links to the H5N1 bird flu pandemic.
The fundamental motivation for scientific advancement and the development of vaccinations and other more potent public health measures is frequent technological competition. It’s possible, though, that scientists have caused more issues than they have solved for humanity.
More About Bird Flu Viruses
The flu virus comes in four different varieties: A, B, C, and D. As of right now, only type A viruses are capable of causing worldwide pandemics. When an influenza virus can spread from person to person for an extended period among a population that has little immunity to the virus, a pandemic may result. Three type A flu viruses—H1N1 (1918), H2N2 (1957), and H3N2 (1968)—have historically caused human pandemics.
Influenza A virus’s two types of glycoproteins on its surface are used to classify viruses into dozens of subgroups.
Hemagglutinin (H), the initial glycoprotein, enables the virus to attach to the sialic acid cell surface receptor and penetrate the cell. Its capacity to induce red blood cells to aggregate into masses is where it gets its name. Neuraminic acid’s glycosidic linkages are broken by the second one, neuraminidase (N), an enzyme and protein that destroys receptors and aids in the release of fresh virus particles from infected cells. The equilibrium between the H and N functions may have consequences for interspecies pathogenicity, host adaptation, and transmission.
Eleven N proteins (N1–N11) and nineteen H proteins (H1–H19) have been found in total. A virus that causes influenza can be named using several combinations of H and N. There are two types 5 H and type 1 N, so its name is H5N1.
The nomenclature “H5Nx” designates the pairing of various neuraminidase types (including N1, N2, N6, and N8) with the H5 protein.
Similar to a branch on a family tree, a “clade” A clade of viruses in a family of viruses is a collection of viruses with comparable traits that shared a common ancestor. Many viruses from H5N1, H5N2, H5N5, H5N6, and H5N8 are included in Clade 2.3.4.4b.
There are five subtypes of avian influenza A viruses that are known to have infected humans: H5, H6, H7, H9, and H10.
Bird flu viruses are categorized according to the severity of the sickness they cause, as low or highly pathogenic avian influenza.
Extremely pathogenic subtypes include H5 and H7. Particularly, the majority of human cases of avian influenza A have been linked to the A(H5N1) and A(H7N9) viruses.
In recent years, human illnesses have also been caused by the HPAI A(H5N6) and LPAI A(H9N2) viruses.
As recently reported by GreatGameIndia, the founder of the Raw Milk Institute and Fresno’s Raw Farm, Mark McAfee, claimed that raw milk enthusiasts are demanding milk infected with bird flu.
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