Tag: Infection

Hope for global pandemic treaty rises — despite missed deadline

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Delegates to the World Health Assembly, which concluded on 1 June, failed to reach agreement on a pandemic treaty. Credit: WHO/Pierre Albouy

Countries have failed to hammer out a global pandemic treaty by their original deadline, but there is growing optimism that an extension until 2025 will allow them to reach consensus.

Despite a deadlock over issues of equity, member states of the World Health Organization (WHO) gave themselves another 12 months to work on the pact, which aims to improve the world’s response to future pandemics. That willingness to extend the talks signals nations’ commitment to the treaty, say public health specialists. Observers cited another reason for hope: countries did manage to adopt a separate agreement to prevent the global spread of infectious diseases, a success that could help to build momentum for the pandemic treaty discussions.

The agreement and the extension were both announced on 1 June, the final day of the 2024 World Health Assembly, the WHO’s annual decision-making meeting in Geneva.

Preparing the world for the next pandemic

“There was a great weariness setting in Geneva,” says Lawrence Gostin, a specialist in health law and policy at Georgetown University in Washington DC, who closely followed the negotiations. But the new deadline “was a good outcome. It showed that there still is a political will to try to get this accomplished and not walk away from the table.”

“One year is a good, reasonable time” to conclude the negotiations, says KM Gopakumar, a senior researcher with the Third World Network, a research and advocacy organisation in Penang, Malaysia. He says that rushing the discussions to meet the original deadline could have compromised the legitimacy of the process and even reinforced inequities.

A final text is expected by the next assembly, to be held in May 2025.

Sticking points

Member states agreed on many items in the agreement’s draft, but they could not reach consensus on some key topics, among them the sharing of samples and genomic sequences of pathogens that could cause a pandemic. Many low- and middle-income countries argue that nations that promptly give access to pathogen data should have automatic access to vaccines, medications and tests developed using those data. But other countries, mainly those with strong pharmaceutical industries, oppose such conditions for data sharing.

Another important measure still in dispute, according to Michelle Childs, policy advocacy director at the non-profit Drugs for Neglected Diseases initiative in Geneva, is a potential requirement that vaccines and drugs developed with government funding are shared more equitably than during the COVID-19 pandemic. “There is already a provision in the draft text, but it has a number of recently proposed caveats that could water down its purpose and effect,” she says.

Defining ‘pandemic’

During the assembly, countries did succeed in agreeing to a package of amendments to the International Health Regulations (IHR), legally binding rules designed to curb the spread of infectious diseases between countries. The amendments include the introduction of a “pandemic emergency” definition. Until now, the WHO could not officially declare a pandemic, only a “public health emergency of international concern”. The new definition represents a higher level of alarm that would trigger a more effective international response.

Why did the world’s pandemic warning system fail when COVID hit?

Several delegates speaking at the assembly said the adoption of the amendments would re-energize the efforts to forge a pandemic treaty. “This in our view will create a pivotal moment to accelerate the discussions in the pandemic agreement and complete our unfinished work,” said Mekdes Daba, Ethiopia’s minister of Health, speaking on behalf of a large group of African member states.

The updated IHR might also provide clarity on the remaining pandemic treaty discussions, as some of the instruments’ goals overlap, Gostin adds.

But not all observers are optimistic about the treaty’s future. “They could eventually approve some sort of agreement,” says Nina Schwalbe, a public health researcher and founder of public health think tank Spark Street Advisors, in New York City. “But the question is whether it will represent a meaningful step change for equity or have any commitment to accountability.”

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June 3, 2024
A global pandemic treaty is in sight: don’t scupper it

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Social distancing during the COVID-19 pandemic (pictured in Singapore).Credit: Ore Huiying/Getty

At the start of this month, it looked as though talks on a pandemic agreement — designed to prevent, prepare for and improve the world’s response to an event such as the global COVID-19 outbreak — were heading for the rocks, with countries riven by deep divisions.

The world was still in a pandemic when discussions kicked off in 2021. The World Health Assembly (WHA), the decision-making body of the World Health Organization (WHO) that is akin to a parliament for the world’s health ministers, told negotiators to finalize a text by this month. The latest text, dated 10 May, that was circulated to negotiators showed that gaps are being bridged. Talks are now due to end on 24 May, just in time for the start of this year’s WHA meeting, starting on 27 May in Geneva, Switzerland.

Global ‘pandemic treaty’: nations wrestle with how to fairly share virus data

This is the right course. The world needs this treaty, without delay: there’s been no let-up in public-health threats, and the next pandemic will not respect any human timetable. But the world also needs the right treaty. As in all complex negotiations, compromise — on all sides — will be necessary to get the final version over the finishing line. But all sides must also remember that there is little point to an agreement that doesn’t improve pandemic preparedness and response — or one that ignores or undermines the principle of equity between nations.

According to the latest draft, the agreement, once finalized, would be similar to many United Nations conventions. Decisions would be made at periodic ‘conferences of the parties’, as they are at UN climate conferences, for example. The WHO would act as the secretariat, in addition to its various existing roles in global public health.

However, significant sticking points remain, among them Articles 11 and 12. Article 11 is on arrangements to transfer technology so that, during pandemics, low- and middle-income countries (LMICs) can make necessary health products, such as vaccines, drugs and testing kits, without delay. Article 12 is a proposal for a system in which countries would promptly share samples and genomic sequences of pathogens with pandemic potential — setting in stone the way in which scientific knowledge was shared during the COVID-19 pandemic. In exchange for sharing such information during emergencies, LMICs would receive some pandemic-related products at no cost or at affordable prices when a pandemic is declared.

Another proposal on the table links the issues in Articles 11 and 12 by requiring relevant technologies to be transferred during a health emergency, in exchange for prompt access to pathogen data. But these measures are opposed by countries with significant interests in pharmaceutical research and development. These countries want to mandate data sharing during a pandemic, but do not want to be compelled to share technologies that are created using those data.

The necessity of information-sharing during a public-health emergency cannot be overstated. COVID-19 was eventually controlled with vaccines in no small part because virus samples and sequencing data were shared quickly and continuously.

Global pandemic treaty: what we must learn from climate-change errors

But how the pandemic unfolded also makes a powerful case for the need to connect data-sharing to technology transfer. The Omicron variant of SARS-CoV-2, the virus that causes COVID-19, was sequenced and shared by researchers in South Africa and Botswana (R. Viana et al. Nature 603, 679–686; 2022) — and these data were used in the development of vaccines. These were the same vaccines that LMICs had to wait for until wealthier nations were supplied, sometimes with more doses than were needed. Researchers have found that more than one million lives were lost as a result of such vaccine hoarding (S. Moore et al. Nature Med. 28, 2416–2423; 2022).

The latest text of the proposed treaty shows some progress towards finding common ground. For example, Article 13 mandates that parties publish the terms of purchase agreements with companies making pandemic-related health products, ensuring pricing transparency. This did not happen during the COVID-19 pandemic. When an essential product is scarce, such as vaccines in a pandemic, and there is no pricing transparency, companies can charge what they like, with the highest bidder taking the spoils. This creates unfair competition and is the wrong thing to do when scarce resources need to be shared equitably.

At present, the text for Article 11 also proposes that “government-owned” technologies could be licensed “for the benefit of developing countries”. Often, patented health-care products are the result of close public–private partnerships, and this provision gives more weight to the idea that publicly funded technologies should be more readily available in a pandemic.

But talks on Article 12 remain deadlocked. An earlier draft attempted a compromise by saying that the WHO should be given the authority to distribute 20% of pandemic-related health products to countries most in need. More details on defining which products, and whom they must benefit, would have been finalized by May 2026 in a new and legally binding section of the agreement. But not every higher-income country was on board and the latest text indicates a lack of agreement.

No more time must be lost in finding a compromise. As WHO director-general Tedros Adhanom Ghebreyesus has said: “Give the people of the world, the people of your countries, the people you represent, a safer future. So I have one simple request: please, get this done, for them.”

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May 21, 2024
Could bird flu in cows lead to a human outbreak? Slow response worries scientists

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Dairy cows in nine US states have tested positive for the H5N1 influenza virus, but tests have found no infectious virus in pasteurized milk.Credit: Justin Sullivan/Getty

Researchers worry that insufficient collection and reporting of data are hampering efforts to assess the scale of the bird-flu outbreak in US cattle — and could hold back efforts to bring the virus under control.

“We are not doing enough,” says Isabella Eckerle, head of the Geneva Centre for Emerging Viral Diseases in Switzerland. For now, the strain of the influenza virus is a long way from being able to transmit easily to and between humans. “But the moment it does, it will be an emergency.”

For now, the viral strain infecting cows, called H5N1, still prefers to bind to the receptor it uses to infect birds. This receptor is not common in the upper airways of people, says Thomas Peacock, a virologist at Imperial College London. But the virus has acquired some changes that make it better at making copies of its genome in mammals, “which is the first step of the pandemic stairs”, says Peacock. Adapting to receptors prevalent in humans is “several steps further up”.

Scientists are eager to deploy a host of tools to monitor the pathogen’s evolution. But for these tools to be useful, Eckerle says, “you need to have the data about where the infections are happening right now” — and those data have not been forthcoming.

“Actually changing government policy based on guesses rather than information that we could get, but are not getting, is the real problem,” says Angela Rasmussen, a virologist at the University of Saskatchewan in Saskatoon, Canada.

Data deficit

Gaps in the data have been apparent since US officials first announced the outbreak in March. An analysis of viral genomes found that H5N1 probably jumped from an infected wild bird to a cow, perhaps as early as November. The virus has been circulating in cattle ever since. The delay in identifying the outbreak suggests that surveillance programmes are not robust, says Jonathan Pekar, an evolutionary biologist at the University of California, San Diego. “The infrastructure we have in place is insufficient to prevent future pandemics,” he says.

Shilo Weir, a public-affairs specialist at the US Department of Agriculture (USDA), disagrees with that assessment. “This event highlights the success of our animal health network,” Weir says. It “shows that our surveillance program is incredibly effective at early identification of emerging disease trends.”

Bird flu virus has been spreading in US cows for months, RNA reveals

Researchers say that surveillance has continued to falter. The USDA did not release the first viral sequences until weeks after the outbreak was announced. For many of these sequences, the agency has still not released crucial details about when, where and from which species each was collected — information that could offer insight into how the virus is moving between herds, as well as how it is evolving, say researchers. “There’s not a huge amount of information coming through, or it’s coming through very slowly,” says Peacock. “From a pandemic-potential perspective, to try and understand how bad this is and what’s going on, it’s frustrating.”

Weir says that to expedite public access, sequence data are initially shared with general ‘USA’ and ‘2024’ tags, but polished sequences with more detailed information will be uploaded on the the widely used repository GISAID.

Researchers also say that information about what percentage of all sampled animals the sequences represent hasn’t been made available. “We don’t know the full extent of testing,” says Rasmussen. That means that researchers can’t assess whether the outbreak is growing, has peaked or is experiencing a downturn, says Peacock.

Weir says that national laboratories have conducted more than 7,500 tests since the start of the outbreak. But that number does not reflect exactly how many animals have been tested because some animals might have been sampled multiple times, or swabs from multiple animals could have been pooled into one test, says Weir.

On 24 April, the USDA mandated testing of lactating dairy cows prior to their movement between states, and reporting of positive influenza A test results in livestock. The USDA expects this federal order to improve the understanding of the virus’s distribution and reduce the risk of its further spread, says Weir.

Testing shortfall

Researchers also say more sampling is needed. Almost 50 herds of dairy cattle across 9 US states have had confirmed cases of H5N1, and one infected person has been linked to the outbreak. But the actual numbers are probably much higher, scientists say. “There’s almost certainly been a lot more human cases than just the one,” says Peacock.

How to stop the bird flu outbreak becoming a pandemic

Cattle and people working on farms should be tested not just for the presence of viral RNA — which indicates an active infection — but also for antibodies against H5N1, which circulate in the body for longer after an infection. “This is something that should be done immediately,” says Eckerle. Antibody studies could help scientists to determine how many people and cattle have been exposed to the virus and had infections that went unnoticed, possibly because they did not show symptoms or were not tested.

Weir says that the USDA plans to adapt a commercially available antibody test for birds for use in cattle serum and milk.

The sampling of faeces and organs from infected animals would help to identify where in the body the virus is replicating, how it is being excreted and how it is spreading between animals. If the virus is spreading through contact with contaminated milk, that would be relatively straightforward to control, says Eckerle. But transmission through respiratory secretions would be more difficult to control and would make farm work more risky.

Weir says the USDA is continuing to collect epidemiological data, and to study disease pathology and transmission to better understand the virus in cattle.

Incentivizing farmers

Some of the data that researchers are calling for could already have been collected but not publicly shared, says Meghan Davis, an environmental and veterinary epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. This lack of transparency “undermines the speed and other capacities for the response”, she says.

One barrier to testing has been the lack of incentives for farmers to step forward if they suspect the virus has infected their animals, say researchers.

On 10 May, the USDA announced a plan to compensate farmers affected by H5N1 outbreaks, and those who cooperate in studies, which could see testing ramp up. Davis says these measures should have been introduced weeks ago, especially in an industry in which there are some 25,000 farms making individual decisions. Farm workers should also receive sufficient protection, so that if they fall ill they are comfortable disclosing it, says Pekar.

Information about how and where the virus has spread is important for informing the response. If the outbreak is not widespread and is moving slowly, public-health officials could decide to cull affected herds and eradicate the virus in cattle, says Eckerle. But if it is too widespread or fast-moving, they might have to resign themselves to a new reality in which cattle are a reservoir of H5N1, and focus on restricting its jump to people. “I would not say it’s too late” to decide between these two pathways, says Eckerle — but “we need data”.

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May 17, 2024
Bird flu in US cows: where will it end?

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Dairy cattle seem to survive infection with the H5N1 strain of influenza virus, which has killed millions of wild birds.Credit: Ben Brewer/Reuters

Concerns that pasteurized milk in the United States is teeming with H5N1 avian influenza virus are over. But there’s no sign that the outbreak in cows is over, and scientists are increasingly concerned that cattle will become a permanent reservoir for this adaptable virus — giving it more chances to mutate and jump to humans.

New data show that the virus can hop back and forth between cows and birds, a trait that could allow it to spread across wide geographical regions. Although the virus kills many types of mammal, most infected cows don’t develop severe symptoms or die¹, meaning that no one knows whether an animal is infected without testing it. Moreover, a single cow can host several types of flu virus, which could, over time, swap genetic material to generate a strain that can more readily infect humans.

“Eventually the wrong combination of gene segments and mutations inevitably comes along,” says Michael Worobey, an evolutionary biologist at the University of Arizona in Tucson. “Whatever opportunity we may have had to nip it in the bud we lost by a really slow detection.”

Viral expansion

H5N1 isn’t a new virus — various forms of it have been circulating since the 1990s. A particularly deadly variant that was first detected in 1996 has killed millions of birds and has been found in numerous mammalian species, including seals and mink. But until now, cows were not among the virus’s known hosts.

US officials first announced on 25 March that H5N1 had been found in cattle, and cows from 36 herds in 9 states have tested positive as of 7 May. Tests of pasteurized milk have found no living virus. But the virus’s increasing ubiquity has made scientists uneasy.

“Every time it gets a new mammalian host species like cows, there’s more risk of human transmission and reduced human immunity,” says Jessica Leibler, an environmental epidemiologist at Boston University in Massachusetts.

Bovine breakthrough

Genomic data are starting to shed light on the origins of the cattle outbreak. In a 1 May preprint² posted on bioRxiv, scientists at the US Department of Agriculture analysed more than 200 viral genomes taken from cows and found that the virus jumped from wild birds to cattle in late 2023. That result corroborates findings by Worobey and others in an analysis posted on the discussion forum virological.org on 3 May. (Neither article has yet been peer reviewed.)

Want to prevent pandemics? Stop spillovers

Because cows infected with H5N1 generally don’t die of the flu, they are “effective mixing vessels” in which viruses can swap genetic material with other viruses, says Angela Rasmussen, a virologist at the University of Saskatchewan in Saskatoon, Canada. Even worse, the current strain seems to infect several species equally well. “If you have a virus that’s hopscotching back and forth between cows, humans and birds, that virus is going to have selective pressures to grow efficiently in all those species,” she says.

The larger the number of infected animals, Rasmussen says, the more chances the virus has to acquire helpful mutations, such as the ability to grow in the upper respiratory tract, which could make it more transmissible between people.

Dangerous reservoir

From a human perspective, Worobey says, cows might be one of the worst possible animal reservoirs for influenza because of their sheer number and the degree to which humans interact with them. Culling poultry has curbed previous bird flu outbreaks, but Rasmussen says that isn’t a viable option for cattle. The animals are too valuable and, unlike birds, don’t seem to die from the infection.

H5N1 could even become endemic in cows, says Gregory Gray, an infectious-disease epidemiologist at the University of Texas Medical Branch at Galveston. Other strains related to H5N1 are already endemic in chickens and pigs in some parts of the world.

Flu on the farm

Researchers aren’t sure how the virus is spreading between herds. Wild birds, which congregate around cattle feed and defecate in the cows’ water supply, are one probable source. “Cattle are just one big birdfeeder,” Gray says, adding that birds can spread infections much further than cows can and are much less controllable.

Some evidence has suggested that farm equipment, such as milking machines, could be to blame, but several scientists worry that it could be airborne. “I’m really thinking that’s occurring and we’ve not been able to study it,” Gray says, mainly because farmers have been reluctant to allow inspectors to test their cattle. Some related variants that infect horses have been found to spread through the air for kilometres, which could explain how the current strain has moved between dairy farms.

Until more is known about the virus’s transmission route, Worobey says, it’s hard to determine the best way to contain it. Since late April, the US Department of Agriculture has required that cows are tested before being transported across state lines. That won’t necessarily stop the virus’s spread, but it could at least help researchers to understand where it’s going.

Herd immunity

If the virus is airborne, Gray says, vaccinating cows might be an option. H5N1 vaccines have not yet been used in US cattle. But influenza vaccines have proved effective in pigs and poultry, and researchers are beginning to test them against the H5N1 strain infecting dairy herds.

Data on how well the virus spreads between people are scarce. A study³ published on 3 May in the New England Journal of Medicine confirmed that one dairy worker in Texas had been infected and that the worker experienced mild symptoms. But the people who worked and live with the infected person have not been tested.

Still, US officials have not reported a large number of deaths or severe cases in humans, suggesting that the virus hasn’t become highly transmissible or deadly, Worobey says.

Below the radar

But Gray says that there have been anecdotal reports of many more human cases. Leibler suspects that exposure of farm workers is widespread. “When you see symptomatic patients, that’s the tip of the iceberg,” she says. In the worst-case scenario, she says, the virus would spread undetected in several species for a long time, accumulating mutations that prime it for causing a pandemic in the future. “We have an awareness now from the COVID pandemic of how devastating that could be,” she says.

Leibler hopes that public-health efforts will begin testing workers and their families so that any transmission in humans will quickly be detected. “H5N1 is with us,” she says. “It’s not a virus that’s going to disappear by any means.”

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May 8, 2024
UTIs make life miserable — scientists are finding new ways to tackle them

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As the threat of antibiotic resistance grows, researchers are developing ways to prevent recurrent and chronic urinary tract infections (UTIs) without antibiotics. UTIs disproportionately affect women and can cause debilitating symptoms. The latest approaches include an oral vaccine that in trials prevented recurrent UTIs for nine years, as well as the development of non-antibiotic drugs. Scientists are also testing safer ways to use antibiotics, which often cause side effects, to treat the infections.

“I’ve been on about five or six antibiotics and the one I’m on now is probably the only one that doesn’t give me really bad symptoms,” says Gemma Perry, aged 43, who has had a chronic UTI for 12 years and wants to raise awareness of the condition.

UTIs include bacterial infections of the bladder, kidneys and the tubes that connect them. Symptoms include a burning sensation when urinating, an urge to pee more often than usual, and abdominal pain. Around 40–60% of women have at least one infection in their life. Of these women, about 20% have recurring UTIs — at least two within six months, or at least three infections in a year.

UTI symptoms often disrupt Perry’s daily life. “When it was really bad, I was going to the toilet probably around 20 times in a day and I was in a lot of pain,” she says. “It’s horrendous.” Perry takes a daily dose of antibiotics that reduces the growth of bacteria that persist in her bladder. Most antibiotics she has tried caused side effects such as tingling fingers and an irregular heartbeat, she says. “The racing heart was probably the scariest.”

Promising vaccine

Researchers presented their latest results of the oral vaccine, called MV140, last month at the 6th European Association of Urology Congress in Paris. MV140 — developed by biotechnology company Inmunotek in Madrid more than a decade ago — contains four inactivated species of bacteria that commonly cause UTIs. The pineapple-flavoured vaccine is sprayed under the tongue daily for three months.

Urologist Bob Yang at the Royal Berkshire Hospital in Reading, UK, and his colleagues have been trialling MV140 since 2014, and early results showed that it could reduce the risk of UTIs for up to 6 months. The team tracked the medical records of 89 people who were vaccinated in 2014 — most of them women — and found that around half of them did not develop a UTI for up to nine years. “Over 50% of women remained infection free, which is excellent,” says Yang. “There weren’t any long-term side effects or long-term complications.”

“It’s really flabbergasting,” says Jennifer Rohn, a cellular microbiologist at University College London. Although the vaccine will not work in everybody because of the variation in how UTIs develop, it could benefit a lot of people, she says. Still, the study was small, has yet to be peer-reviewed, and focused on people with relatively simple UTIs, says Rohn. “It would be great to have more people, and more complicated cases tested.”

The team plans to test the vaccine on more complex UTIs, for example in people who have spinal injuries and have a raised risk of the infections for anatomical reasons. But it’s likely to be years before the vaccine is approved for wider use. “This won’t be a quick process,” says Yang.

Targeted treatments

In another conference talk, researchers showed that delivering the antibiotic gentamicin directly into a person’s bladder, rather than using oral antibiotics, can reduce antibiotic resistance among UTI-causing bacteria.

Urologist Pragnitha Chitteti at James Cook University Hospital in Middlesbrough, UK, and her colleagues treated 37 people — mainly women whose UTIs did not respond to low-dose antibiotics — with gentamicin. Trial participants were trained to infuse gentamicin directly into their bladders through a catheter inserted into the vagina or penis. They received varying doses of gentamicin for months.

Before treatment with gentamicin, multidrug resistance was present in bacteria sampled from 44% of the people treated. After treatment, this dropped to just 10%. Moreover hospital admission rates among the participants dropped from 41% of people before treatment, to just 5% after treatment. And in 76% of people, the treatment reduced frequency of UTIs.

Antibiotic alternative

Other approaches to tackling antibiotic resistance include the use of a non-antibiotic drug called methenamine hippurate to treat UTIs. The drug was designed to prevent UTIs decades ago, but fell out of favour among urologists because of a lack of studies that directly compare its efficacy to that of antibiotics, says Ased Ali at the University of Newcastle.

In a 2022 study¹ involving around 240 women, the medication cut the risk of recurrent UTIs similarly well to standard antibiotics. The findings spurred the European Association of Urology, which provides UTI treatment guidelines to clinicians across Europe, to strongly recommend the use of methenamine hippurate to prevent UTIs in people without anatomical abnormalities of the urinary tract. “That was fantastic,” says Ali. The UK National Institute for Health and Care Excellence, which creates guidelines for physicians, is also considering updating its guidance, says Ali.

Perry knows that it could take years before improved therapies are widely available. “I’m aware that throwing antibiotics down my neck is not ideal, but I’ve got no other option.”

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May 2, 2024
Scientists tried to give people COVID — and failed

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When Paul Zimmer-Harwood volunteered to be intentionally infected with SARS-CoV-2, he wasn’t sure what to expect. He was ready for a repeat of his first brush with COVID-19, through a naturally acquired infection that gave him influenza-like symptoms. But he hoped his immunity would help him feel well enough to use the indoor bicycle trainer that he had brought into quarantine.

It turned out that Zimmer-Harwood, a PhD student at University of Oxford, UK, had nothing to worry about. Neither he nor any of the 35 other people who participated in the ‘challenge’ trial actually got COVID-19.

Scientists deliberately gave people COVID — here’s what they learnt

The study’s results, published on 1 May in Lancet Microbe¹, raise questions about the usefulness of COVID-19 challenge trials for testing vaccines, drugs and other therapeutics. “If you can’t get people infected, then you can’t test those things,” says Tom Peacock, a virologist at Imperial College London. Viral strains used in challenge trials take many months to produce, making it impossible to match emerging circulating variants that can overcome high levels of existing immunity in populations.

Researchers use challenge trials to understand infections and quickly test vaccines and therapies. In March 2021, after months of ethical debate, UK researchers launched the world’s first COVID-19 challenge trial. The study² identified a minuscule dose of the SARS-CoV-2 strain that circulated in the early days of the pandemic that could infect about half of the participants, who had not previously been infected with the virus (at that time, vaccines weren’t yet widely available).

In parallel, a team led by Helen McShane, an infectious-disease researcher at Oxford, launched a second SARS-CoV-2 challenge study in people — including Zimmer-Harwood — who had recovered from naturally caught SARS-CoV-2 infections, caused by a range of variants. The trial later enrolled participants who had also been vaccinated.

Evolving strains

The first participants got the same tiny dose of the ‘ancestral’ SARS-CoV-2 strain as did those in the first trial. When nobody developed a sustained infection, the researchers increased the dose by more and more in subsequent groups of participants, until they reached a level 10,000 times the initial dose. A few volunteers developed short-lived infections, but these quickly vanished.

These volunteers want to be infected with disease to aid research — will their altruism help?

“We were quite surprised,” says Susan Jackson, a study clinician at Oxford and co-author of the latest study. “Moving forward, if you want a COVID challenge study, you’re going to have to find a dose that infects people.”

An ongoing COVID-19 challenge trial at Imperial College London, in which participants have been exposed to the Delta SARS-CoV-2 variant, has also encountered problems with infecting participants reliably, says Christopher Chiu, an immunologist and infectious-disease physician at Imperial who is leading that trial and was involved in the other challenge trials. Some participants have experienced infections, but probably not enough for a study testing whether a vaccine works, adds Chiu.

“We need a challenge strain that’s more representative of what’s circulating in the community,” says Anna Durbin, a vaccine scientist at Johns Hopkins University School of Medicine in Baltimore, Maryland, who was a member of the board that oversaw the safety of the latest ‘reinfection’ trial.

Viral strains used in challenge trials are produced under stringent conditions, a process that can take six months or longer, say scientists, making it impossible to match circulating variants perfectly. McShane and Chiu are readying a challenge trial using the BA.5 Omicron subvariant that emerged in 2022.

Raising doses

Researchers are looking at other ways to give people COVID-19. Jackson says that an even higher SARS-CoV-2 dose might be needed — one similar to doses used in influenza challenge trials, in which participants have substantial immunity. Another method could be giving participants multiple doses. Chiu says that his team is exploring the possibility of screening potential participants to identify those with low levels of immune protection against the BA.5 variant and any future challenge strains.

Chiu is leading a consortium that in March was awarded US$57 million by the European Union and CEPI, the Coalition for Epidemic Preparedness Innovations in Oslo, to use challenge trials to test inhaled and intranasal COVID-19 vaccines that might also block transmission. He’s hopeful that such changes to trial protocols will do the trick. “What you really want is a model that replicates a genuine infection and ideally one that cause some symptoms,” he adds.

Zimmer-Harwood, who also works for a non-profit organization that advocates for challenge trials and their participants, says he would welcome changes that make COVID-19 challenge trials more useful to researchers — even if that means a bit less time on the bicycle trainer.

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May 1, 2024
is the milk supply safe?

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Cows are milked on a farm in New York State.Credit: Angela Weiss/AFP via Getty

The outbreak of avian influenza in US dairy cattle shows no signs of slowing. Over the past three weeks, the number of states where cows infected with bird flu have been detected has risen from six to eight. A preprint¹ posted on 16 April reported the discovery of the virus in raw milk from infected cows, and US federal authorities said on Wednesday that the virus had been found in lung tissue collected from a seemingly healthy cow.

Also on Wednesday, US officials confirmed at a media briefing that genomic material from the H5N1 strain, which is causing the outbreak, had been detected in milk sold in shops.

Detection of viral particles in milk sold to consumers suggests that avian flu in cows could “be more widespread than initially thought”, says food scientist Diego Diel at Cornell University in Ithaca, New York. “Increased surveillance and testing in dairies should be an important part of control measures going forward.” Nature looks at the implications for human health and the future of the outbreak.

What does it mean that H5N1 is in retail milk?

It’s still unclear how many milk samples the FDA has tested or where the samples were collected. The agency said that it would release more information in the coming days and weeks.

After it leaves the farm and before it hits the shelves, milk is pasteurized to inactivate pathogens. To detect H5N1, the FDA used a test called quantitative polymerase chain reaction (qPCR), which picks up viral RNA. Because it detects fragments of the viral genome, the test cannot distinguish between living virus and the remnants of dead virus, says dairy scientist Nicole Martin at Cornell University.

Bird flu outbreak in mink sparks concern about spread in people

“The detection of viral RNA does not itself pose a health risk to consumers, and we expect to find this residual genetic material if the virus was there in the raw milk and was inactivated by pasteurization,” she says.

The presence of viral material in commercially available milk does have broader implications, however. There are several possible explanations, says virologist Brian Wasik, also at Cornell University. It could be that the outbreak is more pervasive than farmers realized, and that milk from infected animals is entering the commercial supply. Another possibility, he says, is that “asymptomatic cows that we are not testing are shedding virus into milk”. But it’s also possible that both scenarios are true.

US federal rules require milk from infected cows to be discarded, but it’s not yet clear whether cows often start shedding the virus before they look sick or produce abnormal milk. The 16 April preprint, which has not yet been peer reviewed, includes reports that milk from infected cows is thicker and more yellow than typical milk and that infected animals eat less and produce less milk than usual.

Is milk with traces of H5N1 in it a threat to humans?

There is no definitive evidence that pasteurization kills H5N1, but the method kills viruses that multiply in the gut, which are hardier than flu viruses, says Wasik. “Influenza virus is relatively unstable,” he says, “and is very susceptible to heat.” Pasteurization of eggs, which is done at a lower temperature than pasteurization of milk, does kill H5N1.

It’s possible that pasteurization would be less effective at killing relatively high viral concentrations in milk, says Wasik. Finding out whether this is the case requires experimental data. In the absence of a definitive answer, keeping milk from infected cows out of the commercial supply is extremely important.

When Nature asked when to expect more evidence on whether pasteurization kills H5N1, Janell Goodwin, public-affairs specialist at the FDA in Silver Spring, Maryland, said that the agency and the US Department of Agriculture (USDA) “are working closely to collect and evaluate additional data and information specific to” H5N1.

Is milk spreading bird flu among cows?

USDA researchers have tested nasal swabs, tissue and milk samples of cows from affected dairy herds and have found that milk contained the highest viral concentrations. This indicates that the virus could be spreading through milk droplets.

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If so, milking equipment could be involved. “The teat cups of a milking machine could transfer remnants of H5N1-containing milk from one cow to the teats of the next cow being milked,” says virologist Thijs Kuiken at Erasmus University Medical Centre in Rotterdam, the Netherlands. “Even if they are washed and disinfected, the levels of virus in the milk of infected cattle are so high that one could not exclude the possibility of infectious virus being transferred from cow to cow by this route.” In fact, in some equipment set-ups, workers spray down milking machines with high-pressure hoses to clean them, which would aerosolize any infected milk, says Wasik.

The USDA website concurs that viral spread is “likely through mechanical means”.

Is enough being done to stop the spread?

The FDA announced on Wednesday that cows must test negative for bird flu before they can be moved across state lines. That might help to stem the outbreak, scientists say. Animals in the US dairy industry move around a lot, Wasik says. Calves are moved to be raised into milk cows, cows are moved when they stop producing milk and farmers sell the animals. Such movement is probably “a main driver” of the outbreak, Wasik says.

Diel would like to see surveillance of bulk milk samples at farms. Wastewater testing and environmental sampling could be useful, too, Wasik says, particularly around farms near outbreaks or farms where cows have been moved. He also advocates for a quarantine or observation period of 24 or 48 hours when cattle are moved to a new farm.

Such surveillance measures “could really buy us time, slow down the outbreak”, says Wasik, so researchers and agencies can “get a better handle on it. Because time is what’s of the essence.”

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April 25, 2024
what does that mean for future pandemics?

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The World Health Organization (WHO) has changed how it classifies pathogens that spread through the air, such as SARS-CoV-2. The redefinition has been two years in the making and comes after criticism that during the COVID-19 pandemic, the WHO was too slow to acknowledge that COVID was airborne. The change aims to provide clarity during pandemics, but some researchers are not convinced.

Virologists now acknowledge that SARS-CoV-2 spreads mostly by airborne transmission of small particles that are inhaled and that can remain in the air for hours — a method that was previously called ‘aerosol’ transmission. It also spreads by larger ‘droplets’ of virus-containing particles on surfaces, including hands, or ejected over short distances.

Why the WHO took two years to say COVID is airborne

However WHO didn’t publicly acknowledge the importance of airborne transmission until October 2020, a decision that outgoing chief scientist Soumya Swaminathan said in November 2022 said should have been made much earlier based on the available evidence. It didn’t amend its official document on COVID-19 transmission to include airborne transmission until December 2021. As a result, early infection control and prevention advice focused mainly on surface cleaning, hand-washing and social distancing, rather than mask-wearing and improved ventilation.

Some researchers say earlier recognition of airborne transmission by the WHO could have saved lives, noting mounting evidence that pointed to airborne transmission before its official acknowledgement.

Technical report

To clarify the distinction between airborne, droplet and aerosol, the WHO released a technical report on 18 April after more than two years of consultation with more than 100 experts from a range of scientific disciplines. The report does away with the division between ‘droplets’ and ‘aerosols’ used during the pandemic to distinguish between particles above or below five micrometres in diameter. Instead, it proposes the term ‘infectious respiratory particles’ to describe all such particles, regardless of size.

However the report still shies away from describing all pathogens that spread through the air as ‘airborne’. Instead, the document uses the umbrella term ‘through the air’ to describe any mode of transmission that “involves the pathogen travelling through or being suspended in the air”. That is then further broken down into two categories: ‘airborne transmission/inhalation’ is when infectious respiratory particles are inhaled from the air into the respiratory tract; while ‘direct deposition’ is when those particles travel over short range to land directly on the mouth, nose or eyes of another person.

Under this terminology, COVID-19 would be recognized as spreading through the air by airborne/inhalation transmission, with a much smaller risk of transmission by direct deposition.

Up in the air

It’s a mixed result for many scientists. “The positive thing which I see of this report is the fact that the report removes this division of five micrometres between aerosols and droplets,” says Lidia Morawska, an aerosol scientist at the Queensland University of Technology in Brisbane, Australia. That distinction was the justification for emphasis on hand-washing, distancing and surface-cleaning, rather than mask-wearing and ventilation — a distinction Morawska says was unscientific. It was also the distinction that justified WHO’s March 2020 assertion that COVID-19 was not airborne.

But that achievement of the report has been tarnished for some by the classification of ‘through the air’, instead of airborne.

“The simplest and clearest way to describe it is to call it airborne transmission,” says Linsey Marr, environmental engineer at Virginia Tech in Blacksburg, United States, whose research focuses on the transmission of infectious disease via aerosols and who was involved in the report. “We talk about waterborne transmission, blood-borne transmission, vector-borne transmission; it seems very logical and simple to me that we would call this airborne transmission.”

WHO Chief Scientist Jeremy Farrar says ‘through the air’ allows for recognition of both airborne transmission in which infectious respiratory particles are inhaled, and the less common transmission via direct deposition. “It’s not a dichotomy of mutually exclusive transmission routes,” he says. The recognition of both ‘airborne’ and ‘direct deposition’ under the umbrella of ‘through the air’ avoided going back to the divide between aerosols and droplets, Farrar says. ‘Through the air’ is comparable with vector-borne and waterborne, he says, but acknowledges that “there is a direct deposition element, even if that is not the major way it transmits.”

Julian Tang, a clinical virologist at the University of Leicester in the United Kingdom, who was also involved with the report, says there was vigorous debate among experts about the term airborne and what it conveys. Some of the scientists on the team that prepared the report argued that it would be problematic to use ‘airborne’ for all pathogens that spread through the air. “They think it’s too scary, too frightening, has too many connotations and it will cause panic, so they chose ‘through the air’,” Tang says.

Farrar says he has no reticence to use the term ‘airborne’. He stresses that this technical report is merely the ‘base camp’ of an ongoing process to refine terminology and its practical applications. “I’m not saying everybody is happy, and not everybody agrees on every word in the document, but at least people have agreed this is a baseline terminology.”

But Morawska, who also consulted on the report, argues that division between airborne and direct deposition is not justified. “It is just confusing the issues,” she says.

Even the co-chair of the group that developed the document, environmental engineer Yuguo Li from the University of Hong Kong, says he prefers the term ‘airborne’ to ‘through the air’. However he says what’s important is how the concept is applied in practice. “In theory, airborne is a perfect umbrella term as waterborne and vector-borne, but it means different things to different people,” Li says. “The issue is not only about terminologies, it’s about the need to work with public health experts, medical experts to understand those responses.”

COVID-19 rarely spreads through surfaces. So why are we still deep cleaning?

Tang says the document sets an important benchmark for how the world responds to the next pandemic. “The next pandemic will most likely be a respiratory virus again because that’s normally the pathogen that mutates the fastest,” he says. The report’s clarity around transmission will help public health providers to respond appropriately. “They will then consider masking early, they’ll consider ventilation early, they’ll consider all these precautions early because a precedent has been set already.”

The report notes that measures to address through-the-air transmission must take into account both the risk posed by the infection itself – for example, disease severity – and the resources available, which may be limited in low or middle-income countries.

Farrar believes this new definition could save lives in future pandemics. “What’s needed now is moving on from base camp to now understanding actually, the non-pharmacological interventions that really matter, and if they work, and the evidence of it.”

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April 24, 2024
Bacteria deploy umbrella toxins against their competitors

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Nature, Published online: 17 April 2024; doi:10.1038/d41586-024-01016-5

Bacteria make protein toxins to compete with other bacteria in microbial communities. A study of a common soil bacterium has revealed a previously unknown type of antibacterial toxin that forms a striking umbrella-like structure.

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April 17, 2024
Bird flu outbreak in US cows: why scientists are concerned

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A dairy worker in Texas has become infected with a strain of avian influenza similar to that infecting dairy cattle in several US states.Credit: Adam Davis/EPA-EFE/Shutterstock

Researchers are closely monitoring the spread of a worrisome strain of avian influenza to cattle — and one person — at farms in six US states.

These infections represent the first widespread outbreak of bird flu in cows. The outbreak is concerning because humans frequently come into contact with cattle on farms, giving the virus ample opportunity to spread to people, says Daniel Goldhill, an evolutionary virologist at the Royal Veterinary College in Hatfield, UK.

Health officials have said that the overall threat to people remains low, for now, but they are watching the situation unfold closely. “There’s always a worry that viruses will surprise us,” Goldhill says. “We don’t know what they’ll do next.”

Scientists are scrambling to assess how well candidate vaccines and antiviral drugs will work against the circulating strain and to update diagnostic kits for identifying infections in people quickly. They are also trying to understand whether the cows were infected by birds or another source, and are on alert for any changes in the situation that could raise the risk for people.

“There are a lot of questions and, so far, not a lot of answers,” says Florian Krammer, a virologist at Icahn School of Medicine at Mount Sinai in New York City.

Where was the virus found previously, and what’s happening now?

In 1996, the influenza strain called H5N1 was first detected in birds in China. It has been spreading ferociously in birds since 2021, killing hundreds of millions of domestic and wild birds around the world. It has also occasionally infected mammals, including seals and bears, which have become “accidental hosts” of what is mostly an avian virus, says Kanta Subbarao, director of the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia.

Bird flu outbreak in mink sparks concern about spread in people

In the past two weeks, health officials have detected H5N1 in cows from 16 herds across six states — a number that is likely to increase as US surveillance is stepped up. Researchers have previously documented¹ sporadic infections of cows with flu viruses closely related to H5N1, but no widespread outbreaks had been detected until now.

The more mammalian species the virus infects, the more opportunities it has to evolve a strain that is dangerous to humans, Goldhill says. One dairy worker in Texas has been infected, but the US Centers for Disease Control and Prevention (CDC) reports that the person is recovering. The worker’s only symptom was eye inflammation, and viral levels in their nose were low, suggesting that they don’t have a respiratory infection, according to the CDC.

The virus infecting the worker is closely related to the strains found in dairy cattle in Texas, with one notable distinction: the worker’s variant has a mutation that is linked to more-efficient spread in mammals. Goldhill says the presence of the mutation in the human sample was not surprising; it has appeared many times, including in foxes² and cats³ infected with H5N1.

Is the virus spreading between cows, and why does that matter?

A key question for researchers is how the cows are getting infected. The answer will be important for controlling H5N1’s spread to other farms and people. “This is a controllable situation, we just have to understand how this virus is getting around,” says Richard Webby, a virologist at St. Jude Children’s Research Hospital in Memphis, Tennessee.

Avian flu freezes coastal bird research in South Africa

Of particular interest is whether the virus is passing from infected cows to uninfected ones, because that would suggest the virus has become more adept at transmission in mammals. Given that the virus has been detected at several farms across the United States, epidemiological data make it “pretty clear now we’re seeing cow-to-cow spread”, and that wild birds are not necessarily involved in viral spread in the farms, says Webby. But there aren’t enough viral sequences of animals infected later in the outbreak for genomic data to confirm cow-to-cow spread, he says.

If the virus is spreading between cows, it will be important to work out precisely how, Webby says. Evidence so far suggest that virus levels are highest in the animals’ milk, according to a report in Science. That suggests that H5N1 might not be spreading between cows through the air, a transmission pathway that would be difficult to control and could allow for relatively quick spread, Webby says. If cows are becoming infected by touching contaminated surfaces, such as milking machines, the virus would be transmitted more slowly than if it is airborne.

Gathering evidence to address these questions could help to answer why infections have only recently cropped up in cattle, and only in the United States, despite the virus’s global spread in the past few years. Marion Koopmans, a virologist at Erasmus University Medical Center in Rotterdam, the Netherlands, wonders whether there is something unique about how cattle are kept in the region, for example, or whether the virus has gained new abilities to persist in the environment. Addressing these questions will offer insights into how widespread bird flu infections could be in cattle globally, she says. It will be important for health officials outside the United States to start looking for evidence of overlooked outbreaks, Krammer says.

What would increase concern among researchers?

Scientists say that, although bird flu is unlikely to spread widely in people, they are closely monitoring samples of H5N1 globally for mutations known to signal that it is becoming better at spreading in mammals. The virus has not spread widely in humans in part because it can’t readily enter the cells that line the nose and mouth. But it would be problematic if the virus developed mutations that would help it to gain entry to these cells, Goldhill says.

Krammer says he would look specifically for changes to the section of the viral genome that encodes a type of enzyme known as a polymerase. A portion of this enzyme is known to be “a hotspot for adaptation to mammals”. Researchers are also looking out for mutations that would make the strain less susceptible to antiviral drugs, says Webby.

The animal that no virologist wants to see a flu outbreak in, is the pig. Pigs host many influenza A viruses, making them a ‘mixing vessel’ in which strains of avian and mammalian viruses can mix and match and become more efficient at transmitting to people, says Krammer.

What do we know about how well existing vaccines and drugs will work against this strain?

The WHO maintains a list of candidate vaccines that provide protection against H5N1 and that could be mass-produced. And some countries, including the United States, maintain a small stockpile of vaccine doses should they need to vaccinate at-risk populations, such as front-line workers.

The CDC has reported that the viral strain isolated from the infected person is closely related to two strains targeted by a candidate vaccine. Webby says that his team has confirmed in laboratory studies that the WHO vaccines can protect against viral samples collected from cows early in the outbreak, and they will continue to test new samples as the outbreak progresses. Specifically, the vaccine includes antibodies produced against a human H5N8 virus isolated in Russia and an avian H5N1 virus isolated in the United States. They can “recognize this cow virus very, very well”, says Webby.

It would be useful to get more information on how much immunity these candidate vaccines produce against the circulating strain, especially because people don’t have pre-existing protection against H5N1 and closely related viruses, says Subbarao.

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April 8, 2024