Tag: Virology

What does peak emissions mean for China — and the world?

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The world might be witnessing the bending of a key climate curve. Various projections have suggested that carbon emissions from China, the world’s largest emitter, will probably peak soon — if they haven’t already — well ahead of Beijing’s pledge that they would peak before 2030.

“What happens with China’s emissions in the next year and next decade is absolutely decisive for the success of the global climate effort,” says Lauri Myllyvirta, an analyst who has tracked China’s emissions trends for more than a decade and is a fellow at the Asia Society Policy Institute, a think-tank based in Washington DC.

“Once China’s emissions peak, it’s likely that global emissions will also reach their peak,” says Dave Jones, an electricity analyst at Ember, a London-based think-tank.

But some researchers say that current peak predictions have big uncertainties owing to various factors, such as the future path of China’s economy. And although reaching the peak will be a major climate milestone, China’s emissions must continue to fall to net zero, which could be challenging, say some researchers.

Early peak

China reports its greenhouse-gas emissions to the United Nations through a national communication on climate change every four years and a separate report every two years. But those statistics have a major lag, and China’s latest ones were for 2018.

Assessments by Myllyvirta suggest that China’s emissions have been declining since March. This points to a possible 2023 peak, he says, but only if China’s clean-energy production can stick to last year’s record-breaking growth rate in 2024 and its energy consumption drops to its pre-pandemic level. China installed a staggering 217 gigawatts of solar-power capacity in 2023 alone. The United States has installed 137 gigawatts in its entire history.

Myllyvirta calculates China’s monthly CO₂ emissions by analyzing energy, industrial and customs data from the Chinese government, industry bodies and commercial companies. Analysts can also estimate how much China’s emissions have changed every year by analyzing data released by China annually, he said. He thinks the current downward trend is largely because of the growth of clean energy.

Peak still to come

Modelling by Ryna Cui, a researcher who specializes in coal transition at the University of Maryland in College Park, and her team predicts emissions will peak before 2025. Cui’s team found that rapid deployment of green technologies and shrinking demand for emissions-intensive products, such as steel and cement, are pushing emissions down. But she cautions: “Emissions peaking can be a complex process, with possible small fluctuations, instead of one single point.”

Short-term fluctuations have happened before. China’s emissions declined between 2013 and 2016 after coal use had dropped under a government campaign to tackle air pollution. But a rebound occurred after fossil-fuel consumption went up again.

Other analysts think that it will take another year or so to confidently assess whether China’s recent emissions decline is temporary or the beginning of a long-term trend. “There are very, very big uncertainties,” says Bill Hare, a climate scientist and chief executive of Climate Analytics, headquartered in Berlin. Normally, researchers would need five years of emissions data to make a call on a trend, he explains.

Life after peak

Peak emissions are just the beginning. China must also double down on its efforts to reduce emissions to net-zero to prevent global warming from getting worse, says Gunnar Luderer, an energy researcher at the Potsdam Institute for Climate Impact Research in Germany. China has pledged to reach this before 2060.

Hare and his colleagues are assessing China’s technology and policy trends to project its emissions trajectory. They forecast two scenarios, one showing emissions staying flat for a few years, whereas in the other, emissions begin to decline. The unknowns include whether China will put many of the coal-power plants it is currently building into operation and how fast it will deploy renewable-energy plants over the next few years.

China approved 83% less coal-power capacity in the first half of 2024 than in the year before, owing to massive renewable advancements, according to a report released in August by the Helsinki-based think-tank Centre for Research on Energy and Clean Air and Global Energy Monitor, a non-governmental organization based in Covina, California. This spells a possible end to China’s coal-power capacity expansion in the next few years, once the projects that are under construction and waiting to be built are complete, Cui says.

Although to slash emissions, China will have to wean itself off coal entirely, and Myllyvirta foresees there will be “a lot of opposition from vested interests” in the coal industry, such as state-owned enterprises and local governments.

Time pressure

China will have a much shorter time frame to achieve net zero, compared with the European Union and the United States, whose emissions peaked around 1979 and 2005, respectively.

Nevertheless, Sun Yongping, a climate economist at Huazhong University of Science and Technology in Wuhan, China, is confident about China’s ability to reduce emissions after they peak. “Decarbonization requires two things: technologies and manufacturing capacity to bring these technologies into reality. China has both,” Sun says.

For others, China’s peaking will have a more profound significance. “The current global emission growth is largely driven by developing countries’ economic expansion,” says Mi Zhifu, a researcher in climate change economics at the University College London. “China’s experience in decarbonization could offer valuable lessons for other developing nations striving to decouple economic growth from their emissions.”

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September 19, 2024
Is bird flu spreading among people? Data gaps leave researchers in the dark

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These bird flu virus particles (artificially coloured) were imaged by an electron microscope.Credit: Eye of Science/Science Photo Library

All eyes are on Missouri.

Researchers are anxiously awaiting data from the midwestern state about a mysterious bird flu infection in a person who had no known contact with potential animal carriers of the disease. The data could reveal whether the ongoing US bird flu outbreak in dairy cattle has reached a dreaded turning point: the emergence of a virus capable of spreading from human to human.

Huge amounts of bird-flu virus found in raw milk of infected cows

Thus far, data from the mysterious infection are few and far between: small snippets of the H5N1 virus’s genome sequence and an incomplete infection timeline. Ratcheting up concerns is the fact that no Missouri dairy farms have reported a bird flu outbreak; this might be because there really are no infections, or because the state does not require farmers to test their cows for the virus.

“The fear is that the virus is spreading within the community at low levels, and this is the first time that we’re detecting it,” says Scott Hensley, a viral immunologist at the University of Pennsylvania Perelman School of Medicine in Philadelphia. “There’s no data to suggest that to be the case, but that’s the fear.”

A mystery case

On 6 September, Missouri public-health officials and the US Centers for Disease Control and Prevention (CDC) announced that an adult in the state had developed symptoms including chest pain, nausea, vomiting and diarrhea, and was hospitalized owing to other medical conditions. That person did not become severely ill and has recovered from the infection. Tests revealed it to be H5N1 influenza, often referred to as bird flu.

Since March, when the H5N1 virus was first detected in US dairy cattle, there have been more than a dozen cases of human infection that were traced back to contact with infected animals, including cows and birds. The Missouri case stands out because investigators found no such link and no tie to unprocessed food products, such as raw milk, from potentially infected livestock.

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This raised the possibility that the virus might have evolved to not only infect humans, but also to spread between people. If so, this increases the risk of it sweeping through human populations, potentially triggering a dangerous outbreak.

But that’s not the only possibility, cautions Jürgen Richt, a veterinary virologist at Kansas State University in Manhattan. “It’s a mystery case,” he says. “So you have to throw your net a little wider. Maybe they cleaned out a bird feeder in the household. Did they go to a state fair? What kind of food did they consume?”

More concerns were raised about the Missouri case on 13 September, when the CDC announced that two people who had close contact with the hospitalized person had also become ill around the same time. One of them was not tested for flu; the other tested negative.

That test result is encouraging but not definitive, says Hensley, because the sample could have been collected when the individual’s viral levels were too low for detection — after they started to recover, for instance. A key next step will be to test all three people for antibodies against the strain of H5N1 bird flu that has been infecting cattle. Such antibodies, particularly in the two contacts, would be definitive evidence of past infection.

Genomic sleuthing

While researchers await the antibody results, they are combing through patchy genome-sequence data from virus samples from the hospitalized person. This could yield any signs that the virus might have adapted to human hosts. The search is a challenge, however: the samples contained very low levels of viral RNA — so little that some researchers have shied away from analysing the sequences altogether.

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

“What I would want to see is higher quality,” says Ryan Langlois, a viral immunologist at the University of Minnesota Medical School in Minneapolis. “I am very leery about interpreting anything from partial sequences.”

But for Hensley, one feature of the sequence fragments immediately leapt out: a single change in the string of amino acids that form a flu protein called hemagglutinin (the ‘H’ in H5N1). That protein sits on the surface of influenza viruses, where it helps the viruses bind to and infect host cells. It is also a target of flu vaccines.

The change that Hensley found creates a site to which a large sugar molecule can bind. That sugar, he says, could then act as an umbrella, shielding the swath of hemagglutinin beneath it. It is a change that his laboratory has studied in other flu strains, and it could affect how the virus binds to host cells — as well as whether vaccines being developed against the H5N1 virus found in cattle can recognize and perform well against the virus detected in Missouri.

Surveillance gaps

Even if the sequences were available, researchers know little about which genetic changes might allow bird flu viruses to better infect humans or to become airborne, says virologist Yoshihiro Kawaoka at the University of Wisconsin–Madison. Previous studies¹^,² had suggested that changes to a gene encoding a protein responsible for copying the viral genome could be crucial for allowing the virus to replicate in mammalian cells. But researchers were unable to sequence that gene from the isolate from Missouri.

Meanwhile, the CDC has issued contracts to five companies in the United States to provide testing services for H5N1 and other emerging pathogens. Testing of cattle also needs to be improved so that public-health officials will know which regions of the country to surveil for infections in humans, says Seema Lakdawala, a virologist at Emory University in Atlanta, Georgia. In the United States, most testing of cattle is regulated at the state level, but only a handful of states have required routine testing on some dairy farms.

Public-health workers still don’t have a good handle on how many US herds have cows infected with H5N1, or whether cattle have immunity after contracting bird flu or can become reinfected, she says.

While researchers wait for more information, Hensley cautions against panic. “This could still be a one-off case and not the sign of something bigger,” he says.

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September 19, 2024
Where did viruses come from? AlphaFold and other AIs are finding answers

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The structure of a dengue virus protein predicted using ColabFold–AlpahFold2.Credit: Spyros Lytras and Joe Grove

Artificial intelligence (AI) is helping to redraw the virus family tree. Predicted protein structures generated by AlphaFold and chatbot-inspired ‘protein language models’ have uncovered some surprising connections in a family of viruses that includes pathogens that infect humans as well as emerging threats.

Ex-Meta scientists debut gigantic AI protein design model

Much of scientists’ understanding of viral evolution is based on genome comparisons. But the lightning-quick evolution of viruses — particularly those with genomes written in RNA — and their tendency to acquire genetic material from other organisms mean that genetic sequences can hide deep and distant relationships between viruses, which can also vary depending on the gene examined.

By contrast, the shapes, or structures, of the proteins encoded by viral genes tend to change slowly, which makes it possible to suss out these hidden evolutionary connections. But until the dawn of tools such as AlphaFold, which can predict protein structures at scale, it was not possible to compare protein structures across an entire viral family, says Joe Grove, a molecular virologist at the University of Glasgow, UK.

In a paper published this month in Nature¹, Grove and his team demonstrate the power of a structure-based approach in the flaviviruses — a group that includes the hepatitis C, dengue and Zika viruses, as well as some major animal pathogens and species that could be emerging threats to human health.

How viruses enter

Much of researchers’ understanding of flavivirus evolution has been based on sequences of slow-evolving enzymes that copy their genetic material. However, researchers know remarkably little about the origins of the ‘viral entry’ proteins that flaviviruses use to invade cells and which determine the range of hosts they can infect. This gap, Grove argues, has slowed the development of an effective vaccine against hepatitis C, which kills hundreds of thousands of people each year.

Could AI-designed proteins be weaponized? Scientists lay out safety guidelines

“At the sequence level, things are so divergent that we can’t tell if they’re related or not,” he says. “The advent of protein structure prediction unlocks the whole question, and we can see things quite clearly.”

The researchers used DeepMind’s AlphaFold2 model and ESMFold, a structure-prediction tool developed at tech giant Meta, to generate more than 33,000 predicted structures for proteins from 458 flavivirus species. ESMFold is based on a language model trained on tens of millions of protein sequences. Unlike AlphaFold, it requires only a single input sequence, rather than relying on multiple sequences from similar proteins, so it might be especially useful for scrutinizing the most mysterious viruses.

A hepatitis C virus glycoprotein structure prediction. Credit: Spyros Lytras and Joe Grove

The predicted structures allowed the authors to identify viral entry proteins with very different sequences to those of known flaviviruses. They found some unexpected links. For instance, the subset of viruses that includes hepatitis C infects cells using a system similar to one they discovered in the pestiviruses — a group that includes classical swine fever virus, which causes haemorrhagic fever in pigs, and other animal pathogens.

The AI-enabled comparisons showed that this entry system is distinct from those of many other flaviviruses. “For hep C and its relatives, we don’t know where its entry system came from. It may have been ‘invented’ by those viruses way back when,” says Grove.

Stolen from bacteria

The predicted structures also revealed that the well-studied entry proteins of Zika and dengue virus have the same origins as those of what Grove describes as “weird and wonderful” flaviviruses with giant genomes, including Haseki tick virus, which can cause fever in humans. Another big surprise was the discovery that some flaviviruses have an enzyme that seems to have been stolen from bacteria.

‘Set it and forget it’: automated lab uses AI and robotics to improve proteins

“This would be unprecedented,” says virologist Mary Petrone, at the University of Sydney, Australia, were it not for her team’s discovery this year of a similar theft in an especially weird and wonderful flavivirus species². “Genetic piracy could have played a larger role in shaping the evolution of the flavivirids than previously thought,” she adds.

David Moi, a computational biologist at the University of Lausanne, Switzerland, says that the flavivirus study is the tip of the iceberg, and that the evolutionary histories of other viruses and even some cellular organisms are likely to be rewritten with AI. “We’ll be retelling their stories with a new generation of tools,” he says. “Now that we can see a bit farther, all of these things are going to have to have a little bit of an update.”

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September 16, 2024
New virus-genome website seeks to make sharing sequences easy and fair

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Genome sequences of West Nile virus (pictured) are being uploaded and shared on a new online database. Credit: Dr Linda Stannard, UCT/Science Photo Library

A new database for researchers to share the genomes of dangerous viruses promises to solve many of the problems that hamper existing alternatives. But first, researchers must be convinced to use it.

Pathoplexus — a portmanteau of pathogen and plexus — was launched last month, and the team of scientists behind the database hopes that it will encourage more researchers to share genetic sequences of known and emerging viruses of public-health importance.

Sharing sequences as quickly as possible is important for identifying new viruses and tracking changes that could make them more dangerous to humans, as well as for designing vaccines, says Edward Holmes, a virologist at the University of Sydney in Australia.

Pathoplexus currently focuses on four viruses that are not specifically included in other databases: Crimean–Congo Hemorrhagic Fever Virus, Ebola Sudan, Ebola Zaire and West Nile Virus. Other pathogens will be added later, the team says.

Existing hurdles

Among the largest existing repositories is GenBank in the United States, which offers unrestricted access to its genomic data. But public access means that anyone can theoretically use the data to publish scientific papers, without acknowledging the data owners. This has discouraged scientists, particularly those from lower-income countries, from sharing their data quickly, such as during a public-health emergency. An alternative repository, GISAID, requires users to register, agree to acknowledge the data owners and make their best efforts to collaborate with the owners. The database was designed to ensure the rights of data submitters.

GISAID was hugely popular during the COVID-19 pandemic, and it contains close to 17 million sequences of SARS-CoV-2, the virus behind COVID-19. But researchers have raised concerns around transparency in its governance, how it mediates disputes over credit and how it sanctions those it believes to have violated its conditions for use.

“GISAID has led to a lot of frustration in the past few years,” but the scientific community have also learnt lessons on how to do things better, says Spyros Lytras, an evolutionary virologist at the University of Tokyo. “Starting from scratch is what we need as a community, and Pathoplexus might be the solution.”

A representative for GISAID said, in an email, that the trust it has with the scientific community is strong, and that more than 70,000 researchers use the site. The roles of its governing bodies and funding sources are displayed on its website, and their terms of use haven’t changed since it was founded in 2008, the representative said.

Building trust

Pathoplexus offers some protections for users. For instance, researchers can set restrictions on how their data are used, such as not allowing them to be included as a key focus of scientific publications for up to a year without their explicit permission. This should give data owners enough time to submit a manuscript on their findings.

Users must also credit the data owners in their publications. “We aim to build a community where researchers feel confident that their contributions will be respected and properly credited,” says Jamie Southgate, a member of Pathoplexus and the head of operations at the global coalition Public Health Alliance for Genomic Epidemiology, based in Cape Town, South Africa.

Pathoplexus doesn’t block individuals who breach the terms of use from accessing the site, which GISAID has done in rare cases. Instead, if published data breach the terms, the team will approach the journals to ensure that the data are used in accordance with the way in which they were shared, says Emma Hodcroft, a co-founder of Pathoplexus and a molecular epidemiologist at the Swiss Tropical and Public Health Institute in Basel, Switzerland. “We have tried to be incredibly explicit” about the terms, she says.

“It’s a good, clever solution,” says Senjuti Saha, a molecular microbiologist at the Child Health Research Foundation in Dhaka, who agrees with the approach of reaching out to publishers. “That’s the way it should be.” She thinks that Pathoplexus’s transparency will breed trust among the scientific community.

But it’s too early to say whether the repository will solve the current data-sharing problems, says Saha. “It is an excellent and fantastic first step.”

Users might also stick to sharing sequences on local databases. For instance, in China, researchers are probably more likely to publish sequences for emerging viruses on Chinese databases, says Shi Mang, an evolutionary biologist at Sun Yat-sen University in Shenzhen, China, who is also on Pathoplexus’s scientific advisory board. But for established viruses, they are likely to use repositories with well-maintained collections, which Pathoplexus offers.

Improved experience

Pathoplexus’s creators have tried to improve the user experience, such as making uploading as easy as possible. Pathoplexus also checks for errors in the sequence data and accompanying information and assists with organizing viruses into subtypes. “This is actually what attracted me to this database,” says Shi. Incorrect sequences in current repositories can cause lots of trouble for researchers, he says.

So far, Pathoplexus has used GenBank data for the four viruses to populate the site. Thousands of people have visited the site, and 50 have created accounts to submit data, but none have submitted sequences, says Hodcroft. “We did not expect high volumes of data for the pathogens that we’ve launched with.”

Researchers who work on other viruses will have to wait until the database expands to include them. And to expand, the team needs to secure long-term funding. The site is currently being run by volunteers and donated computing time, which ends in about six months. Hodcroft says her priority right now is to appeal to donors. “I’m cautiously hopeful.”

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September 9, 2024
Mpox is spreading rapidly. Here are the questions researchers are racing to answer

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Monkeypox virus particles (shown in this coloured electron micrograph) can spread through close contact with people and animals.Credit: NIAID/Science Photo Library

When the World Health Organization (WHO) declared a public-health emergency over mpox earlier this month, it was because a concerning form of the virus that causes the disease had spread to multiple African countries where it had never been seen before. Since then, two people travelling to Africa — one from Sweden and one from Thailand — have become infected with that type of virus, called clade 1b, and brought it back to their countries.

Monkeypox virus: dangerous strain gains ability to spread through sex, new data suggest

Although researchers have known about the current outbreak since late last year, the need for answers about it is now more pressing than ever. The Democratic Republic of the Congo (DRC) in Central Africa has spent decades grappling with clade I virus — a lineage to which Ib belongs. But in the past, clade I infections usually arose when a person came into contact with wild animals, and outbreaks would fizzle.

Clade Ib seems different, and is spreading largely through human contact, including through sex. Nearly 18,000 cases of mpox, many of them among children, and at least 600 deaths have been reported this year in the DRC alone.

How does this emergency compare with one declared in 2022, when mpox cases spread across the globe? How is this virus behaving compared with the version that triggered that outbreak, a type called clade II? And will Africa be able to rein this one in? Nature talks with researchers about information they are rushing to gather.

Is clade Ib more deadly than the other virus types?

It’s hard to determine, says Jason Kindrachuk, a virologist at the University of Manitoba in Winnipeg, Canada. He says that the DRC is experiencing two outbreaks simultaneously. The clade I virus, which has been endemic in forested regions of the DRC for decades, circulates in rural regions where people get it from animals. That clade was renamed Ia after the discovery of clade Ib. Animal studies suggest that clade I is deadlier than clade II¹ — but Kindrachuk says it’s hard to speculate what that means for humans at this point.

Even when not fatal, mpox can trigger fevers, aches and painful fluid-filled skin lesions.

Growing mpox outbreak prompts WHO to declare global health emergency

Although many reports claim that 10% of clade I infections in humans are fatal, infectious disease specialist Laurens Liesenborghs at the Institute of Tropical Medicine in Antwerp, Belgium, doubts that this figure is accurate. Even the WHO’s latest estimate of a 3.5% fatality rate for people with mpox in the DRC might be high.

There are many reasons fatality estimates might be unreliable, Liesenborghs says. For one, surveillance data captures only the most severe cases; many people who are less ill might not seek care at hospitals or through physicians, so their infections go unreported.

Another factor that can confound fatality rates is a secondary health condition. For example, people living with HIV — who represent a significant proportion of the population in many African countries — die from mpox at twice the rate of people who do not have compromised immune systems, especially if their HIV is untreated². And the high death rate among children under age 5 could be partly due to malnutrition, which is common among kids in rural parts of the DRC, Liesenborghs says.

Is clade Ib more transmissible than other types?

The clade 1b virus has garnered particular attention because epidemiological data suggest that it transmits more readily between people than previous strains, including through sexual activity, while clade Ia mostly comes from animals. An analysis published ahead of peer review last week to the preprint server medRxiv³ shows that clade Ib’s genome contains genetic mutations that seem to have been induced by the human immune system, suggesting that it has been in humans for some time. Clade Ia genomes have fewer of these mutations.

But Liesenborghs says that the mutations and clades might not be the most important factor in understanding how the monkeypox virus spreads. Although distinguishing Ia from Ib is useful in tracking the disease, he says, severity and transmissibility of disease could be more affected by the region where the virus is circulating and the people there. Clade Ia, for instance, seems to be more common in sparsely populated rural regions where it is less likely to spread far. Clade Ib is cropping up in densely populated areas and spreading more readily.

Jean Nachega, an infectious disease physician at the University of Pittsburgh in Pennsylvania, says that scientists don’t understand many aspects of mpox transmission — they haven’t even determined which animal serves as a reservoir for the virus in the wild, although rodents are able to carry it. “We have to be very humble,” Nachega says.

How effective are vaccines against the clade I virus?

Just as was the case during the COVID-19 pandemic, health experts are looking to vaccines to help curb this mpox outbreak. Although there are no vaccines designed specifically against the monkeypox virus, there are vaccines proven to ward off a related virus — the one that causes smallpox. Two currently exist. Jynneos, made by Bavarian Nordic in Hellerup, Denmark, contains a type of poxvirus that can’t replicate but can trigger an immune response. LC16m8, made by KM Biologics in Kumamoto, Japan, contains a live — but weakened — version of a different poxvirus strain.

Hopes dashed for drug aimed at monkeypox virus spreading in Africa

Still, it’s unclear how effective these smallpox vaccines are against mpox generally. Dimie Ogoina, an infectious disease specialist at Niger Delta University in Wilberforce Island, Nigeria, points out that vaccines have been tested only against clade II virus in European and American populations because these shots were distributed by wealthy nations during the global outbreak that started in 2022. And those recipients were primarily young, healthy men who have sex with men, the population that drove that outbreak. One study in the United States found that one dose of Jynneos was 80% effective at preventing the disease in people at risk while two doses was 82% effective⁴; the WHO recommends getting both jabs.

People in Africa infected with either the clade Ia or 1b virus — especially children and those with compromised immune systems — might respond differently, although one study in the DRC found that the Jynneos vaccine could generally raise antibodies against mpox in about 1,000 healthcare workers who received it⁵.

But researchers are trying to fill in some data gaps. A team in the DRC is about to launch a clinical trial of Jynneos in people who have come into close contact with the monkeypox virus — but have not shown symptoms — to see whether it can prevent future infection, or improve outcomes if an infection arises.

Will the vaccines help to rein in the latest outbreak?

Mpox vaccines have so far been largely unavailable in Africa, but several wealthy countries have pledged to donate doses to the DRC and other affected African nations. The United States has offered 50,000 Jynneos doses from its national stockpile, and the European Union has ordered 175,000, with individual member countries pledging additional doses and Bavarian Nordic adding another 40,000. Japan has offered 3.5 million doses of LC16m8 (which requires only one jab instead of two).

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None of them has arrived yet, though, says Espoir Bwenge Malembaka, an epidemiologist at the Catholic University of Bukavu in the DRC. Low- and middle-income nations that rely on vaccine donations cannot receive them until the WHO has determined that the jabs are safe and effective. And so far, the WHO has not given its thumbs up. It is evaluating additional data that it received from vaccine manufacturers, delaying donors’ ability to send the vaccines.

Even when the vaccines arrive, Bwenge Malembaka says, “it’s really a drop in the bucket.” The African Centres for Disease Control and Prevention in Addis Ababa, Ethiopia, estimates that 10 million doses are needed to rein in the outbreak.

Bwenge Malembaka says that the uncertainty over vaccine arrival has made it difficult for the government to form a distribution plan. “I don’t know how one can go about this kind of challenge,” he says. Bwenge Malembaka suspects children are likely to receive doses first, because they are highly vulnerable to clade I, but officials haven’t decided which regions to target. It’s also unclear how the government would prioritize other vulnerable populations such as sex workers, who have been affected by clade Ib. Their profession is criminalized in the DRC, so they might not be able to come forwards for treatment.

Researchers lament that public-health organizations didn’t provide vaccines and other resources as soon as the clade I outbreak was identified, especially given lessons learned from the 2022 global mpox outbreak. “The opportunity was there a couple months ago to cut this transmission chain, but resources weren’t available,” Liesenborghs says. “Now it will be more challenging to tackle this outbreak, and the population at risk is much broader.”

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August 28, 2024
Mysterious Oropouche virus is spreading: what you should know

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The Southern house mosquito (Culex quinquefasciatus; artificially coloured) can transmit Oropouche virus to humans, but the main vector is the midge Culicoides paraensis.Credit: Dennis Kunkel Microscopy/Science Photo Library

Once confined to the Amazon region, the mysterious virus that causes the disease called Oropouche fever has been expanding its range since late 2023, spurring international concern. The virus has already caused more than 8,000 human infections in the Americas this year, most in Brazil but also in Peru, Bolivia, Colombia and Cuba.

In July, authorities in Brazil reported the deaths of two adults from the disease — the first since the virus was identified almost 70 years ago. Brazilian officials are also investigating cases of fetal deaths and malformations that might have been caused by the virus, which has now been shown to spread from a pregnant person to their fetus. There are no vaccines or treatments targeting the disease.

Earlier this month, the Pan-American Health Organization upgraded its risk level for Oropouche from moderate to high, citing the virus’s geographical spread and the occurrence of fatal cases in a disease that has been historically known to cause mild to moderate symptoms. On 23 August, the World Health Organization published a note confirming the public health risk posed by the virus as high at the regional level, and low at the global level. The US Centers for Disease Control and Prevention has advised close surveillance of people returning from affected areas. Cases of Oropouche in the United States, Spain, Italy and Germany have been identified in travellers coming from Brazil and Cuba.

Nature spoke with Gonzalo Bello, a public health specialist at the Oswaldo Cruz Institute in Rio de Janeiro, Brazil, who has studied the lineage of the Oropouche virus currently spreading in the Americas.

What is Oropouche?

Oropouche is a virus of the genus Orthobunyavirus. It differs from other better-known vector-borne viruses like dengue, Zika, yellow fever or chikungunya because it is typically transmitted to humans by a midge, Culicoides paraensis, rather than by mosquitoes. But we cannot rule out the possibility that other vectors might be involved. [The virus has been found in other insects, including the mosquito Culex quinquefasciatus.]

For how long has this virus been around?

It was discovered in 1955 in Trinidad and Tobago, in the Caribbean. In 1960, it was first detected in Brazil from a blood sample taken from a sloth. Since the 1960s, it has been identified in outbreaks in humans more or less intermittently in the Amazon region [a vast area that spans nine countries in South America]. That’s why we say it’s a re-emerging virus, because it has been circulating for many decades at least in the Amazon, which is considered an endemic region.

Why are we only hearing about it now? Is this the biggest outbreak we’ve seen?

When it comes to the Amazon region, it is difficult to say whether the current outbreak is larger than in previous decades. For the first time, a molecular surveillance diagnostic system is being implemented, something that didn’t exist in past epidemics.

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The geographic extension of the outbreak does represent a change. The number of municipalities and states affected is much higher. Additionally, the virus has spread outside the Amazon region. Again, we don’t know whether this is the first time because there was no surveillance of Oropouche outside the Amazon before.

What also raises concern is the finding of local transmission in Cuba for the first time. and imported cases in Europe and in the United States. As the Culicoides paraensis midge is found throughout the Americas, from the United States to Argentina, whenever there are infected people and there are vectors, there may be local transmission events. So, any infected individual can generate a local epidemic, that’s the main concern.

What are the symptoms?

The symptoms are similar to [those of] other arboviruses such as dengue: fever, headache, muscle or joint pain, pain behind the eyes, vomiting and nausea. So, it’s very difficult to diagnose an Oropouche infection only from symptoms, you really need to have a molecular laboratory diagnosis. A few cases may evolve into more severe forms, with neurological or hemorrhagic manifestations, but most cases are mild and resolve after seven or eight days.

Is the virus becoming more dangerous? Can it cause microcephaly, an abnormally small head, in babies?

For the first time, the presence of antibodies against Oropouche, indicative of a recent infection, was found in newborns with microcephaly. This suggests an association, but because of the study’s limitations, it wasn’t possible to establish a causal relationship between infection during intrauterine life and the neurological malformations.

Massive mosquito factory in Brazil aims to halt dengue

But it was possible to establish proof of mother-to-child transmission in cases of fetal and newborn death. In one case, a pregnant woman had symptoms of Oropouche and, weeks later, fetal death was confirmed. The Oropouche genome was detected in several organs of the fetus. In another recent case, a pregnant woman tested positive for Oropouche. The baby was born but died days later. Post-mortem examination identified the virus genome in various tissues, including the brain.

There were also two deaths of previously healthy young women who had symptoms similar to severe dengue. They were not pregnant. These were the first cases in the literature classified as deaths associated with Oropouche infection.

It is not yet possible to establish how frequently these fatal cases would be happening, either in adults or fetuses. So far, there is no evidence that the symptoms have changed compared with previous outbreaks.

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August 26, 2024
Birth of protein folds and functions in the virome

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Preparation of protein sequences

Protein sequences for eukaryotic viruses present in RefSeq⁵⁴ were collected through the NCBI Viruses portal (https://www.ncbi.nlm.nih.gov/labs/virus) in July 2022. GenPept files were downloaded for viruses that were annotated by NCBI to have an eukaryotic host. Because not all viruses have a host labelled by NCBI, GenPept files of human-infecting viruses annotated by ViralZone (https://viralzone.expasy.org/678) were also downloaded. Finally, proteins from all coronaviruses present in RefSeq, regardless of NCBI-labelled host, were downloaded.

Each GenPept file was processed such that polyproteins with defined ‘mature peptide’ fields produced separate protein sequences for each mature peptide. GenPept files without a mature peptide field were output as full amino acid sequences. These processing steps are present in the vpSAT github directory (https://github.com/jnoms/vpSAT) in the process_gbks.py file. Proteins larger than 1,500 residues, or in some cases 1,000 residues, were excluded. Only 1,706 proteins were excluded for this reason.

Structure prediction

MSAs were generated with MMseqs2 release version b0b8e85f3b8437c10a666e3ea35c78c0ad0d7ec2. To increase MSA generation speed, the RefSeq virus protein database (downloaded on 6 June 2022) was used as the target database for MSA generation. Structures were predicted with ColabFold¹⁵ (downloaded 22 June 2022). The majority of samples used three recycles, three models, stop_at_score=70, and stop_at_score_below=40. MMseqs2 and Colabfold_batch were run with a Nextflow⁵⁵ pipeline, and all parameters used can be found at https://github.com/jnoms/vpSAT. Information on all viruses and structures included in this manuscript is present in Supplementary Table 1.

Protein cluster generation

All proteins were initially clustered with MMseqs2, with a requirement of at least 20% sequence identity and 70% query and target coverage. MMseqs2 cluster mode 0 was used, meaning that many but not all pairs of aligned proteins are placed into the same sequence cluster. Predicted structures for each sequence cluster representative were subjected to an all-by-all alignment using Foldseek¹⁷, requiring the alignment to consist of at least 70% query and target coverage and an alignment E-value less than 0.001. The resultant structural alignment file was then filtered using SAT aln_filter to keep alignments with a TMscore of at least 0.4. Clusters were generated from this alignment file using SAT aln_cluster in a similar manner as Foldseek cluster mode 1, wherein all query-target pairs are assigned to the same cluster. Cluster information from sequence and structure clustering were merged using SAT aln_expand_clusters. Taxonomic counts information was generated using SAT aln_taxa_counts, producing a ‘tidy’ table for each cluster_ID with the number of members of each taxon at multiple taxonomy levels. Taxonomy information was also added directly to the merged cluster file using SAT aln_add_taxonomy.

Cluster purity analysis

To determine the structural consistency of the clusters, all clusters with at least 100 members were selected for analysis. DALI was used to align the cluster representative with each cluster member. Clusters whose members were on average smaller than 150 residues were excluded. This led to the analysis of 49 clusters. Cluster members that failed to align to their representative were assigned a z value of 0. For each cluster, the average z-score between the representative and each member was determined and plotted. All scripts used to run DALI can be found in vpSAT’s dali_format_inputs.sh and dali.sh files. Dalilite version 5 was used. DALI output files were parsed into a tabular format using SAT’s aln_parse_dali.

Phylogenetics

Phylogenetic reconstructions were conducted using all sequence cluster representatives, or in the cases of clusters 56 and 735, all members within each cluster. For the nucleoside transporter tree, all herpesvirus sequence representatives of cluster 119, as well as a F. catus gammaherpesvirus 1 protein (YP_009173937) from a singleton cluster, were used as queries. Iterative sequence similarity searches against the NCBI non-redundant database were performed using standalone PSI-BLAST v2.15.0, using the following parameters⁵⁶: -num_iterations 10, -max_hsps 1, -subject_besthit, -gapopen 9, -inclusion_ethresh 1e-15, -evalue 1e-10, and -qcov_hsp_perc 70. For the LigT-like PDE tree, this search was restricted to only viral targets. Each of these protein sets were then clustered by utilizing mmseqs2 v15.6f452 with high sensitivity (command line option: -s 7.5) to compress the amount of highly similar sequences into cluster representatives. Subsequently, these sequence sets were aligned using Clustal Omega v1.2.4 with default settings⁵⁷. Comprehensive taxonomic information for each aligned sequence was integrated into the unique sequence identifiers by utilizing the biopython v1.81 package⁵⁸. Phylogenetic trees were reconstructed using IQTREE v2.3.3⁵⁹ with -m TEST -B 1000 options for model testing and bootstrapping. The best model was selected for each tree based on Bayesian Information Criterion (BIC), and were as follows: Nucleoside transporters, VT + F + G4; LigTs, VT + F + G4; cluster 28, VT + G4; cluster 55, VT + I + G4; cluster 56, VT + G4; cluster 735, VT + I + G4. Trees were visualized with the Interactive Tree of Life (iTOL)⁶⁰. Code used for this analysis can be found at https://github.com/Doudna-lab/nomburg_j-LigT_phylogeny.

Structural alignments against the AlphaFold databases

In Fig. 1i, Foldseek was used to align a protein representative from every viral protein cluster against 2.3 million protein cluster representatives from the AlphaFold database³. For Fig. 3, all 67,715 viral protein structures were searched against the pre-made Foldseek databases of the original release of the AlphaFold database, consisting of proteins from 48 organisms and including members of the bacterial, eukaryote, and archaeal superkingdoms. For this search, the full AlphaFold database of over 200 M structures was not used because it contains many viral proteins misannotated as non-viral proteins (these misannotations reflect errors in Uniprot metadata). Alignments were filtered to keep only those with a minimum TMscore of 0.4 and an E-value of less than 0.001.

DALI alignments of specific non-viral proteins against the viral protein database

Following Foldseek alignments against the AlphaFold database, specific hits of interest (for example, ENT4) were selected. These structures were downloaded and imported to the DALI database format using vpSAT’s dali_format_inputs.sh. They were then aligned against the full viral protein structure database using vpSAT’s dali.sh, which lists all parameters. Dalilite version 5 was used. DALI output files were parsed into a tabular format using SAT’s aln_parse_dali.

Identification of annotated protein sequence clusters

Each protein in the database was searched against the Pfam²³, CDD²⁴, and TIGRFAM²⁵ databases using InterProScan²². A sequence cluster was considered annotated if more than 25% of members had any InterProScan alignment, and was considered unannotated if otherwise. Note that some proteins without an InterProScan alignment have existing annotations through other methods, including manual curation. Values of RMSD in Fig. 3 were calculated using DALI.

DALI alignments to identify shared domains

This analysis used the structure representatives from clusters with at least 2 members, resulting in 5,700 cluster representatives. Structures from these representatives were imported to the DALI database format using vpSAT’s dali_format_inputs.sh. To compare eukaryotic virus protein cluster representatives, an all-by-all alignment was conducted using vpSAT’s dali.sh, which lists all parameters.

Dalilite version 5 was used. DALI output files were parsed into a tabular format using SAT’s aln_parse_dali. All DALI alignments were filtered for an alignment length of at least 120, and for a z-score greater than or equal to (alignment length/10) − 4.

MSA generation using the full ColabFold MMseqs2 database

We selected the protein cluster representatives from the top 100 protein clusters by size, as well as 100 randomly selected singleton clusters, for analysis. ColabFold was used with FASTA inputs, such that MSAs were generated using the MMseqs2 ColabFold server (which maps each sequence against UniRef, BFD and Mgnify), and this MSA was used for structure prediction.

Benchmarking sequence and structure methods

For all protein clusters with at least two sequence clusters, we conducted all-by-all alignments between members using MMseqs2 (version b0b8e85f3b8437c10a666e3ea35c78c0ad0d7ec2), DIAMOND blastp⁶¹ (version 0.9.14), or jackhmmer⁶² (version 3.1b2). These alignments and subsequent clustering occur separately for each protein cluster. From these alignments, we conducted connected-component clustering using sat.py aln_cluster. Here, all proteins that align will be assigned to the same resultant cluster. Thus, each original protein cluster (determined through our approach, combining sequence alignment with MMseqs2 and structure alignment with Foldseek) now has a set of clusters identified through each of the sequence-only methods. We then measured, for each original protein cluster, how many clusters created by each of the sequence-only methods and how many proteins fall into the largest cluster generated by these sequence methods.

For benchmarking virus–non-virus alignments, we conducted sequence alignments (again using MMseqs2, DIAMOND blastp, and jackhmmer) analogous to the DALI structural alignments present in Extended Data Fig. 4, using the same query against all viral proteins included in the dataset. We then determined the fraction of DALI-identified targets were identified for each non-viral query and through each sequence method.

For the comparison between hhPred⁴³ and DALI, we identified 4,409 sequence clusters that contained more than 1 member and for which fewer than one-quarter of members had an InterProScan alignment. We then identified sequence cluster representatives that were well folded, with an average pLDDT of at least 70. This resulted in a final set of 1,326 proteins. We used DALI to align each of these proteins against the PDB25 database provided by the DALI authors. Alignments were considered high-confidence if they contained a z-score of at least 7. DALI alignments were conducted with vpSAT’s dali.sh. For hhPred searches, we established a local pipeline using HHsuite’s (v3.3.0) HHblits and HHsearch modules. For each query protein, we first used HHblits to align them against the Uniref30 HMM database provided by the HHsuite authors, using the flags -n 2 and -cov 20. We then used HHsearch to align each resultant MSA against the HHsuite-provided PDB database with the flag -cov 20. Alignments were considered high-confidence if they had an E-value of less than or equal to 0.001.

Searching the TCDB

We used a map of PDB accession to TCDB classification (https://www.tcdb.org/cgi-bin/projectv/public/pdb.py) to download all experimental structures associated with TCDB classifications. For subsequent processing, we used a maximum of five structures per TCDB classification. One structure was excluded (PDB: 1HXI) as it is highly truncated. Nine additional structures failed to import to DALI database files, typically due to small protein size. For PDB entries that contained multiple chains, we selected the first chain for alignment. Due to the absence of experimental structures, the AlphaFold models for ENT3 (AF-Q9BZD2-F1-model_v4) and ENT4 (AF-Q7RTT9-F1-model_v4) were added to the dataset. For the 46 protein structures with multiple classifications, one classification was chosen at random. This ultimately resulted in a dataset of 1,812 structures from 485 classifications, with an average of 3.7 structures per classification. Structures were imported to the DALI database format using vpSAT’s dali_format_inputs.sh. The predicted structure of EBV BMRF2 (YP_001129455) was aligned against this structure database using dali.sh.

PDE cloning and activity assays

Two tandem STREP2 tags, following a GGS linker, were appended to the end of each putative LigT-like PDE. Sequences were codon-optimized for humans, and gBlocks encoding each product were ordered from IDT and cloned into a custom lentiviral expression vector. PDE mutants have dual H>A mutations of the catalytic histidines (or, in the case of MHV NS2a and pigeonpox PDE, one H>A and one H>R mutation).

The 293T cells were seeded into 96-well plates at 20,000 cells per well. The 293T cells were kindly provided by the Ott laboratory, and were originally from ATCC. The 293T cells were screened for Mycoplasma within the last year, and were not otherwise authenticated. The day after plating, each well was transfected with 15 ng STING (pMSCV-hygro-STING R232, Addgene 102608), 20 ng firefly luciferase driven by an IFNB promoter (IFN-Beta_pGL3, Addgene 102597), 5 ng Renilla luciferase (pRL-TK, Promega E2241), and 20 ng of each putative PDE using the Mirus TransITX2 transfection reagent. After at least 4 h, cells were treated with 0.1 μM diABZI (Invivogen) or transfected with 10 μg ml⁻¹ 2′,3′-cGAMP (Invivogen) using TransITX2. The next day, firefly and Renilla luciferase were measured using the Promega Dual-Glo luciferase assay system. Three wells were transfected per condition, and experiments are representative of at least two independent experiments. The ‘no STING’ conditions were transfected with both reporters and a noncoding transgene, but no STING plasmid.

PDE western blots

The 293T cells were plated in 6-well dishes at 5 × 10⁵ cells in 2 ml per well. The next day, each well was transfected with 200 ng of the indicated transgene using Mirus TransITX2. The following day, cells were lysed using RIPA buffer (ThermoFisher) supplemented with protease/phosphatase inhibitor (ThermoFisher), and lysate protein concentrations were determined using the Pierce BCA assay kit. All samples were then normalized to the same protein concentration. Bio-Rad Criterion 4%–20% acrylamide gels were loaded with 30 µg of protein per well, followed by transfer to a 0.2-µm nitrocellulose membrane. For visualization of the Strep-tagged PDEs, the Streptactin HRP (IBA 2-1502-001IAB) antibody was used (1:100,000 dilution, 1 h at room temperature). For visualization of GAPDH, we used Santa Cruz Biotech Mouse anti GAPDH (sc-365062) primary (1:1,000 dilution, incubation at 4 °C overnight) and ECL Anti-mouse IgG (Amersham NXA931) secondary (1:5,000 dilution, 1 h at room temperature).

Recombinant protein expression and purification

Expression plasmids for pigeon poxvirus PDE (wild-type and H72 A/H167R), MHV nonstructural protein 2A (NS2A), and T4 anti-CBASS protein 1 (Acb1) were cloned into custom pET-based vectors by Gibson assembly to yield N-terminal His₁₀-MBP-TEV constructs. Proteins were expressed from 4 l Escherichia coli Rosetta 2 (DE3) pLysS by growing to an of OD₆₀₀ of 0.4–0.6 in 2× yeast extract tryptone medium at 37 °C and induced with 0.5 mM isopropyl β-d-1-thiogalactopyranoside. After induction, cells expressing each protein were grown overnight at 16 °C to an OD₆₀₀ of 1.2–1.4. Cells were collected by centrifugation for 20 min at 4,000 rpm at 4 °C and resuspended in 20 mM Tris-HCl, pH 8.0, 10 mM imidazole, 2 mM MgCl₂, 500 mM KCl, 10% glycerol, 0.5 mM TCEP and Roche protease inhibitor. Cells were lysed by sonication and cell lysate was clarified by centrifugation at 17,000g, 4 °C for 0.5 h. The supernatant was bound to 5 ml Nickel-NTA affinity resin for 1 h at 4 °C. Supernatant was discarded and resin was washed 5 × 30 ml wash buffer (20 mM Tris-HCl, pH 8.0, 500 mM KCl, 30 mM imidazole, 10% glycerol and 0.5 mM Tris(2-carboxyethhyl) phosphate). Protein was eluted in 10 ml elution buffer (20 mM Tris-HCl, pH 8.0, 500 mM KCl, 300 mM imidazole, 10% glycerol, and 0.5 mM Tris(2-carboxyethyl) phosphate). Each protein was concentrated to 10 mg ml⁻¹ during buffer exchange to storage buffer (20 mM Tris-HCl, pH 8.0, 500 mM KCl, 30 mM imidazole, 10% glycerol and 0.5 mM Tris(2-chloroethyl) phosphate) using a 10 kDa MWCO centrifugal filter (Amicon). A total of 5–15 mg target protein fused to N-terminal His₁₀–MBP–TEV was stored at −80 °C.

In vitro characterization of PDEs

Recombinant enzymes were assessed for PDE activity by in vitro cGAMP degradation reactions and downstream analysis by TLC. Reactions were initiated by the addition of recombinant enzyme (40 μM) in reaction buffer (50 mM Tris, pH 8.0, 10 mM MgCl_2, 100 mM NaCl) to 1.25 mM 2′,3′-cGAMP or 3′,3′-cGAMP (Biolog). The reaction mixture was incubated at 37 °C for 18 h and stopped by vortexing for 20 s.

Silica gel TLC plates (5 cm × 10 cm) with fluorescent indicator 254 nm were spotted with 2 μl in vitro enzymatic reaction. Separation was performed in an eluent of n-propanol/ammonium hydroxide/water (11:7:2 v/v/v). The plate was allowed to dry fully and visualized with a short-wave ultraviolet light source at 254 nm.

Data analysis and plotting

All analysis, plotting, and statistical tests used R version 4.0.3. The genome type and average genome size were determined from information downloaded from the NCBI Virus portal (https://www.ncbi.nlm.nih.gov/labs/virus/vssi/#/).

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

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August 26, 2024
First biolab in South America for studying world’s deadliest viruses is set to open

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Last month, Brazil celebrated breaking ground on what it hopes will become the first maximum-security biosciences laboratory in Latin America. Many researchers are excited at the prospect of a facility where they can safely study the most dangerous pathogens in the region. However, some wonder about the cost of maintaining such a lab and are concerned about the pushback they are sure to receive from members of the public over housing deadly organisms there.

The need for a biosafety-level-4 (BSL-4) laboratory in Brazil is unquestionable, says Flávio Fonseca, a virologist at the Federal University of Minas Gerais in Belo Horizonte, Brazil. “We have seen the number of epidemic, even pandemic, outbreaks increase in the last 100 years,” he says. When an outbreak happens, researchers want to be able to work safely with the live virus to understand it and to develop vaccines and treatments.

“We’re sitting on a powder keg” in terms of pathogens that might emerge in Latin America, says Fernando Spilki, a veterinary virologist at Feevale University in Novo Hamburgo, Brazil, agreeing that such a facility is necessary. In particular, humans are clearing more and more of the Amazon rainforest for agriculture and other uses, and so are frequently coming into contact with animals that can harbour previously unknown viruses. And climate change is driving some species out of remote locales and into more populated areas. “We need a laboratory like this so we can give quick responses” to these challenges, Spilki says.

A first for Latin America

The lab, dubbed Orion, is being constructed at the Brazilian Center for Research in Energy and Materials (CNPEM) in Campinas, about 100 kilometres northwest of São Paulo, and is scheduled to be complete by 2026 and operational by 2028. It will also host lower-level biosafety labs, including BSL-2 and BSL-3 facilities.

BSL-4 labs are the most secure of the bunch. In these facilities, isolated from the others, researchers work with pathogens that can be transmitted through the air, that are deadly and for which there are no vaccines or treatments. Scientists must shower and change clothes before entering and leaving; while they are in the labs, they wear specially designed suits connected to a separate air supply.

Brazilian President Luiz Inácio Lula da Silva (centre, in grey jacket) joined CNPEM staff members on 4 July to dedicate the first stone for Orion.Credit: Igor Do Vale/ZUMA via Alamy

According to a report last year by the Global BioLabs initiative, run by researchers at George Mason University in Fairfax, Virginia, and King’s College London, there are 51 BSL-4 labs in operation around the world. Around 70% are in Canada, Europe or the United States. Another 18 are in planning or under construction, including Orion, which is the only one in Latin America.

Having a BSL-4 lab in Brazil could mean more autonomy for the country’s science, Fonseca says, allowing researchers to study local pathogens and develop treatments domestically, rather than travelling to labs elsewhere to do research and then queuing to receive diagnostic tests and vaccines. Five haemorrhagic-fever-causing arenaviruses — which can be studied only in a BSL-4 lab — have been detected in South America. In particular, Sabiá virus was first reported in São Paulo.

Challenges ahead

Once construction on Orion is complete, it will be the first BSL-4 facility in the world equipped with a synchrotron: a particle accelerator that produces high-powered radiation for imaging. Scientists will be able to use three X-ray beamlines derived from the CNPEM campus’s existing synchrotron, Sirius, to reveal the structures of pathogens and the dynamics of how they infect cells, tissues and small organisms.

COVID prompts global surge in labs that handle dangerous pathogens

Connecting the beamlines to a maximum-containment laboratory will, however, be a challenge, says Harry Westfahl, director of the Sirius facility. The beam hardware will need regular calibration and maintenance, so will have to be outside the BSL-4 part of the lab. But “we found a solution”, he says. The beams will pass through an optically transparent recess in a wall separating the synchrotron from the max-security lab. The hardest part, Westfahl says, has been designing that recess so that it is an effective barrier, can stand up to the disinfection required in the BSL-4 facility and is of sufficient optical quality to minimize interference with the precision of the incoming beams.

Another challenge for Orion will be training staff members to work in a type of facility that is new for the region. The facility must also develop a regulatory framework to ensure that risky experiments have oversight from a governing panel, and must install security measures to prevent unauthorized access by people or organizations that might intentionally release pathogens, says Gregory Koblentz, a biodefence specialist at George Mason University and a co-author of the 2023 Global BioLabs report.

Tatiana Ometto, the CNPEM’s high-containment biosafety specialist, acknowledges that Brazil doesn’t yet have an oversight mechanism for BSL-4 experiments. “But with Orion, discussions are taking place,” she says. “The Ministry of Health has created a working group to follow, monitor, assess and propose directives for the lab’s development.”

Concerns about proper biosafety and security at such labs have become heightened since the start of the COVID-19 pandemic. The first cases of infection with the coronavirus SARS-CoV-2 were spotted in Wuhan, China, where researchers at the Wuhan Institute of Virology were studying coronaviruses gathered from bats. Although much scientific evidence points to SARS-CoV-2 being passed from a wild animal to humans, some scientists say that an accidental leak from a lab can’t be ruled out.

Biosecurity concerns are important at all BSL-4 labs globally, not just in Brazil, says Juliette Morgan, South America regional director for the US Centers for Disease Control and Prevention, who is based in Brasília. She points out that the CNPEM team has “a very clear understanding of the implications of a BSL-4” lab and has been seeking advice to fill any gaps.

Lab maintenance

The cost of the lab has also been a point of concern. The Brazilian government is investing $1 billion reais (about US$180 million) into Orion’s construction.

“There’s no doubt about the need for a laboratory of this kind in Brazil,” says Odir Dellagostin, president of the Brazilian National Council for State Funding Agencies. “But we lack the funds for other very important research” projects, he adds. In particular, he says, maintaining the facility will be very expensive. In 2022, Thomas Ksiazek, head of high-containment operations at Galveston National Laboratory, a BSL-4 facility in Texas, told Nature that his lab required almost US$12 million a year for maintenance and operations — $2 million of which was spent on 24-hour security.

CNPEM director Antônio José Roque da Silva says that Orion is less expensive to build than other BSL-4 facilities. “The average cost of a lab like this in the United States is about a billion dollars,” he says. “We’re using one-fifth of that to build one that will allow greater research autonomy.” He does admit, however, that maintenance will be a burden. CNPEM, he adds, is seeking funds from other ministries and sources now to “build a resilient system”.

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August 21, 2024
Hopes dashed for drug aimed at monkeypox strain spreading in Africa

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Tecovirimat, an antiviral drug, has been used to treat mpox.Credit: Elijah Nouvelage/Bloomberg/Getty

The drug tecovirimat did not accelerate healing for people in a clinical trial in the Democratic Republic of the Congo (DRC) who were infected with a concerning strain of the monkeypox virus, according to the US National Institutes of Health (NIH). The strain, called clade I, has been spreading across Africa and is thought to be more lethal than the one that caused a global mpox outbreak that began in 2022, known as clade II.

Growing mpox outbreak prompts WHO to declare global health emergency

Tecovirimat, an antiviral, is commonly used to treat mpox, despite limited clinical evidence that it resolves symptoms. The drug was originally developed to treat smallpox, which is caused by a related orthopoxvirus.

“These are certainly not the ideal results that we were all hoping for,” says Jason Kindrachuck, a virologist at the University of Manitoba in Winnipeg, Canada.

Clade I’s spread in the DRC and other countries in Africa prompted the World Health Organization (WHO) to declare a public health emergency of international concern on 14 August — its highest level of alarm. A day earlier, the Africa Centres for Disease Control and Prevention (Africa CDC) declared its first-ever public-health emergency over the outbreak.

And yesterday, Sweden reported its first case of a person infected with a variant of clade I, called clade Ib, that scientists reported in April as being able to spread among people through sexual contact. Prior to last year, clade I was thought to transmit through household contact and through contact with infected wild animals.

Disappointing results

During the trial, launched by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the DRC’s National Institute of Biomedical Research, people infected with clade I were given either tecovirimat or a placebo pill. According to the NIH, which announced early results on 15 August, the antiviral did not reduce the duration of mpox symptoms compared with placebo.

Can a smallpox drug treat monkeypox? Here’s what scientists know

Mpox, the disease caused by the monkeypox virus, can cause fluid-filled lesions, fever, headache and, in severe cases, death.

Significantly, however, the study participants’ mortality rate, regardless of whether they received tecovirimat or placebo, was lower than the overall mortality rate for any type of mpox typically reported in the DRC: 1.7% versus 3.6%.

This could be because of the care that the participants received during the trial. The 597 people enroled in the trial were hospitalized for at least 14 days, a period in which they received, among other things, nutritional support; proper hydration; treatment of any other infections or diseases they might have, including malaria; and psychosocial support.

“The level of care was very high,” says Lori Dodd, a biostatistician at NIAID in Bethesda, Maryland, and the project leader for the trial. Maintaining that high quality of care outside of a clinical trial could be challenging, she adds, “so the team will be working on how to translate that care model for people with mpox who are recovering on an outpatient basis and in resource-limited settings”.

Hope for specific groups

The maker of tecovirimat, New York City-based SIGA Technologies, suggested in a press release that trial participants who received early treatment with the drug and those with severe disease had a “meaningful improvement”. But the full data have not been released. They are being analysed, and a manuscript is being prepared for submission to a peer-reviewed journal, Dodd says.

“We are all eager to see the paper, in particular to see if there is any group that could be selectively targeted for treatment, especially people with HIV”, says Piero Olliaro, an infectious-disease specialist at the University of Oxford, UK, adding that outcomes for people with advanced HIV and who get infected with the monkeypox virus tend to be worse¹.

Monkeypox virus: dangerous strain gains ability to spread through sex, new data suggest

It’s not yet clear whether the trial results can be extrapolated to clade Ib. “We don’t know a lot about clade Ib for the time being, and we need more investigations into the clinical presentation and outcomes to inform whether new clinical trials are required,” Olliaro says.

Although these preliminary results for tecovirimat are disappointing, Kindrachuck says, they do point to the fact that “if we get resources into the DRC and beyond for support for patients with clade I mpox, we can actually increase recovery”.

Nicaise Ndembi, a virologist at Africa CDC who is based in Addis Ababa, says that the results do not change the response plan to the current outbreaks, which includes enhancing surveillance, increasing laboratory testing, strategically distributing the limited vaccine doses available and negotiating the acquisition of additional doses. But he says that they highlight the fact that appropriate standard-of-care is crucial to reduce mortality related to mpox.

Although a vaccine against mpox, made by biotechnology firm Bavarian Nordic in Hellerup, Denmark, exists, it is still largely unavailable in African countries. Bavarian’s chief executive Paul Chaplin, however, reported to STAT News that the European Union has placed an order for 175,000 doses to be donated to Africa CDC.

With additional reporting from Max Kozlov.

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August 16, 2024
Huge amounts of bird-flu virus found in raw milk of infected cows

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The H5N1 virus can persist for hours in spattered droplets of milk from infected cows. Credit: Juancho Torres/Anadolu Agency/Getty

Milk from cows infected with bird flu contains astronomical numbers of viral particles, which can survive for hours in splattered milk, new data shows¹^,². The research adds to growing evidence that the act of milking has probably been driving viral transmission among cows, other animals and potentially humans.

That’s a better scenario for public health than transmission through airborne particles, which would be more difficult to contain. “It’s good news it’s probably spreading by the milking process,” says Martin Beer, a virologist at the Federal Research Institute for Animal Health in Greifswald, Germany. This means that changes to milking procedures could help to bring the outbreak under control and prevent human infections.

A virus that’s going places

Since it was first isolated in 1996³, the highly pathogenic bird-flu virus H5N1 has caused outbreaks in domestic and wild birds around the world, and it has occasionally infected mammals such as seals and foxes. On 25 March, US health officials announced that H5N1 had been detected in dairy cows for the first time. As of 5 June, infections have been confirmed in more than 80 dairy herds in nine states and in three dairy farm workers, all of whom had mild symptoms.

Scientists had not previously suspected that cattle could easily become infected with bird flu, because the animals were thought to lack the receptor allowing the virus to enter their cells. But reports of sick cattle with inflamed udders raised suspicions that the virus can infect the animals’ mammary glands.

New studies⁴^,⁵ support this idea, showing that cells lining cows’ milk glands have abundant receptors for H5N1 and that this bird-flu strain proliferates in these cells rather than in the respiratory tract, which influenza viruses usually infect. “The mammary glands seem to be the main target of viral replication,” says Diego Diel, a virologist at Cornell University in Ithaca, New York, who co-authored one of the studies. But some infected cows also experience mild respiratory symptoms, Diel and his colleagues report.

The studies were posted on the preprint server bioRxiv and have not yet been peer reviewed.

Viral milkshake

Diel and his colleagues examined the milk of cows with H5N1 and found astonishing amounts of virus: some samples contained hundreds of millions of infectious particles, a level “that is higher than we can grow in the lab” for experiments, says Seema Lakdawala, an influenza virologist at Emory University School of Medicine in Atlanta, Georgia. “In ideal conditions, we don’t get that — this is crazy high.”

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This abundance could help to explain why H5N1 viral fragments have been found in one in five retail milk samples⁶: a small number of infected cows could taint the milk supply with many particles. (Pasteurization inactivates H5N1 in milk, according to a preprint⁷ posted last week.)

Beer sees opportunity in the sky-high numbers of infectious virus particles in milk. It means that testing milk pooled from all of a farm’s cows is likely to reveal the presence of even a few infected ones, and this is easier than testing individual animals. Pooled testing could inform workers on when to be on the lookout for sick animals, which could then be isolated.

Spilt milk

The findings suggest that minimizing exposure to raw milk could be an important way to prevent transmission. But the enormous scale of US milking operations means that stopping the spread will be complicated, says Juergen Richt, a veterinary virologist at Kansas State University in Manhattan.

To begin with, the same milking equipment is used on many cows, offering the virus ample opportunity to spread. And milking is messy. Milk often spills onto the floor, and when equipment that suctions to cows’ udders is released, the liquid sprays out in every direction. This endangers dairy workers, Lakdawala adds. “That isn’t normally a big deal for people who work there — they’re used to it — but that means they’re bombarded with virus.”

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Data collected by Lakdawala and her colleagues support her worries: infectious virus can persist in milk droplets and on milking machines for hours, they found. On the basis of these data, she urges farms to consider disinfecting equipment between uses, installing proper ventilation and offering protective equipment, such as face shields, to farm workers to prevent further spread.

To complicate matters, lactating cows — infected or not — must be milked regularly to avoid serious injury to the animal. That means that dairy farms, which typically send raw milk to large-scale facilities for processing, need money and equipment to inactivate the virus in milk from infected cows. Otherwise, it might be dumped it in a place where other animals, such as farm cats, could encounter it, Lakdawala says.

Richt and his colleagues are collecting data to determine whether non-lactating cows and male cattle are also susceptible to the virus, but for now, he says that focusing on milking can help to control the outbreak.

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June 5, 2024