Virus World

Federal public health officials are turning to wastewater surveillance to help fill in the gaps in efforts to track H5N1 bird flu outbreaks in dairy cows. R eluctance among dairy farmers to report H5N1 bird flu outbreaks within their herds or allow testing of their workers has made it difficult to keep up with the virus’s rapid spread, prompting federal public health officials to look to wastewater to help fill in the gaps. On Tuesday, the Centers for Disease Control and Prevention is expected to unveil a public dashboard tracking influenza A viruses in sewage that the agency has been collecting from 600 wastewater treatment sites around the country since last fall. The testing is not H5N1-specific; H5N1 belongs to the large influenza A family of viruses, as do two of the viruses that regularly sicken people during flu season. But flu viruses that cause human disease circulate at very low levels during the summer months. So the presence of high levels of influenza A in wastewater from now through the end of the summer could be a reliable indicator that something unusual is going on in a particular area.

Wastewater monitoring, at least at this stage, cannot discern the sources — be they from dairy cattle, run-off from dairy processors, or human infections — of any viral genetic fragments found in sewage, although the agency is working on having more capability to do so in the future. CDC wastewater team lead Amy Kirby told STAT that starting around late March or early April, some wastewater collection sites started to notice unusual increases in influenza A virus in their samplings. Those readings stood out because by the last week of March, data the CDC tracks on the percentage of people seeking medical care for influenza-like illnesses suggested that the 2023-2024 flu season was effectively over. The increases were very site-specific, she said, and were not reflected in other areas. In fact, she called it “a very limited phenomenon. … The vast majority of our sites are not seeing this.” To date there has been little information in the public sphere about where infected cattle herds have been located. When the U.S. Department of Agriculture announces positive test results, it merely names the state in which the herd was located when the testing took place. Last week, the USDA reported that six additional herds — in Michigan, Idaho, and Colorado — had tested positive for H5N1, bringing the total to 42....

The avian influenza virus that has been infecting dairy cows and spreading alarm in the United States was expected to reach Germany this week. But that’s actually good news. A shipment of samples of the H5N1 virus from Cornell University virologist Diego Diel is destined for the Federal Research Institute for Animal Health in Riems, which has one of the rare high-security labs worldwide that are equipped to handle such dangerous pathogens in cattle and other large animals. There, veterinarian Martin Beer will use the samples to infect dairy cows, in search of a fuller picture of the threat the virus poses, to both cattle and people, than researchers have been able to glean from spotty data collected in the field. Six weeks into the outbreak that has spread to farms in nine U.S. states, the flow of data from those locations remains limited as public health officials sort out authorities and some farms resist oversight. “It’s incredibly difficult to get the right sample sets off the infected farms,” says Richard Webby, an avian influenza researcher at St. Jude Children’s Research Hospital. “It’s clearly a barrier to understanding what’s going on. … That’s why these experimental infections of cows are really going to be super informative.”

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota.

Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Published in PNAS (April 22, 2024):

https://doi.org/10.1073/pnas.2319566121

New research presented at the ESCMID Global Congress (formerly ECCMID) in Barcelona, Spain (27–30 April) shows that in a VACCELERATE Consortium survey study in which infectious diseases experts were asked to rank pathogens in order of their pandemic potential, influenza was considered the pathogen of highest pandemic risk, with 57% ranking influenza as number one, and a further 17% ranking it second. The study is by Dr. Jon Salmanton-García, University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany, and colleagues from across Europe, and published in the journal Travel Medicine and Infectious Disease. Other highly ranked pathogens included Disease X (as yet unknown disease) with 21% ranking this number one and 14% second. SARS-CoV-2 was third in terms of number one responses on 8%, with 16% voting it number two, while the original SARS-CoV virus that circulated in 2002–03 was voted number one by 2% of respondents and second by 8%. Crimean-Congo hemorrhagic fever virus (CCHF virus) and Ebola virus were joint fifth, with 1.6% respondents voting them first. Nipah virus, henipavirus, and Rift Valley fever virus were among the pathogens ranked lowest in terms of their perceived pandemic potential.

The World Health Organization (WHO) has outlined a comprehensive Research and Development (R&D) Blueprint for Action to Prevent Epidemics, focusing on key infectious diseases that pose significant threats to public health. These diseases were selected after rigorous evaluation, taking into account factors like transmissibility, infectivity, severity, and their potential for evolution. In alignment with the WHO's R&D Blueprint, the VACCELERATE Site Network (a pan-European network of sites collaborating on COVID-19, other infectious diseases and general pandemic preparedness infectious diseases) engaged infectious disease experts from around the world, both among and outside its members, to rank the diseases listed in terms of their perceived risk of instigating a pandemic. Participants were tasked with ranking various pathogens based on their perceived pandemic risk, encompassing diseases featured in the WHO R&D Blueprint and additional pathogens. Experts could rank up to 14 pathogens in the order of their perceived risk (the 13 pathogens listed plus Disease X—as yet unknown pathogen) in any order, and also suggest pathogens not listed to include in their maximum of 14. Each pathogen received a score based on its positions. A total of 187 responses were collected from infectious disease experts hailing from 57 different countries Among the countries providing the highest number of responses, Germany accounted for 27 replies (14%), followed by Spain with 20 replies (11%), and Italy with 14 replies (8%). Influenza viruses emerged as the most concerning pathogen with other highly ranked pathogens including Disease X, SARS-CoV-2, SARS-CoV, and the Ebola virus. Conversely, Hantavirus, Lassa virus, Nipah virus, henipavirus and Rift Valley fever virus were among the pathogens ranked lowest in terms of their pandemic potential.

The authors conclude, "The study revealed that influenza, disease X, SARS-CoV-1, SARS-CoV-2, and the Ebola virus are the most worrisome pathogens concerning their pandemic potential. These pathogens are characterized by their transmissibility through respiratory droplets and a history of previous epidemic or pandemic outbreaks." Commenting on the top ranking of influenza, Dr. Salmanton-García adds, "Each winter we have an influenza season. One could say that this means that every winter there are little pandemics. They are more or less controlled because the different strains are not virulent enough. Yet, every season the strains involved change, that is the reason why we can get influenza several times in life and vaccines change year to year. In case a new strain becomes more virulent, this control could be lost." But he adds the world is now much more prepared due to the COVID-19 pandemic, whereas before a lot of the focus had been on a potential influenza pandemic. He says, "In COVID-19 pandemic we have learned many things on how to approach a respiratory virus pandemic. This includes social distancing, hand cleaning, face masks, a renewed focus on vaccination, and trust in health care institutions. In parallel, institutions have also learnt a lot. Preparedness and surveillance are now, vitally, better-funded."

Study published in Travel Medicine and Infectious Disease (Feb. 2024):

https://doi.org/10.1016/j.tmaid.2023.102676

U.S. regulators confirmed that sick cattle in Texas, Kansas and possibly in New Mexico contracted avian influenza. They stressed that the nation’s milk supply is safe. A highly fatal form of avian influenza, or bird flu, has been confirmed in U.S. cattle in Texas and Kansas, the Department of Agriculture announced on Monday. It is the first time that cows infected with the virus have been identified. The cows appear to have been infected by wild birds, and dead birds were reported on some farms, the agency said. The results were announced after multiple federal and state agencies began investigating reports of sick cows in Texas, Kansas and New Mexico. In several cases, the virus was detected in unpasteurized samples of milk collected from sick cows. Pasteurization should inactivate the flu virus, experts said, and officials stressed that the milk supply was safe.

“At this stage, there is no concern about the safety of the commercial milk supply or that this circumstance poses a risk to consumer health,” the agency said in a statement. Outside experts agreed. “It has only been found in milk that is grossly abnormal,” said Dr. Jim Lowe, a veterinarian and influenza researcher at the College of Veterinary Medicine at the University of Illinois at Urbana-Champaign. In those cases, the milk was described as thick and syrupy, he said, and was discarded. The agency said that dairies are required to divert or destroy milk from sick animals....

USDA report (March 25, 2024):

https://www.aphis.usda.gov/aphis/newsroom/news/sa_by_date/sa-2024/hpai-cattle 

NIH researchers explore hidden, vulnerable region of influenza neuraminidase.

Researchers at the National Institutes of Health have identified antibodies targeting a hard-to-spot region of the influenza virus, shedding light on the relatively unexplored “dark side” of the neuraminidase (NA) protein head. The antibodies target a region of the NA protein that is common among many influenza viruses, including H3N2 subtype viruses, and could be a new target for countermeasures. The research, led by scientists at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center, part of NIH, was published today in Immunity. Influenza, or flu, sickens millions of people across the globe each year and can lead to severe illness and death. While vaccination against influenza reduces the burden of the disease, updated vaccines are needed each season to provide protection against the many strains and subtypes of the rapidly evolving virus. Vaccines that provide protection against a broad range of influenza viruses could prevent outbreaks of new and reemerging flu viruses without the need for yearly vaccine reformulation or vaccinations. One way to improve influenza vaccines and other countermeasures is to identify new targets on the virus’s surface proteins in “conserved” regions—portions that tend to be relatively unchanged between different strains of the virus. Influenza NA is a surface protein containing a globular head portion and a narrow stalk portion. The underside of the NA head contains a highly conserved region with targets for antibodies—known as epitopes—that make it vulnerable to antibody binding and inhibition of the virus, as well as not being impacted by mutations common in drug-resistant strains. This region is termed the “dark side” due to its partially hidden location and relatively unexplored characteristics.

The researchers isolated human antibodies that target the NA dark side from the blood of two people who had recovered from influenza type A subtype H3N2, a major subtype of seasonal flu viruses. In lab tests, the antibodies inhibited propagation of viruses from subtype H2N2, the subtype that caused pandemic influenza in 1957-58, and H3N2 viruses from humans, swine, and birds. The antibodies also protected mice from lethal infection by a subtype H3N2 virus when given to the animals either one day before or two days after infection, showing that the antibody may treat and prevent influenza in this model. The scientists analyzed the structure of two of the antibodies while bound to NA using advanced microscopy techniques known as cryogenic electron microscopy. Each antibody targeted different, nonoverlapping regions of the dark side, demonstrating that this region has multiple areas that may be useful to explore for countermeasure development. These findings show that the NA dark side has unique, previously untapped epitopes that could be applied to the development of new vaccine and therapeutic strategies. They suggest that antibodies targeting the NA dark side could be useful in combination with antivirals or other types of antibodies for interventions against influenza, as they are effective against influenza viruses with drug-resistant mutations. The researchers also note that NA dark side targets could be included in the next generation of broadly protective vaccines against influenza.

Study published in Immunity (March 24, 2024):

https://doi.org/10.1016/j.immuni.2024.02.003 

Repair of lung injury due to viral infection can be facilitated by nanoparticle-delivered mRNA targeting TGF-βR2 signaling. Respiratory infections, such as those caused by SARS-CoV-2 or influenza, can damage the lungs’ delicate network of capillary blood vessels, compromising oxygen delivery and carbon dioxide removal. To overcome this damage, the lungs depend on the regenerative capacities of vascular endothelial cells. As valuable as these cells are, they can, according to University of Pennsylvania scientists, benefit from a little help. The scientists, led by Andrew Vaughan, PhD, focused on a repair pathway involving vascular endothelial growth factor α (Vegfa) and the TGF-β receptor 2 (TGF-βR2). Using animal models and human tissue samples, the scientists showed that delivering Vegfa via lipid nanoparticles (LNPs) greatly enhances modes of repair for damaged blood vessels. “Mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair,” the article’s authors wrote. “Loss of endothelial Tgfbr2 prevented autocrine Vegfa expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange.” “We developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP),” the authors continued. “Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of endothelial cell Tgfbr2 deficiency during influenza injury.”

Vaughan’s team and other investigators had previously shown that endothelial cells are among the unsung heroes in repairing the lungs after viral infections. But Vaughan’s team noted that its work demonstrated that a “more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium” could inform efforts to facilitate therapeutic vascular repair. “Here we’ve identified and isolated pathways involved in repairing this tissue, delivered mRNA to endothelial cells, and consequently observed enhanced recovery of the damaged tissue,” Vaughan said. “These findings hint at a more efficient way to promote lung recovery after diseases like COVID-19.” The team found Vegfa’s involvement in this recovery, while building on work in which they used single-cell RNA sequencing to identify TGF-βR2 as a major signaling pathway. The researchers saw that when TGF-βR2 was missing, it stopped the activation of Vegfa. This lack of signal made the blood vessel cells less able to multiply and renew themselves, which is vital for the exchange of oxygen and carbon dioxide in the tiny air sacs of the lungs. “We’d known there was a link between these two pathways, but this motivated us to see if delivering Vegfa mRNA into endothelial cells could improve lung recovery after disease-related injury,” said first author Gan Zhao, PhD, a postdoctoral researcher in the Vaughan laboratory. The Vaughan laboratory then reached out to Michael J. Mitchell, PhD, of the School of Engineering and Applied Science, whose laboratory specializes in LNPs, to see if delivery of this mRNA cargo would be feasible.

“LNPs have been great for vaccine delivery and have proven incredibly effective delivery vehicles for genetic information,” said Mitchell, who is an associate professor of bioengineering at Penn Engineering and a co-author of the paper. “But the challenge here was to get the LNPs into the bloodstream without them heading to the liver, which is where they tend to congregate as its porous structure lends favor to substances passing from the blood into hepatic cells for filtration. So, we had to devise a way to specifically target the endothelial cells in the lungs.” The Mitchell laboratory’s LNPs proved effective in delivering Vegfa into endothelial cells, and as a result, the researchers saw a marked improvement in vascular recovery in their animal models. Within the animal models, the researchers saw improved oxygen levels, and in some, the treatment helped them recover their weight better than the control group. These treated mice also had less lung inflammation, shown by lower levels of certain markers in their lung fluid, and their lungs showed less damage and scarring, with more healthy blood vessels. “We’re looking forward to testing this delivery platform for other cell types in the lung, and it will be important to evaluate whether TGF-βR2 signaling is important in other injury contexts including chronic conditions like emphysema and chronic obstructive pulmonary disease,” Vaughan said. “With this proof-of-concept being well validated, we’re sure that we’ll pave the way for new mRNA-based strategies for treating lung injury.”

Published in January 31, 2024 in Science Translational Med:

https://doi.org/10.1126/scitranslmed.adg6229 

Tissue samples from a polar bear that was found dead have tested positive for the virus. A highly lethal form of bird flu that has been spreading across the world has now been detected in a dead polar bear in Alaska. It is the first known case in the Arctic animals, which are listed as threatened under the Endangered Species Act.

Why It Matters: The virus is a new threat for many wild mammals.

The infected polar bear provides further evidence of how widespread this virus, a highly pathogenic form of H5N1, has become and how unprecedented its behavior has been. Since the virus emerged in 2020, it has spread to every continent except for Australia. It has also infected an unusually broad array of wild birds and mammals, including foxes, skunks, mountain lions and sea lions. “The number of mammals reported with infections continues to grow,” Dr. Bob Gerlach, Alaska’s state veterinarian, said. In most cases, the virus has not caused mass die-offs in wild mammal populations. (South American sea lions have been one notable exception.) But it does represent a new threat for the already vulnerable polar bear, which is imperiled by climate change and the loss of sea ice. “The concern is that we don’t know the overall extent of what the virus may do in the polar bear species,” Dr. Gerlach said.

Background: The bear showed signs of disease.

The polar bear was found dead this past fall in far northern Alaska, near Utqiagvik. Swabs collected from the animal initially tested negative for the virus. But when experts conducted a more comprehensive work-up, performing a necropsy and collecting tissue samples from the bear, they found clear signs of inflammation and disease, Dr. Gerlach said. Last month, tissue samples from the bear tested positive for the virus, according to the Alaska Department of Environmental Conservation. The virus was ultimately identified in multiple organs, Dr. Gerlach said. “I think it would be a safe thing to say that it died from the virus,” he said. Alaska has previously reported infections in a brown bear and a black bear, as well as in several red foxes.

Like Covid, flu carries significant risk of ongoing disability and disease, researchers say. People who have been hospitalised with flu are at an increased risk of longer-term health problems, similar to those with long Covid, data suggests. While the symptoms associated with such “long flu” appear to be more focused on the lungs than ongoing Covid symptoms, in both cases the risk of death and disability was greater in the months after infection than in the first 30 days. “It is very clear that long flu is worse than the flu, and long Covid is worse than Covid,” said Dr Ziyad Al-Aly, a clinical epidemiologist at Washington University in St Louis, Missouri, who led the research. He was motivated to study the phenomenon after observing the scale of long-term illness experienced by people who have recovered from Covid.

“Five years ago, it wouldn’t have occurred to me to examine the possibility of a ‘long flu.’ But one of the major lessons we learned from this pandemic is that a virus we all initially thought could only cause acute disease is leaving millions of people with long Covid, he said. “We wondered whether this could be happening with other things. Could this be happening with the flu, for example?” To investigate, Al-Aly and colleagues analysed medical records from 81,280 US patients who were hospitalised with Covid and 10,985 who were hospitalised with seasonal influenza, following them for at least 18 months to learn about their risks of death, hospital readmission and 94 different health problems involving the body’s major organ systems. The research, published in the Lancet Infectious Diseases, found that while Covid patients faced a greater risk of death or hospital readmission in the following 18 months, both infections carried a significant risk of ongoing disability and disease. In both cases, more than half of death and disability occurred in the months after infection as opposed to the first 30 days. And while the symptoms associated with long flu were more likely to centre on the lungs – for example, shortness of breath or a cough – compared with Covid patients, both groups were at greater risk of fatigue, cardiovascular, gastrointestinal and neurological issues and symptoms associated with other organ systems in the following months.

“Many people think they’re over Covid-19 or the flu after being discharged from the hospital. That may be true for some people. But our research shows that both viruses can cause long-haul illness,” Al-Aly said. “Conceptualising these diseases as acute illnesses is really just looking at the tip of the iceberg, and eclipses the much higher toll of adverse health outcomes that are happening in the post-acute phase. “Some people are ending up with serious long-term health issues. We need to wake up to this reality and stop trivialising viral infections and understand that they are major drivers of chronic diseases.” The study was not designed to identify what proportion of those hospitalised with influenza go on to develop further health problems, or whether certain groups are at higher risk, and this is something the team hope to investigate in the coming months. Also unclear is the extent to which people who get flu but are not hospitalised develop ongoing health issues. For now, Al-Aly said the most important thing was to try to reduce the risk of being hospitalised from these illnesses, through vaccination and, in the case of Covid, antiviral drugs.

Research published in The Lancet Infect. Diseases (Dec. 14, 2023):

https://doi.org/10.1016/S1473-3099(23)00684-9 

Genetic changes to avian influenza viruses have led to spread among many wild species, creating an uncontrollable global outbreak. Researchers studying the evolution of the bird flu virus over the past 18 years have shown how the strain currently circulating worldwide, an extremely deadly form of the H5N1 subtype, has become increasingly infectious to wild birds. The strain emerged in Europe in 2020, and has spread to an unprecedented number of countries. The study, published in Nature on 18 October, looked at changes to the virus’s genome over time and used data on reported outbreaks to track how it spread. In 2020, the rate of spread among wild birds was three times faster than that in farmed poultry, because of mutations that allowed the virus to adapt to diverse species. “What was once very clearly a poultry pathogen has now become an animal-health issue much more broadly,” says Andy Ramey, a wildlife geneticist at the US Geological Survey Alaska Science Center in Anchorage. “That has implications for wildlife and domestic poultry as well as us humans that rely upon these resources.”

Persistent outbreaks

H5N1, classified as a highly pathogenic avian influenza (HPAI) virus because of its high death toll in poultry, was first detected in birds in China in 1996. Outbreaks are usually seasonal, synchronizing with bird migration in Northern Hemisphere autumn. But since November 2021, they have become persistent. In 2022, the virus killed millions of birds across five continents and seeded outbreaks among farmed mink and various marine mammals. To study changes in the virus’s behaviour, the authors examined data reported to the Food and Agricultural Organization of the United Nations and the World Organisation for Animal Health between 2005 and 2022, and analysed more than 10,000 viral genomes. Their work reveals that in mid-2020, a new H5N1 strain evolved from an earlier variety, called H5N8, which first emerged in poultry in Egypt between 2016 and 2017 and caused global flare-ups throughout 2020 and 2021 (see ‘Bird flu outbreaks’). The new H5N1 virus mutated through interactions with non-deadly varieties of bird flu, called low-pathogenic avian influenza (LPAI) viruses, that had been circulating among wild birds in Europe since 2019. It developed two subtypes in 2021 and 2022. One spread across the northern coastal regions of central Europe and was eventually carried to North America by birds migrating across the Atlantic Ocean. The other was carried around the Mediterranean Sea and into Africa. Many bird flu outbreaks begin in poultry, but spillover into wild birds has spread the disease into larger areas, creating a global challenge that is difficult to manage, the study found. “Once it’s adapted to wild birds, we have no mechanism to control the virus. And I think that’s the biggest impact that has changed now,” says co-author Vijaykrishna Dhanasekaran, an evolutionary biologist and virologist at the University of Hong Kong. Louise Moncla, an evolutionary virologist at the University of Pennsylvania in Philadelphia, agrees. “Regardless of how much outbreak response you do in poultry, if it’s coming in from wild birds repeatedly, this is going to be really hard to manage.” “This is really something that most of the world at this point has skin in the game,” adds Ramey.

Mixing viruses

LPAI viruses often circulate freely in poultry and wild birds. Previous infection with these non-deadly strains is thought to encourage population immunity in wild birds. “You can think of it as an imperfect vaccine, that doesn’t stop infection, but it helps mitigate the effects of disease,” says Ramey. But “there’s probably two sides of the coin here”, he adds. HPAI viruses can mutate through interactions with LPAI ones. In both, the genome is split into eight segments that can be mixed and matched. “When two viruses co-infect the same cell, they could swap their genes when the virus is getting packaged,” says Dhanasekaran. Because of this, LPAI viruses — especially a strain called H9N2 — play a major part in the evolution of H5N1, he adds. But they are not well monitored. “Eradication or elimination strategies that target these low pathogenic viruses would be a huge step forward in terms of controlling avian influenza itself,” says Dhanasekaran.

Research Cited published in Nature (Oct. 18, 2023):

 https://doi.org/10.1038/s41586-023-06631-2 

At-home testing is becoming a thing not just for COVID-19, but for seasonal flu and other infections. Here's what you need to know. B efore COVID-19, figuring out whether a sore throat, fever, and runny nose were caused by a cold, flu, or strep wasn’t a top priority. You either powered through, knowing you’d be miserable for a few days but would probably feel better soon or you visited the doctor’s office, urgent care, or emergency room where you might get a test to figure out which virus or bacteria was behind your misery, and maybe a prescription to treat it. But even doctors often don’t order tests, preferring instead to make diagnoses based on symptoms. During the pandemic, however, it became more critical to know who was infected with SARS-CoV-2 so those people could isolate and not spread the virus. At-home test kits became household products, and most people are by now adept at squeezing out a few drops of solution onto a card, sticking a swab up their nose, swirling the swab in the testing liquid, and waiting for a result.

Tests for COVID-19

A number of companies, offer at-home test kits for COVID-19 that people can buy without a prescription. Most of these are rapid antigen tests, which pick up antigens, or substances that the SARS-CoV-2 virus makes. While they are relatively accurate, because it takes some time for levels of these antigens to build up after an infection, these tests are less reliable in the day or so immediately after exposure to the virus. That’s why doctors recommend repeating the test a couple of days apart. Then there are PCR, or molecular, tests, that are closer to the gold standard used in laboratories, and rely on finding the smallest genetic signatures of the virus and amplifying them. Cue Health sells a palm-sized COVID-19 PCR device that people can purchase for $300 that allows for 10 at-home tests and doesn’t require a prescription. The device reads a saliva sample and provides results to a smartphone app in 20 minutes. Other testing companies, such as Labcorp and Everlywell, also sell PCR-based tests for COVID-19, but they are technically collection kits, which means that you have to send a saliva sample into a lab to get results, which can mean critical days will pass before you get results.

Tests for seasonal flu

There is only one at-home test authorized by the FDA for influenza: Lucira, now owned by Pfizer, makes a combined flu and COVID-19 molecular test. The kit uses a PCR-related method of amplifying and reading any viral genes in a sample, providing a result in about 30 minutes. In coming months, eMed, a digital health company that sells test kits and telehealth services, plans to offer that kit, as well another that is currently being reviewed by the U.S. Food and Drug Administration. (The combined kit currently available on eMed’s website only tests for COVID-19 and provides a survey to help telemedicine professionals determine if a user likely has the flu.)

Tests for RSV

There currently aren’t at-home tests for RSV, because typically only infants and the elderly are at risk for severe illness. Doctors’ offices, hospitals, and urgent care centers can perform RSV tests that provide results in about 30 minutes.

The advantages of at-home testing

The currently cumbersome journey from symptoms to treatment rests on people making appointments with their doctors or at an urgent care center and could be contributing to the spread of viruses. Self-testing could reduce some of that risk since people are most infectious while they are waiting to get tested and receive treatment. Ideally, if someone tests themselves at home and finds they are positive for influenza or COVID-19, for example, they don’t necessarily have to physically visit their doctor or go into an urgent care or emergency room, where they could spread the virus to others. Instead, they could video conference with a doctor who could assess their symptoms and at-home test results, then write a prescription for, say, oseltamivir if it’s the flu, or Paxlovid if it’s COVID-19. “If you’re trying to minimize morbidity and mortality, and cut down on transmission, then [at-home] testing is an incredible tool to have,” says Thomas Denny, chief operating officer of the Duke University Human Vaccine Institute....

In June 2023, a fatal disease outbreak in cats occurred in Poland. Most cases tested in Poland (29 of 47) were positive for highly pathogenic avian influenza (HPAI) A (H5N1) virus. Genetic analyses revealed clade 2.3.4.4b with point mutations indicative of initial mammalian hosts adaptations. Cat viral sequences were highly similar (n = 21), suggesting a potential common infection source. To investigate possible infection routes, our group tested food samples from affected households. HPAI H5N1 virus was detected in one poultry meat sample.

Warning issued by European Food Safety Authority after 24 cats test positive for virus in Poland. Cats should be kept indoors to avoid catching bird flu, European health officials have told pet-owners as the continent battles its worst-ever outbreak of the virus. The warning has been issued by the European Food Safety Authority (EFSA) after 24 cats tested positive for the virus in Poland, sparking fear that avian influenza could be evolving to spread among certain mammals. Since late 2021, bird flu has killed millions of birds across Europe and beyond. Last year, 67 countries in five continents reported highly pathogenic H5N1 outbreaks, with more than 131 million domestic poultry lost due to death or culling in affected areas. But the rising number of infections in mammals – outbreaks have been reported in 26 species, including farmed mink in Spain – has generated particular concern. Calling for increased surveillance of bird flu in wild and domesticated mammals, the EFSA said on Thursday that “it is recommended to avoid exposure of domestic cats and dogs, and in general carnivore pets, to dead or diseased animals”. It added: “Possible measures are keeping dogs on a leash, and confining cats indoors in areas where extensive circulation of HPAI [highly pathogenic avian influenza] viruses in wild birds has been confirmed.”

In Poland, the deaths of around 70 domestic cats since June 23 are being investigated, according to local media reports.  At least 24 tested positive for H5N1, with the source of the infections yet to be determined. Reports have linked the outbreak to raw poultry meat contaminated with the virus. Elsewhere, five dogs and a cat have been infected with bird flu in Italy. The EFSA has also called for research to investigate the role that farmed and domesticated mammals could be playing in harbouring the bird flu virus and potentially driving its ability to spread beyond avian species. “Prompt generation and timely sharing of sequence data is highly recommended to promptly identify the emergence of variants with a possible increased ... potential” to jump into humans, the agency said. Earlier this week, the World Health Organisation (WHO) said that “some mammals may act as mixing vessels for influenza viruses, leading to the emergence of new viruses that could be more harmful to animals and humans.” In a statement released on Wednesday, it said that the recent surge in bird flu outbreaks among mammals could help the virus spread in humans. “Avian influenza viruses normally spread among birds, but the increasing number of H5N1 avian influenza detections among mammals – which are biologically closer to humans than birds are – raises concern that the virus might adapt to infect humans more easily.” In April, the virus was also found to “efficiently” spread between ferrets in a laboratory, the first study confirming that the virus can spread from mammal to mammal.

Avian influenza (serotype H5N1) is a highly pathogenic virus that emerged in domestic waterfowl in 1996. Over the past decade, zoonotic transmission to mammals, including humans, has been reported. Although human to human transmission is rare, infection has been fatal in nearly half of patients who have contracted the virus in past outbreaks. The increasing presence of the virus in domesticated animals raises substantial concerns that viral adaptation to immunologically naive humans may result in the next flu pandemic. Wastewater-based epidemiology (WBE) to track viruses was historically used to track polio and has recently been implemented for SARS-CoV2 monitoring during the COVID-19 pandemic.

Here, using an agnostic, hybrid-capture sequencing approach, we report the detection of H5N1 in wastewater in nine Texas cities, with a total catchment area population in the millions, over a two-month period from March 4th to April 25th, 2024. Sequencing reads uniquely aligning to H5N1 covered all eight genome segments, with best alignments to clade 2.3.4.4b. Notably, 19 of 23 monitored sites had at least one detection event, and the H5N1 serotype became dominant over seasonal influenza over time. A variant analysis suggests avian or bovine origin but other potential sources, especially humans, could not be excluded. We report the value of wastewater sequencing to track avian influenza.

Preprint in medRxiv ( May 10, 2024):

https://www.medrxiv.org/content/10.1101/2024.05.10.24307179v1.full.pdf 

Testing conducted by the FDA on pasteurized commercially purchased milk has found genetic evidence of the H5N1 bird flu virus, the agency confirmed Tuesday. But the testing, done by polymerase chain reaction, or PCR, cannot distinguish between live virus or fragments of viruses that could have been killed by the pasteurization process. The agency said it has been trying to see if it could grow virus from milk found to contain evidence of H5N1, which is the gold standard test to see if there is viable virus in a product. The lengthy statement the agency released does not explicitly say FDA laboratories were unable to find live virus in the milk samples, but it does state that its belief that commercial, pasteurized milk is safe to consume has not been altered by these findings. “To date, we have seen nothing that would change our assessment that the commercial milk supply is safe,” the statement said.

The document was long on assurances but short on details of what has been undertaken or found. It does not specify how many commercial samples were taken or in how many markets, nor does it indicate what percentage of the samples were PCR-positive for H5N1. The statement did not indicate if the testing suggested the amounts of viral genetic material in the milk were low or high. Furthermore, the statement did not reveal if the milk products were purchased in parts of the country where outbreaks have occurred, or in areas where cows haven’t been seen to have been infected. The FDA did say it is testing milk from infected animals, in the processing system, and from store shelves with the goal of producing a “large representative national sample” of the milk supply. Beyond assessing the safety of the supply, such a sample could enable the agency to construct a more robust picture of H5N1’s spread among dairy cows nationally. The agency emphasized that testing of commercially available milk is ongoing, and this includes efforts to discern any potential differences between different dairy products, such as cream and whole milk....

Researchers at UC Riverside have developed a new vaccine approach using RNA that is effective against any strain of a virus and can be used safely even by babies or the immunocompromised. Every year, researchers try to predict the four influenza strains that are most likely to be prevalent during the upcoming flu season. And every year, people line up to get their updated vaccine, hoping the researchers formulated the shot correctly. The same is true of COVID vaccines, which have been reformulated to target sub-variants of the most prevalent strains circulating in the U.S. This new strategy would eliminate the need to create all these different shots, because it targets a part of the viral genome that is common to all strains of a virus. The vaccine, how it works, and a demonstration of its efficacy in mice is described in a paper published today in the Proceedings of the National Academy of Sciences.

“What I want to emphasize about this vaccine strategy is that it is broad,” said UCR virologist and paper author Rong Hai. “It is broadly applicable to any number of viruses, broadly effective against any variant of a virus, and safe for a broad spectrum of people. This could be the universal vaccine that we have been looking for. Traditionally, vaccines contain either a dead or modified, live version of a virus. The body’s immune system recognizes a protein in the virus and mounts an immune response. This response produces T-cells that attack the virus and stop it from spreading. It also produces “memory” B-cells that train your immune system to protect you from future attacks. The new vaccine also uses a live, modified version of a virus. However, it does not rely on the vaccinated body having this traditional immune response or immune active proteins — which is the reason it can be used by babies whose immune systems are underdeveloped, or people suffering from a disease that overtaxes their immune system. Instead, this relies on small, silencing RNA molecules.

Mechanism and Efficacy of RNA-Based Vaccine

“A host — a person, a mouse, anyone infected— will produce small interfering RNAs as an immune response to viral infection. These RNAi then knock down the virus,” said Shouwei Ding, distinguished professor of microbiology at UCR, and lead paper author. The reason viruses successfully cause disease is because they produce proteins that block a host’s RNAi response. “If we make a mutant virus that cannot produce the protein to suppress our RNAi, we can weaken the virus. It can replicate to some level, but then loses the battle to the host RNAi response,” Ding said. “A virus weakened in this way can be used as a vaccine for boosting our RNAi immune system.” When the researchers tested this strategy with a mouse virus called Nodamura, they did it with mutant mice lacking T and B cells. With one vaccine injection, they found the mice were protected from a lethal dose of the unmodified virus for at least 90 days. Note that some studies show nine mouse days are roughly equivalent to one human year.

There are few vaccines suitable for use in babies younger than six months old. However, even newborn mice produce small RNAi molecules, which is why the vaccine protected them as well. UC Riverside has now been issued a US patent on this RNAi vaccine technology. In 2013, the same research team published a paper showing that flu infections also induce us to produce RNAi molecules. “That’s why our next step is to use this same concept to generate a flu vaccine, so infants can be protected. If we are successful, they’ll no longer have to depend on their mothers’ antibodies,” Ding said.  Their flu vaccine will also likely be delivered in the form of a spray, as many people have an aversion to needles. “Respiratory infections move through the nose, so a spray might be an easier delivery system,” Hai said. Additionally, the researchers say there is little chance of a virus mutating to avoid this vaccination strategy. “Viruses may mutate in regions not targeted by traditional vaccines. However, we are targeting their whole genome with thousands of small RNAs. They cannot escape this,” Hai said. Ultimately, the researchers believe they can ‘cut and paste’ this strategy to make a one-and-done vaccine for any number of viruses. “There are several well-known human pathogens; dengue, SARS, COVID. They all have similar viral functions,” Ding said. “This should be applicable to these viruses in an easy transfer of knowledge.”

Publised in PNAS (April 17, 2024):

https://doi.org/10.1073/pnas.2321170121

Health Alert: First Case of Novel Influenza A (H5N1) in Texas, March 2024 Health Alert April 1, 2024 Summary The Texas Department of State Health Services (DSHS) is reporting the first human case of novel avian influenza A(H5N1) in Texas. The patient became ill following contact with dairy cows presumed to be infected with avian influenza. The patient’s primary symptom was conjunctivitis. This is the second case of avian influenza A(H5N1) identified in a person in the United States and is believed to be associated with the recent detections of avian influenza A(H5N1) in dairy cows announced by the Texas Animal Health Commission. DSHS along with local, regional, state, and federal partners, is investigating this ongoing situation. Avian influenza A(H5N1) viruses have only rarely been transmitted from person to person. As such, the risk to the general public is believed to be low; however, people with close contact with affected animals suspected of having avian influenza A(H5N1) have a higher risk of infection.

DSHS is issuing this health alert to provide awareness to healthcare providers and ask them to be vigilant for people with signs and symptoms of avian influenza A(H5N1). Suspicion for avian influenza A(H5N1) should be heightened for people who have had contact with animals suspected of having avian influenza A(H5N1)...

PRNewswire -- SEKISUI Diagnostics, a global medical diagnostics manufacturer, has received EUA clearance for the OSOM Flu SARS-CoV-2 Combo Test for  use in professional and home testing settings.

The OSOM® Flu SARS-CoV-2 Combo Test is a lateral flow immunochromatographic assay intended for in vitro rapid, simultaneous qualitative detection and differentiation of influenza A and influenza B nucleoprotein antigens and SARS-CoV-2 nucleocapsid antigen. As with other OSOM Rapid Tests, it is made in the USA and supported by a highly skilled technical support team of medical technologists/professionals. "The utility of detecting COVID and Flu on one test is now more important than ever having moved into the endemic phase of COVID. The OSOM test is the first antigen, visual, home test to receive EUA status, which allows us to get these diagnostic tools into the hands of healthcare providers and consumers well before the next respiratory season.  This helps minimize the spread of these diseases and allows prescribing appropriate treatments once viruses start circulating.", said Lee Lipski, Sr. VP, Strategy & Business Management.   

SEKISUI Diagnostics is a well-known provider of many rapid diagnostic solutions to the professional and home testing markets through a portfolio of tests under the OSOM® and Acucy® brands. They also supply COVID Ag tests through the HHS/ASPR program (COVIDTests.gov) which delivers tests for free to households across the country. "We first entered the home testing market with our COVID-19 test as we understand these are valuable tools to reduce the spread of respiratory infections and improve the health of all people.  The OSOM Flu SARS-CoV-2 Combo Test takes our offering to the next level with the ability to get two answers with one sample providing fast, actionable results to consumers as well as healthcare professionals.", said Erica Blight, VP, Clinical Research, Customer Care and Marketing.

About SEKISUI Diagnostics:

With over 40 years of experience, SEKISUI Diagnostics' mission is to provide intelligent solutions to enhance life with science and improve the health of all people.  We supply innovative medical diagnostics globally to physicians, hospitals, laboratories and alternate testing locations.   Our product lines include clinical chemistry reagents, point-of-care tests, pre-analytic systems as well as enzymes and specialty biochemicals.    The OSOM® Flu SARS-CoV-2 Combo Test is test is authorized for use at the Point of Care (POC), i.e., in patient care settings operating under a CLIA Certificate of Waiver, Certificate of Compliance, or Certificate of Accreditation and the OSOM® Flu SARS-CoV-2 Combo Home Test is authorized for non-prescription home use with self-collected or adult-collected anterior nares nasal swab samples from individuals aged 14 years or older with signs and symptoms of SARS-CoV-2, influenza A and influenza B. The OSOM Flu SARS CoV-2 Combo Test and the OSOM Flu SARS CoV-2 Combo Home Test are only for in vitro diagnostic use under the Food and Drug Administration's Emergency Use Authorization. This product has not been FDA-cleared or approved.

FDA EUA  letter  (Feb. 29, 2023):

https://www.fda.gov/media/176716/download 

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI).

HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33°C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.

Preprint in bioRxiv (Dec.19, 2023):

https://doi.org/10.1101/2023.12.18.571720 

Purpose

Since the worldwide spread of SARS-CoV-2, different strategies have been followed to combat the pandemic and limit virus transmission. In the meantime, other respiratory viruses continued to circulate, though at decreased rates.

Methods

This study was conducted between June and July 2022, in a hospital in the metropolitan region of Rio Grande do Sul state, in the southernmost state of Brazil. The 337 hospitalized patients included those with respiratory symptoms without delimitation of age. Reverse transcription-quantitative real-time polymerase chain reaction detected 15 different respiratory viruses and confirmed coinfections in the samples. Different statistical tests were applied to evaluate the association between associations of clinical characteristics and coinfection.

Results

Sampling corresponds to 337 selected and 330 patients analyzed. The principal clinical outcome found was hospital discharge in 309 (94%) cases, while 21 (6%) resulted in death. The principal viral agents related to coinfections were Human rhinovirus, Human enterovirus, and Respiratory syncytial virus. The most frequent viral agent detected was SARS-CoV-2, with 60 (18%) infections, followed by 51 (15%) cases of Respiratory syncytial virus B (15%) and 44 (13%) cases of Human rhinovirus 1. Coinfection was mainly observed in children, while adults and the elderly were more affected by a single infection. Analyzing COVID-19 vaccination, 175 (53%) were unvaccinated while the remainder had at least one dose of the vaccine.

Conclusions

This study presents information to update the understanding of viral circulation in the region. Furthermore, the findings clarify the behavior of viral infections and possible coinfections in hospitalized patients, considering different ages and clinical profiles. In addition, this knowledge can help to monitor the population’s clinical manifestations and prevent future outbreaks of respiratory viruses.

Published in Respiratory Research (FEb. 5, 2024):

https://doi.org/10.1186/s12931-024-02708-2 

Scientists identified a new class of antibodies in human blood that are able to target multiple strains of influenza A virus in the lab. A newly discovered class of antibodies in human blood can neutralize different types of the flu virus and could be key to the development of broadly protective vaccines against the seasonal viruses, scientists say.  Circulating flu viruses constantly mutate, so "we need annual influenza virus vaccines to keep pace with continuing viral evolution," the researchers behind the discovery said in a statement. "Our work suggests that the barriers to eliciting more broadly protective immunity may be surprisingly low," they said.  There are four types of flu virus, known as influenza A, B, C and D, with A and B being responsible for the seasonal flu epidemics in the U.S. every year. Influenza A comes in many subtypes whose differences lie in two proteins that the virus uses to infect our cells: hemagglutinin (H) and neuraminidase (N). For example, H1N1 and H3N2 are subtypes of influenza A that routinely infect people. Within each subtype are different "strains" that constantly tweak their genetic code. For example, a strain of H1N1 is currently the dominant virus causing flu in the U.S. Influenza B, meanwhile, is divided into two lineages — Yamagata and Victoria — and is typically responsible for a much smaller proportion of flu cases.

Making effective flu shots relies on harnessing the protective power of antibodies — immune proteins that attack invading pathogens — but the virus' ability to quickly mutate makes this challenging. Flu vaccines prime the immune system to produce specific antibodies that latch onto a flu virus and prevent it from infecting cells after it invades the body. However, these vaccines are formulated to target specific strains, and because those strains mutate year over year, people then need a new flu shot each year to keep up. In the new study, published Thursday (Dec. 21) in the journal PLOS Biology, scientists described a newfound class of antibodies in human blood samples that target multiple forms of the influenza A virus.  The research was conducted only in the lab, so the scientists aren't sure exactly how these antibodies contribute to the body's flu shot response. However, one day, these antibodies could be used to develop vaccines that are more effective at protecting people from multiple strains of flu at the same time.  To guard against influenza A, conventional flu vaccines usually prompt the immune system to produce antibodies against the H protein on the surface of the virus. Antibodies have previously been discovered that target two main types of hemagglutinin, called H1 and H3, at the same time. However, they can only do this if there is a specific mutation in H1, namely the insertion of an amino acid in the outer edge of the protein that binds to a receptor on the outside of our cells. This consequently limits the antibodies' efficacy against different flavors of flu virus. 

Through lab experiments, the study authors identified antibodies that are abundant in human blood and can bind to certain H1 and H3 strains of influenza A, whether or not this hemagglutinin mutation is present. This means that they'd theoretically be able to provide broad protection against both subtypes of virus, potentially even as circulating strains mutate over time.  The authors also looked at how well these antibodies targeted strains of H1 and H3 that have circulated in the past. The antibodies reacted with H3 strains from the late 1980s to late 1990s and H1 strains from the early 2000s through to 2015.  This suggests the patients whose blood was sampled originally made the antibodies in response to H3 strains of the virus. Then, after a later exposure to H1 strains at a later date through either infection or vaccination, the antibodies became primed to target H1 as well. These findings may have important applications for future vaccine design.  "Given the right series of influenza virus exposures/vaccinations, it is possible for humans to mount robust antibody responses that neutralize divergent H1N1 and H3N2 viruses, opening new avenues to design improved vaccines," the authors said in the statement.  In other words, there may be a way to ensure vaccines trigger the production of these broad-acting antibodies, to ensure the shots guard against both subtypes of the virus equally well.

GETTING a cough, fever or sore throat at this time of year could be down to any number of things, from a common cold to Covid-19. With a new strain of swine flu being detected in the UK

The London Medical Laboratory said its test can be taken at 95 selected pharmacies, drop-in clinics and health stores nationwide. You can find a full list of the places they're sold here. Otherwise, you can also order the test online to be delivered to your home. Dr Narayanan said: "The current strains of flu that are circulating may produce only mild illness in one person but may cause severe symptoms and even prove fatal to others. "This is particularly important in people with pre-existing health conditions and long-term diseases. Similarly, while the RSV virus may only produce chesty cold symptoms in some people, it can severely affect elderly people and children. "All of these viruses, including swine flu, display very similar initial symptoms to the common cold, but these symptoms may quickly escalate."

Taking a test to identify which virus is causing your symptoms could bring "peace of mind" to some or ensure "they are not endangering anyone in their family this festive season", the clinical lead claimed. The fact that the UKHSA is still working to ascertain the source of the H1N2 strain spotted in the North Yorkshire resident is another reason people might want to get tested, Dr Narayanan added.

Where else can I get these test?

The 95 pharmacies and clinics aren't the only place you can take a test telling the difference between the viruses. Online pharmacy Chemist Connect sells a kit by the brand CordX that claims to test for Covid, influenza A and B and RSV. It carries a much lower price tag too - £37.95, along with a delivery charge. Granted, that's still a fair amount pay for a test. Alternatively, you can nab Flowflex Flu Test and Covid Test Bundle at your local Boots. It won't be able to test for RSV - but you'll only have to shell out £4 for the two kits that come in the bundle. You can buy a five-pack of Influenza A/B Rapid Test at Tesco for £12. You can't get a free Covid-19 PCR test any more and rapid lateral flow tests are no longer free for most people. But according to NHS guidance, you might be eligible to get them for free if:

• You have a health condition which means you're at high risk of getting seriously ill from Covid
• You work in healthcare settings or in a hospice

A new study highlights both the promise and the limitations of gene editing, as a highly lethal form of avian influenza continues to spread around the world.

The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor.

OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines. A cancer vaccine is delivered to the lung by an engineered attenuated influenza virus.

Published in Nature Biotechnology:

https://doi.org/10.1038/s41587-023-01796-7 

In the wake of the Covid-19 pandemic, we’ve heard a lot about gain-of-function research, and some of its risks, particularly regarding the possible creation of dangerous pathogens. But there’s a lot more to this field than that, including research that could potentially be quite beneficial to human society. If we focus solely on the risks, we may miss those benefits. First, we need clarity on what gain of function is. Gain-of-function is a specific type of life sciences research that confers some new or additional trait to an organism of interest. As other experts have discussed, this research covers a broad range of work for a variety of purposes. This might include directly manipulating microbes to create more salt- and drought-resistant plants to address food security in the face of a changing climate, or indirectly manipulating microbes in labs to select for positive and potentially game-changing functions, such as creating E. coli strains that can consume and degrade plastic waste. Within the context of Covid-19, one specific type of gain-of-function work has become a lightning rod in global conversations: the modification of a pathogen to increase the infectivity or severity of the disease it causes. People have understandable concerns on several fronts, including how such research is conducted, reviewed, approved, and governed, as well as how it may exacerbate biological threats from deliberate, natural, and accidental causes. However, focusing exclusively on this one type of research has created deep rifts across key communities that balance innovation with safety and security in the life sciences. These rifts have made it almost impossible to have necessary, productive conversations to address global problems while ensuring such work is done safely and securely. Narrowing the definition of gain of function to only pathogen modification that prevents or addresses pandemic-level disease outbreaks is impeding progress in this space.

Focusing predominantly on the risks can have three challenging effects. First, it may skew risk assessments to overlook the potential benefits. Critical gain-of-function work is necessary to develop animal models that reasonably mimic human infection. This step minimizes direct human experimentation and provides insights on how diseases enter and progress inside such models. This work then provides crucial insights into how scientists can develop diagnostics and medical countermeasures, including live-attenuated and other types of vaccines, to detect, diagnose, and treat individuals with such emerging diseases. Further, as we have seen with Covid-19, emerging pathogens may evolve and change over time, which means they may overcome or evade detection capabilities and therapeutic interventions: gain-of-function research plays a key role in forecasting what changes may be coming, leading to an improved understanding of these emerging and evolving pathogens for disease surveillance and medical intervention purposes. Second, an overly narrow definition ignores entire areas of research that incorporate components that involve gain-of-function work. For example, a common practice to add a “trait” to a microbe is to introduce a gene encoded on a plasmid — circular strand of DNA — into a cell, where it will express the gene of interest. As part of this process, scientists typically attach a “reporter” gene such as green fluorescent protein, which helps identify successful gene expression. Although technically the addition of green fluorescent protein is a gain of function, its use as a reporter is not a threat to human health or a significant biorisk requiring mitigation. Being cognizant of the variety of ways gain of function manifests itself across life sciences research will be critical to maximize benefits and minimize risks and confusion in this area.

Finally, policymakers must consider the impact that our current information environment has on how science is communicated and perceived by the global community. Misinformation, disinformation, and state-based propaganda are not new phenomena. However, the porous nature of information exchange in an increasingly interconnected world through the internet and social media can be a double-edged sword: While scientific information can be shared more quickly than ever, misinformation can be shared exceptionally quickly as well on scientific activities, leading to an erosion of trust in science. The eroding trust in science — encouraged by certain adversaries taking advantage of the diffuse nature of the internet — is troubling as life sciences research will be critical in the coming years to address the accelerated emergence of biological threats. Scientists predict that diseases that may cause epidemics and pandemics are likely to emerge more frequently due to factors such as climate change, large-scale migration, and destructive land-use practices that bring humans into contact with animals and insects in previously ecologically preserved locations. Given this tension between necessity and hazard, stakeholders must remain clear-eyed about what work is necessary to accomplish scientific goals while effectively mitigating major risks. Despite the challenges, there are paths to move forward to keep the life sciences innovative, address key anticipated issues in the future, and ensure that research is safe and secure. Biosecurity and biosafety are a critical part of this research, and as science evolves, so must the policies.

Addressing these challenges will require four steps.

First, we need a coordinated communication effort that addresses the current disinformation campaign realities across a vast ecosystem of science communicators and stakeholders, from official international and domestic governmental organizations such as the World Health Organization and the U.S. National Science Advisory Board for Biosecurity to local and regional efforts from academic institutions. This will involve frequent communication, coordination, and even camaraderie between key organizations and institutes that deal with life sciences safety, security, and innovation issues. Further, this effort will need to balance the difficulties of technical issues with the need to be transparent to a global audience. Second, it is important to make clear that biosecurity and biosafety efforts do not run counter to gain-of-function research, whether or not they involve potential pandemic pathogens. Biosecurity and biosafety oversight and efforts to understand potential pandemic pathogens, and such work involving gain of function, are meant to work in tandem. In the National Academy of Science’s 2004 report “Biotechnology Research in an Age of Bioterrorism,” the expert committee came to the conclusion that despite certain types of gain-of-function research that raise concerns, “policies to counter biological threats should not be so broad as to impinge upon the ability of the life sciences community to continue its role of contributing to the betterment of life and improving defenses against biological threats.” To this end, the committee identified seven categories of experiments that raise additional concerns, and offered practices and policy recommendations to mitigate the risks associated with these types of experiments. Third, there is a critical need to increase science literacy across local, regional, and global communities. Science literacy not only enables more informed individual and collective decision-making in the biorisk space, but also potentially acts as a buffer against science-related misinformation and disinformation, a prime focus for adversaries seeking to undermine local, regional, and international relationships. Finally, the global community needs to come to terms with the fact that everyone’s risk tolerance is unique, and that includes scientific research. Scientists and stakeholders in this space will likely have different risk tolerances, which creates challenges to building consensus. Therefore, it helps all stakeholders to be curious, humble, and open to communication as we continue the dialogue on the full spectrum that gain-of-function research encompasses, including the purported risks and benefits.