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Tag: SARS-CoV-2

  • What causes long COVID? Case builds for rogue antibodies

    What causes long COVID? Case builds for rogue antibodies

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    Computer model of the secondary structure of immunoglobulin G (IgG) which takes on an equal length Y shape.

    IgG antibodies (artist rendering shown here) taken from people with long COVID and injected into mice give the animals symptoms such as increased pain sensitivity and reduced motor function.Credit: Kateryna Kon/Science Photo Library

    Antibodies isolated from people with long COVID increase pain sensitivity and reduce movement in mice when transferred to the animals, research shows1. The findings suggest that antibodies might drive some symptoms of long COVID — although how that process works is unclear, and the results will need to be replicated in larger studies.

    “I think this will be a beacon of a paper that we can take forwards to further understand long COVID,” says Resia Pretorius, an immunologist at Stellenbosch University in South Africa.

    Previous research has hinted that long COVID might be caused, at least in part, by autoantibodies — rogue antibodies that a person generates that attack their own immune system or tissues. But one big question remained: “Is it really causal?” says Jeroen den Dunnen, an infectious-disease researcher at the Amsterdam University Medical Center. In other words, do autoantibodies cause long COVID symptoms, or are they simply generated in response to a long COVID infection? Along with his colleagues, den Dunnen undertook the latest study to get an answer.

    Complex picture

    Scientists estimate that around 10–20% of people who are infected with the SARS-CoV-2 coronavirus will develop long COVID — a severe condition whose symptoms, including intense fatigue, debilitating brain fog and chronic pain, persist for at least three months after the initial infection. The condition affects at least 65 million people worldwide, but researchers still have little understanding of its causes, and there are no proven treatments.

    Long COVID still has no cure — so these patients are turning to research

    Some studies suggest that long COVID might be caused by persistence of SARS-CoV-2 in the body2. Others indicate that it could arise from tiny blood clots that block blood vessels and limit oxygen exchange in a person’s body3. And then there is the autoantibody hypothesis.

    To explore that mechanism, den Dunnen and his co-workers collected IgG antibodies — the most common type of antibody in human bodily fluids — from blood taken from 34 people. Participants were 43 years old, on average, and developed long COVID after having mild SARS-CoV-2 infections during the first two years of the pandemic. Most participants in the study, which was posted last month ahead of peer review to the preprint server bioRxiv1, experienced fatigue and chronic pain and had to take time off work owing to their condition.

    The researchers assigned the participants to groups on the basis of the concentrations of various inflammatory proteins in their blood, and pooled antibodies from members of each group. They then injected each mouse with one of the pools.

    The various antibody groups had distinct effects on pain perception and motor activity in the mice, says co-author Niels Eijkelkamp, an immunologist at the University Medical Center Utrecht in the Netherlands.

    Long-COVID treatments: why the world is still waiting

    The researchers discovered that mice injected with antibodies from two groups of people with long COVID were more sensitive to being pricked on the paw than were mice injected with antibodies from people who had fully recovered from mild COVID-19. There were no changes in motor function between these two groups and the control group, however.

    But when given antibodies from a third group of people with long COVID, mice walking for half an hour covered 40% less distance, on average, than did animals in the control group. And this group of animals had no change in pain sensitivity compared with control animals. This suggests that antibodies from people with long COVID can trigger a range of symptoms in mice, Eijkelkamp says. He and his colleagues think that the antibodies might cause such effects by attacking healthy tissue.

    Beacon of hope

    This study is really picking up “the mood music in long COVID research”, says Peter Openshaw, a physician and immunologist at Imperial College London, because it is adding to a growing body of evidence that autoimmunity factors into the disease. But it is based on “a relatively small number” of participants and therefore needs to be reproduced independently, he adds.

    That seems to have already happened, at least on a small scale. In a webinar hosted last month by Solve M.E., a non-profit organization based in Glendale, California, that supports long COVID research, David Putrino, a physiotherapist at the Icahn School of Medicine at Mount Sinai in New York City, discussed the results of a similar study, in which researchers injected mice with IgG antibodies from people with long COVID. These mice had increased pain sensitivity compared with those injected with antibodies from healthy people. “It’s great to see that it’s reproducible,” den Dunnen says.

    Rogue antibodies could be driving severe COVID-19

    If the findings hold, clinicians might want to consider excluding individuals with long COVID from making blood donations, says Davide Robbiani, an immunologist at the Institute for Research in Biomedicine in Bellinzona, Switzerland.

    But the results might also present a new animal model for studying long COVID, says Pretorius, who is now collaborating with den Dunnen and Eijkelkamp to investigate the role of microclots in the disease.

    Danny Altmann, an immunologist at Imperial College London, is more sceptical. “Things like long COVID are really, really hard to reiterate in animal models,” he says, and it is unclear how well the symptoms observed in mice really reflect what’s going on in humans. “We’ve invested almost zero in building up those models,” he says, owing to a lack of government interest and “policymaker fatigue” in funding long COVID research. So even “if this study catalyses debate about the vacuum of small-animal models that are really holding back the field, I think it’s helpful”, he adds.

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  • Anthony Fauci denies cover-up of COVID origins during tense hearing

    Anthony Fauci denies cover-up of COVID origins during tense hearing

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    Anthony Fauci, former Director of the National Institute of Allergy and Infectious Diseases, testifies before a congressional committee in the U.S.

    Anthony Fauci, who was US President Joe Biden’s chief medical adviser until December 2022, testified before a panel exploring the origins of the COVID-19 pandemic on 3 June.Credit: Chip Somodevilla/Getty

    Capitol Hill, Washington DC

    Anthony Fauci, the former head of the US National Institute of Allergy and Infectious Diseases (NIAID), emphatically fended off allegations at a Republican-led hearing in Washington DC today that his agency funded research that created the COVID-19 pandemic or that he coordinated a cover-up of the pandemic’s origins, calling the claims “simply preposterous”.

    Fauci responds to Musk’s Twitter attack and rates world’s COVID response

    The 3 June session was one of the most anticipated hearings hosted by the US House of Representatives Select Subcommittee on the Coronavirus Pandemic. The subcommittee has held 27 hearings or briefings over the past 15 months to examine the federal government’s response to the pandemic and to uncover the origins of the SARS-CoV-2 coronavirus.

    As has been the case in most of the hearings, Fauci’s questioning reflected a deep political divide in the US government. Republicans criticized Fauci’s oversight of NIAID-funded research grants and of his staff members, and Democrats sang the praises of the former chief medical adviser to US President Joe Biden, commending him on a distinguished career that has saved lives through his work advancing research on AIDS and developing COVID-19 vaccines.

    Peter Hotez, a vaccine scientist at Baylor College of Medicine in Houston, Texas, told Nature that the hearing was a Republican “attempt at revisionist history” to ignore the policy failures of the administration of former US president Donald Trump early during the pandemic and to “blame the scientists”. Offering another perspective, Roger Pielke Jr, a science-policy researcher at the University of Colorado Boulder, said that the hearing was “substantively frustrating” at times when Fauci, a seasoned public speaker, chose his words carefully and tried to distance himself from people who had been implicated in wrongdoing by the subcommittee’s investigation.

    Allegations of cover-up

    Fauci, who stepped down from his role at NIAID in December 2022 after almost 40 years leading the agency, was the face of the US pandemic response during both the Trump and Biden administrations.

    Some critics have accused Fauci of suppressing the idea early during the pandemic that China might have either accidentally or intentionally released SARS-CoV-2 from a laboratory in Wuhan, the city where the first cases of COVID-19 were detected. Some have alleged that Fauci, along with Francis Collins, former director of the National Institutes of Health (NIH) — of which NIAID is a part — encouraged a group of virologists to publish an article in Nature Medicine1 concluding that a lab-leak scenario was not plausible. (Nature is editorially independent of Nature Medicine, and Nature’s news team is independent of its journals team.)

    US COVID-origins hearing puts scientific journals in the hot seat

    These critics also say that Fauci and Collins were motivated to suppress the lab-leak theory because NIAID had awarded a research grant before the pandemic to New York City-based nonprofit organization EcoHealth Alliance, which had been partnering with the Wuhan Institute of Virology (WIV) to study coronaviruses in bats. They have raised the possibility that the WIV used NIAID resources to conduct research that could have spawned SARS-CoV-2. Fauci responded at the hearing that the available genetic data indicate that the viruses investigated at the WIV “could not be the precursor to SARS-CoV-2”.

    Most virologists say that although a lab-leak origin is possible, the preponderance of scientific evidence points to a zoonotic origin for the COVID-19 pandemic, meaning that the virus spread to humans from wild animals. At the hearing, Fauci said he has always been open to both origin hypotheses, pointing to a February 2020 e-mail to a prominent virologist who was alarmed that SARS-CoV-2 could have leaked from a lab. In the correspondence, Fauci told the scientist to report his concerns to intelligence officials “very quickly” if they were substantiated. “It is inconceivable that anyone who reads this e-mail could conclude that I was trying to cover up the possibility of a laboratory leak,” he testified.

    Raul Ruiz, a Democratic representative from California and ranking member of the subcommittee, said at the hearing that House Republicans have used the guise of investigating the pandemic’s origins to “weaponize concerns about a lab-related origin to fuel sentiment against our nation’s scientists”.

    Heated exchanges

    Fauci, who led NIAID during seven presidential administrations, starting with Ronald Reagan in 1984, is no stranger to controversy. In the 1980s, AIDS activists were highly critical of him because they felt that NIAID’s clinical trials for HIV drugs were moving so slowly that people were dying unnecessarily. Early in the pandemic, while Trump was in office, Fauci drew the president’s ire and was sometimes sidelined, stemming from Trump’s desire to quickly re-open businesses and his reluctance to promote public-health measures such as masking and social distancing.

    During previous hearings, the subcommittee has taken aim at others in Fauci’s sphere. At a 1 May session, Peter Daszak, the head of EcoHealth, was lambasted by both Democrats and Republicans for improperly managing the grant that the non-profit group shared with the WIV to study coronaviruses. In the weeks following that tense session, the US Department of Health and Human Services suspended federal funding to EcoHealth and to Daszak personally, suggesting it would also consider debarring both — a more serious halting of financial support that generally lasts up to three years.

    David Morens is sworn in during a Congressional hearing regarding the Coronavirus Pandemic on Capitol Hill in Washington, DC, U.S. in 2024.

    David Morens, once Fauci’s senior adviser, was grilled before the same House subcommittee on 23 May over his use of personal e-mail to correspond with researchers about a controversial grant awarded by NIAID.Credit: Andrew Harnik/Getty

    The panel grilled David Morens, a top adviser to Fauci during the pandemic, on 23 May over his communications with Daszak and his use of personal e-mail for official work, in an apparent attempt to evade public-records requests. Morens is now on administrative leave from the NIH. At today’s hearing, Fauci distanced himself from Morens, adding that his former adviser’s actions were against policy and inappropriate, and that they had worked in separate buildings.

    ‘He has saved countless lives’: US scientists on Fauci leaving NIH role

    Republicans also ripped into Fauci’s promotion of masking, vaccination and social distancing during the pandemic. Fauci “oversaw one of the most invasive regimes of domestic policy the US has ever seen”, said Brad Wenstrup, a Republican representative from Ohio and chairman of the subcommittee. Fauci countered that although in hindsight some measures might not have been as necessary as others, public-health officials had to make decisions with limited data at the outset of the pandemic, and that other agencies such as the US Centers for Disease Control and Prevention were responsible for implementing these policies.

    In a heated exchange during the hearing, Marjorie Taylor Greene, a far-right Republican representative from Georgia, made a point of refusing to call the infectious-diseases expert “Dr. Fauci”, instead opting for “Mr. Fauci”. Her suggestion that he didn’t deserve the title of doctor drew rebuke from Democrats on the committee. “We should be writing a criminal referral because you should be prosecuted for crimes against humanity,” she told Fauci. “You belong in prison.”

    By the end of 2024, the subcommittee will release a final report with its findings and recommendations from its two-year investigation. But Pielke Jr says he struggles to see how the subcommittee’s work will advance policy to help the country prepare for the next pandemic, given the intense partisanship shown at the hearings. Instead, he wishes the hearing focused more on how to convene independent scientific advisory boards — free from political influence — to help inform public-health decisions such as mandates and investigate pathogen origins. “What legislation is going to emerge from this series of hearings?” he asks. “It’d be hard to put my finger on anything tangible.”

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  • Hope for global pandemic treaty rises — despite missed deadline

    Hope for global pandemic treaty rises — despite missed deadline

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    Dr Tedros Adhanom Ghebreyesus speaks to a crowd of people at a Closing Plenary meeting

    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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  • A global pandemic treaty is in sight: don’t scupper it

    A global pandemic treaty is in sight: don’t scupper it

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    People in masks crossing street in Singapore while social distancing during covid-19 times.

    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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  • US halts funding to controversial virus-hunting group: what researchers think

    US halts funding to controversial virus-hunting group: what researchers think

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    Peter Daszak with papers at a desk in front of the House Select Subcommittee regarding the Coronavirus Pandemic.

    EcoHealth Alliance president Peter Daszak testified before a congressional panel on 1 May, two weeks before the US government suspended the organization’s federal funding.Credit: Andrew Harnik/Getty

    The US Department of Health and Human Services (HHS) has suspended federal funding for EcoHealth Alliance, a New York City-based nonprofit organization that came under scrutiny during the COVID-19 pandemic for collaborating with a virology laboratory in China accused of potentially leaking the SARS-CoV-2 coronavirus. Researchers who spoke to Nature are divided in their reaction to the decision: some think that the HHS made the right call given EcoHealth’s apparent failure to comply with terms of a grant it was awarded, undermining public trust; others say that the decision seems to be unfairly wrapped up in politics.

    The shifting sands of ‘gain-of-function’ research

    In a memo detailing the decision, Henrietta Brisbon, the HHS’s suspension and debarment official, argued that EcoHealth did not provide adequate oversight of research activities at the Wuhan Institute of Virology (WIV), in China. The WIV was a subrecipient on a federal grant awarded to EcoHealth by the National Institutes of Health (NIH), meaning that it was a partner given funds to carry out some of the research. The document also describes how EcoHealth repeatedly failed to provide information pertaining to the research conducted under the grant that was requested by the NIH.

    The decision by the HHS comes two weeks after EcoHealth’s president, infectious-disease specialist Peter Daszak, was grilled during a hearing run by a US House of Representatives subcommittee investigating the origins of the COVID-19 pandemic. During that session, Republican representatives suggested that EcoHealth had conducted risky research with the WIV and Democrats criticized the nonprofit’s lack of transparency.

    In announcing the latest suspension of funding to EcoHealth, the HHS also proposed debarring the organization from federal funding — a more definitive halting of grant money for a period generally of up to 3 years. Debarments of grantees are usually reserved for serious violations: according to a 2022 report, the HHS issued 134 debarments between 2015 and 2019, most of them owing to a criminal conviction or civil judgment.

    In a statement, an EcoHealth spokesperson said that the organization is disappointed by the HHS’s decision and will be contesting the proposed debarment. “We hope we will get a fair chance to present the volumes of evidence we have that all of these allegations are false, and that they do not rise to the level of something that should lead to an organization being debarred in this way,” Daszak told Nature.

    Controversial virus-hunting scientist skewered at US COVID-origins hearing

    It is important for research organizations to demonstrate that they have a robust oversight system, says social scientist Filippa Lentzos, a specialist in biosecurity at King’s College London, “even more so when we’re talking about research with pandemic risks, where potentially the entire world could be affected by an accident”. She adds that the decision to suspend funding seems appropriate: “Whatever the particulars of the EcoHealth Alliance case, it is clear the institution has lost the confidence of the HHS, politicians on both sides of the aisle and many other stakeholders to act safely, securely and responsibly.”

    EcoHealth could have done a better job of explaining its work to the NIH and to the public, acknowledges Lawrence Gostin, a health-law and policy specialist at Georgetown University in Washington DC. But, in his view, the suspension has a strong political bent to it. “It’s not clear to me at all whether this decision was based on science, ethics or politics,” he says. “There’s been this drumbeat of criticism of EcoHealth Alliance, particularly from congressional Republicans, and there’s been this myth that the WIV was responsible for the pandemic, but all of the evidence points in the opposite direction,” to a natural spillover of SARS-CoV-2 from wild animals to humans, he adds.

    Two-year delay

    EcoHealth had been collaborating with scientists in China to study pathogens with pandemic potential for years when, in 2014, it received a grant from the NIH to investigate bat coronaviruses. The NIH would eventually suspend this grant in April 2020, in the early months of the pandemic. This came at a time when then-president Donald Trump had been publicly implying that China might be responsible for the pandemic. The funding was reinstated in May 2023 under extensive restrictions, and the WIV was debarred from receiving US funding through subawards later that year.

    NIH to intensify scrutiny of foreign grant recipients in wake of COVID origins debate

    The current suspension was motivated by the alleged lack of compliance with the 2014 grant’s terms and conditions. One key problem listed by the HHS is EcoHealth’s submission of a grant progress report more than two years past the deadline. The HHS said that this report contains information suggesting that an experiment conducted by the WIV possibly led to enhanced growth of a modified virus beyond a replication limit set by the NIH. EcoHealth and the WIV were modifying a coronavirus linked to Middle East respiratory syndrome (MERS), to study the potential origins of this type of virus in bats. When reviewing progress on the grant, the NIH told EcoHealth that if any virus generated under the grant showed evidence of replication beyond the set threshold, the nonprofit should ensure that all experiments were halted and communicate the issue to the agency, which was not done. This led the HHS to conclude that the research “likely violated protocols of the NIH regarding biosafety”.

    An EcoHealth spokesperson said that it is untrue that the nonprofit violated the terms of the grant, given that the experiments did not rise to a level that would be considered significant enough to report as unusual. Regarding the delay in submitting the report, the spokesperson said that EcoHealth made every effort to file the report on time, “but these were stymied by contradictory advice from NIH grant management officials, and an online system [for submitting the report] that is confusing and error-prone, leading to multiple instances where the system locked us out.”

    The HHS memo says that, according to a forensic audit performed by the NIH, EcoHealth was never locked out of the system.

    Federal auditors have cited the NIH for its part in not pursuing the late report and recommended that the agency intensify its monitoring of foreign institutions that receive NIH funds.

    Responding to the HHS’s allegation that EcoHealth failed to adequately respond to the NIH’s requests for information and materials related to the WIV’s research, the spokesperson said that, considering the geopolitical pressure on US–China relations during the pandemic, and that the HHS, the World Health Organization (WHO) and the intelligence community were all unable to get evidentiary information out of the WIV, “it is outrageous to propose this as grounds to debar our organization”. (The WHO organized an initial investigation into the origins of the COVID-19 pandemic in China, but further efforts were stymied by that country’s lack of cooperation.)

    Questions of oversight

    Amesh Adalja, an infectious-disease specialist at the Johns Hopkins Center for Health Security in Baltimore, Maryland, says that any grant recipient is expected to comply with a series of conditions — which include submitting reports in a timely fashion and overseeing partner institutions — and that the HHS memo seems to indicate that EcoHealth did not fully meet those standards. “There’s enough listed there to call into question what type of stewardship was going on with that taxpayer money,” he says.

    NIH reinstates grant for controversial coronavirus research

    EcoHealth Alliance has played an important role in illuminating scientists’ understanding of novel viruses, Gostin says. In addition to work on coronavirus surveillance in wildlife, the group has studied the spillover of Nipah virus and other pathogens to humans. He worries that the suspension could disincentivize research aimed at pandemic preparedness and prevention done in partnership with other countries. The next pandemic could easily arise in a country that trades wild animals, like China, so the type of research and surveillance that EcoHealth does is important, he says. The decision sends “a chilling signal to any future researcher that might want to better understand zoonotic viruses in the Chinese region”, he adds.

    Before the suspension, EcoHealth had three active NIH-funded grants aiming to study the risk of emerging viruses in countries such as Bangladesh, Myanmar and Vietnam. Since 2008, the organization has been awarded a total of US$90.3 million in federal funding, $19.59 million of which was from the HHS.

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  • Computationally restoring the potency of a clinical antibody against Omicron

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    Antibody and antigen production

    We experimentally validated the 376 designed candidates. To leverage available resources at multiple experimental sites, we split candidates into partially overlapping sets 1 and 2. Set 1 consisted of 230 designs expressed as IgG in HEK-293 cells (ATUM), and set 2 consisted of 204 designs expressed as IgG via a pVVC-mCisK_hG1 vector (Twist BioScience) in transiently transfected CHO cells. Omicron antigens were produced in Expi293F cells (Thermo Fisher Scientific) and purified on HisTrap Excel columns (Cytiva).

    In the following experiments, we selected antigens or viral strains to gauge the success of three goals: (1) improving binding affinity and efficacy to BA.1 and BA.1.1; (2) maintaining efficacy to historical strains, for which design explicitly targeted Delta but experiments often substituted WA1/2020 D614G; and (3) determining robustness to emerging VOCs.

    Designed antibodies maintain expression

    Because in silico derivatization of antibody sequences can compromise production yield, we measured the concentrations of the 230 COV2-2130-derived recombinant antibodies in set 1 and compared these concentrations to that of the parental antibody. The purified concentrations of 73.9% of redesigned antibodies exceeded that of the parental COV2-2130 antibody (170 of 230 monoclonal antibodies at more than 171.2 mg l−1), reaching as high as 305 mg l−1. Our designed candidates for downstream characterization retained fundamental production properties of the parental antibody, with just 10% of designed antibodies producing poor yields relative to the parental molecule (22 of 230 monoclonal antibodies at less than 135 mg l−1, that is, less than 80% of the parental antibody yield).

    Thermostability and binding Omicron

    We screened all designed antibodies for binding to RBDs. Set 1 was screened via a single-concentration immunoassay (Gyrolab xPlore) in the contexts of WA1/2020, Delta, BA.1 or BA.1.1 RBDs (Extended Data Fig. 1). For set 2, we used a multi-concentration immunoassay (ELISA; Extended Data Fig. 2) in the context of wild-type, BA.1 or BA.1.1 RBDs. In the single-concentration immunoassay, this value was chosen as a single dilution factor, causing most designed antibody samples to fall in the dynamic range of the positive control. In both cases, we compared the binding of the designed antibodies with a broadly cross-reactive, non-ACE2-competitive control antibody (S309)24 and the parental COV2-2130 antibody. As intended, most antibody designs had altered binding profiles, indicating that the designed mutations were consequential. Approximately 11% of the designs of set 1 retained WA1/2020 antigen binding at the measured concentration; roughly 6% improved binding to BA.1, and 5% did so to BA.1.1. The corresponding numbers for set 2 were 9% to WA1/2020 and 8% to BA.1. Following this initial screen, we downselected both sets of antibody designs to those with improved binding to Omicron subvariants BA.1 and BA.1.1 for further characterization.

    These downselected antibodies were re-manufactured at larger scale. We characterized the resulting IgG antibodies by immunoassay and thermal shift (melt temperature) assessments. In agreement with our screens, seven of the eight top-performing antibodies preserved comparable binding with WA1/2020 and Delta RBDs, improving over the parental COV2-2130 antibody with respect to their binding to Omicron BA.1 and BA.1.1 RBDs (Fig. 2). Furthermore, seven of the eight antibodies had melting temperatures and expression properties comparable with those of COV2-2130. One antibody, 2130-1-0114-111, had reduced melting temperature (Extended Data Table 1). The antibody 2130-1-0114-112 displayed best-in-class binding across all RBD variants and had no substantial difference in thermal stability compared with the parental COV2-2130 antibody.

    Fig. 2: Computationally designed IgG antibodies improve Omicron binding and maintain parental thermostability and binding to historical strains.
    figure 2

    a, The parental COV2-2130 (orange circles) and computationally designed antibodies (2130-1-0114-112 in purple triangles, 2130-1-0104-024 in blue diamonds and remainder in black) were assayed for thermal shift (n = 3 technical replicates). Melting temperature (Tm ) calculated based on the Boltzmann method. Data are mean and s.d. b–e, The parental COV2-2130 antibody and computationally designed antibodies (see symbols in a) and cross-reactive positive control antibody S309 (magenta squares) were analysed for relative binding to four SARS-CoV-2 spike RBD variants in the Gyrolab immunoassay: WA1/2020 (b), Delta B.1.617.2 (c), Omicron BA.1 (d) and Omicron BA.1.1 (e). Lines represent a four-parameter logistic regression model fit using GraphPad Prism to each titration, executed without technical replicates. mAb, monoclonal antibody.

    Restored pseudoviral neutralization

    We performed pseudovirus neutralization assays to characterize the functional performance of five selected antibody designs (Fig. 3 and Extended Data Table 2), compared with parental COV2-2130; the positive control S2K146 (ref. 25), which competes with ACE2 binding; and the negative control DENV-2D22 (ref. 26). Our designs maintained neutralization activity against pseudoviruses displaying historical spike proteins (WA1/2020 D614G) and achieved neutralization of those with Omicron BA.1 spikes. The single-best candidate design, 2130-1-0114-112, restored potent neutralization in the context of BA.1.1 and showed a two-order-of-magnitude improvement in the half-maximal inhibitory concentration (IC50) versus parental COV2-2130 for BA.1 and BA.4. These pseudovirus neutralization test results showed that our designs neutralized BA.2 and BA.4 more potently than COV2-2130, despite the emergence of these VOCs after the conception of our designs.

    Fig. 3: Designed antibodies improve pseudoviral neutralization over COV2-2130.
    figure 3

    a–e, The parental COV2-2130 antibody (orange circles), the cross-reactive positive control antibody S2K146 (magenta squares), the negative control antibody DENV-2D22 (grey x) and down-selected computationally designed antibodies (symbols as indicated in the key) were assayed by neutralization with lentiviruses pseudotyped with spike variants of WA1/2020 D614G (a), Omicron BA.1 (b), Omicron BA.1.1 (c), Omicron BA.2 (d) and Omicron BA.4 (e). Curves are four-parameter logistic regression models fit to two (a–d) or four (e) replicate serial dilutions using GraphPad Prism.

    Restored authentic virus neutralization

    We evaluated 2130-1-0114-112 (containing four mutations: GH112E, SL32A, SL33A and TL59E) for authentic virus neutralization performance against several strains of SARS-CoV-2 by a focus reduction neutralization test in Vero-TMPRSS2 cells (Extended Data Fig. 3). The strains that we used included several Omicron targets: WA1/2020 D614G, Delta (B.1.617.2), BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, BA.5 and BA.5.5. In all cases apart from Delta, 2130-1-0114-112 had an IC50 < 10 ng ml−1. Compared with the parental COV2-2130, 2130-1-0114-112 restored potent neutralization activity to both BA.1 (8.08 ng ml−1) and BA.1.1 (7.77 ng ml−1), showed a more than fivefold improvement in IC50 to BA.2 (2.4 ng ml−1) and BA.2.12.1 (2.27 ng ml−1), and conferred 50-fold or greater improvements in IC50 to BA.4 (3.16 ng ml−1), BA.5 (3.51 ng ml−1) and BA.5.5 (5.29 ng ml−1). We also evaluated 2130-1-0114-112 and a less-mutated alternative design, 2130-1-0104-024 (containing two mutations: SL32W and TL59E), in plaque assays with Vero E6-TMPRSS2-T2A-ACE2 cells (Extended Data Fig. 4). IC50 values for 2130-1-0104-024 were 37.7 ng ml−1, 75.94 ng ml−1 and 781.7 ng ml−1 for Delta, BA.1 and BA.1.1 viruses, respectively.

    Prophylaxis in vivo

    To compare the prophylactic efficacy of 2130-1-0114-112 and the parental COV2-2130 monoclonal antibody in vivo, we administered a single 100 μg (approximately 5 mg kg−1 total) dose to K18-hACE2 transgenic mice 1 day before intranasal inoculation with WA1/2020 D614G, BA.1.1 or BA.5 (88 mice in total, 9–10 for each monoclonal antibody and viral strain). Although Omicron viruses are less pathogenic in mice than in humans, they replicate efficiently in the lungs of K18-hACE2 mice27,28. Viral RNA levels were measured at 4 days post-infection in the nasal washes, nasal turbinates and lungs (Fig. 4). As expected, the parental COV2-2130 monoclonal antibody effectively reduced WA1/2020 D614G infection in the lungs (180,930-fold), nasal turbinates (42-fold) and nasal washes (25-fold) compared with the isotype control monoclonal antibody. However, the COV2-2130 monoclonal antibody lost protective activity to BA.1.1 in all respiratory tract tissues, whereas to BA.5, protection was maintained in the lungs (13,622-fold) but not in the nasal turbinates or nasal washes. Compared with the isotype control monoclonal antibody (Fig. 4), 2130-1-0114-112 protected against lung infection by WA1/2020 D614G (399,945-fold reduction), BA.1.1 (53,468-fold reduction) and BA.5 (160,133-fold reduction). Moreover, in the upper respiratory tract, 2130-1-0114-112 also conferred protection to WA1/2020 D614G, BA.1.1 and BA.5. The differences in protection between the parental COV2-2130 and derivative 2130-1-0114-112 monoclonal antibodies were most apparent in mice infected with BA.1.1, which directly parallels the neutralization data (Fig. 3 and Extended Data Figs. 3 and 4).

    Fig. 4: 2130-1-0114-112 provides in vivo prophylactic protection against SARS-CoV-2 variants.
    figure 4

    a–i, Eight-week-old female K18-hACE2 mice were administered 100 μg (approximately 5 mg kg−1) of the indicated monoclonal antibody treatment by intraperitoneal injection 1 day before intranasal inoculation with 104 focus-forming units (FFU) of WA1/2020 D614G (a,d,g), Omicron BA.1.1 (b,e,h) or Omicron BA.5 (c,f,i). Tissues were collected 4 days after inoculation. Viral RNA levels in the lungs (a–c), nasal turbinates (d–f) and nasal washes (g–i) were determined by RT–qPCR (lines indicate median of log10 values); n  =  9 (WA1/2020 D614G and BA.1.1 isotype control groups) or 10 (all others) mice per group, from two experiments. The limit of assay detection is shown as a horizontal dotted line. Statistical comparisons between groups were by Kruskal–Wallis ANOVA with Dunn’s multiple comparisons post-test; P values are as listed or not significant (NS) if P > 0.05. All analyses were conducted in GraphPad Prism.

    Source data

    Potency without additional liabilities

    To understand the neutralization breadth of 2130-1-0114-112 relative to its ancestral antibody, we mapped the epitopes for both antibodies using spike-pseudotyped lentiviral deep mutational scanning (DMS)29. For each antibody, we mapped escape mutations in both the BA.1 and the BA.2 spikes. DMS experiments showed that the escape profile of both COV2-2130 and 2130-1-0114-112 in the context of both BA.1 and BA.2 backgrounds is consistent with the epitope of the antibodies, but with differences in sensitivity to particular mutations (Fig. 5). Consistent with live and pseudovirus neutralization assays (Fig. 3 and Extended Data Figs. 3 and 4), mutations at RBD positions R346 and L452 are sites of substantial escape from both antibodies (Fig. 5). In addition, both antibodies lose potency with mutations at site K444 (such as K444T found in BQ.1* variants). The reversion mutation S446G in the BA.1 background increases the neutralization potency of both antibodies (negative escape values in heatmaps) (Fig. 5c) and probably contributes to greater neutralization potency to the BA.2 variant (Fig. 3 and Extended Data Fig. 3), which carries G446. Most mutations at RBD sites K440 and R498 are slightly sensitizing to the COV2-2130 antibody in both BA.1 and BA.2 backgrounds, but provide weak escape for 2130-1-0114-112 in the BA.1 background and have even weaker effect in the BA.2 background. In agreement with pseudovirus neutralization assays (Fig. 3), comparison of mutation-level escape showed that the 2130-1-0114-112 antibody is substantially more potent than COV2-2130 to the BA.1 variant and retains better potency against viruses with additional mutations in both BA.1 and BA.2 backgrounds (Fig. 5a,b). However, even with improved potency, 2130-1-0114-112 is still vulnerable to escape at multiple RBD residues in the 444–452 loop, which is the site of convergent substitutions in several Omicron lineages30. Many of these variants contain multiple substitutions at positions identified by DMS as important for neutralization or in close proximity to the COV2-2130 epitope, including BQ.1.1 (R346T and K444T), XBB (R346T, V445P and G446S) and BN.1 (R346T, K356T and G446S). To understand the impact of these VOCs, we assessed the ability of 2130-1-0114-112 to neutralize BQ.1.1, XBB and BN.1 in pseudoviral neutralization studies. Consistent with the previously known liabilities of COV2-2130 and our DMS results, 2130-1-0114-112 loses neutralizing activity to these VOCs (Extended Data Fig. 5), probably due to substitutions at 444 and combinatorial effects of multiple substitutions within the COV2-2130 epitope present in these variants. Together, these data demonstrate that 2130-1-0114-112 exhibits improved potency against many individual substitutions without incurring additional escape liabilities, although RBD residues such as 444 remain critical for neutralization activity of both 2130-1-0144-112 and COV2-2130.

    Fig. 5: COV-2130 and 2130-1-0114-112 escape mapping using DMS.
    figure 5

    a,b, Comparison between IC50 values measured using DMS for COV-2130 and 2130-1-0114-112 antibodies in BA.1 (a) and BA.2 (b) backgrounds, with key mutations highlighted. Arbitrary units in both plots are on the same scale. Interactive plots that display each mutation can be found at https://dms-vep.org/SARS-CoV-2_Omicron_BA.1_spike_DMS_COV2-2130/compare_IC50s.html for the BA.1 background and at https://dms-vep.org/SARS-CoV-2_Omicron_BA.2_spike_DMS_COV2-2130/compare_IC50s.html for the BA.2 background. c,d, Heatmaps of mutation escape scores at key sites for each antibody in BA.1 (c) and BA.2 (d) backgrounds. Escape scores were calculated relative to the wild-type amino acid in the same virus background. X marks wild-type amino acid in the relevant background. Amino acids not present in the DMS libraries lack squares; grey squares are mutations that strongly impair spike-mediated infection. Mutations identified in a,b are shown with a heavy line surrounding the corresponding box in c,d. Interactive heatmaps for full spike can be found for the BA.1 background at https://dms-vep.org/SARS-CoV-2_Omicron_BA.1_spike_DMS_COV2-2130/COV2-2130_vs_2130-1-0114-112_escape.html and https://dms-vep.org/SARS-CoV-2_Omicron_BA.2_spike_DMS_COV2-2130/COV2-2130_vs_2130-1-0114-112_escape.html for the BA.2 background.

    Structural basis for restored potency

    To elucidate the key intermolecular interactions that form the interface and determine Omicron RBD recognition by 2130-1-0114-112, we performed 3D reconstructions of the complex between the SARS-CoV-2 Omicron BA.2 spike and the 2130-1-0114-112 Fab fragment using cryo-electron microscopy (cryo-EM). Reconstruction using refinement of the full complex gave a map with average resolution of 3.26 Å, but the interface region between the BA.2 RBD and the 2130-1-0114-112 Fab was not well resolved, presumably due to the flexibility of the RBD–Fab region in the reconstruction. To resolve details at the intermolecular interface, we performed focused refinement of this portion of the structure. Focused refinement resulted in an effective resolution of approximately 3.6 Å for this region (Electron Microscopy Data Bank EMD-28198 and EMD-28199, and Protein Data Bank 8EKD) (Fig. 6 and Extended Data Fig. 6).

    Fig. 6: Cryo-EM structure of neutralizing antibodies 2130-1-0114-112 in complex with Omicron BA.2 RBD.
    figure 6

    a, Atomic model of the RBD–Fab complex, coloured by chain: BA.2 RBD in red, 2130-1-0114-112 HC in yellow and 2130-1-0114-112 LC in green. BA.2 RBD mutations are in orange, and 2130-1-0114-112 mutations are in cyan and blue (HC and LC) (left). A close-up view of the RBD–Fab interface, showing WA1 RBD (Protein Data Bank 7L7E, light brown shading) aligned with the BA.2 RBD (right). b–d, Details showing the 2130-1-0114-112 modified residues and their interaction with BA.2 RBD, coloured as in a. Residue labels are shown in black for the BA.2 complex and brown for the overlaid WA1-2130 complex. The orange and green dashed lines indicate hydrogen bond and hydrophobic interactions, respectively; the yellow dashed lines are labelled with distances. CDRH3 residue Glu112 (left) and with the surface coloured by electrostatic potential (right), showing the positive and negative charges of RBD Lys444 and CDRH3 Glu112 (b). CDRL1 Ala32 and Ala33 hydrophobic network (left) and with the nearby RBD surface coloured by hydrophobicity (right; orange to cyan indicates hydrophobic to hydrophilic) (c). CDRL2 Glu59 salt bridge with RBD residue Arg498 (d). e, 2D diagram of Fab 2130-1-0114-112 paratope and epitope residues involved in hydrogen bonds and salt bridges (yellow and red dashed lines, respectively; distances in Å) and hydrophobic interactions (curved lines with rays). Atoms are shown as circles, with oxygen, carbon and nitrogen in red, black and blue, respectively. Interacting residues that belong to CDR loops are coloured in corresponding shades. The asterisks indicate mutated residues. Image created with Ligplot+34.

    This model shows the binding interface of 2130-1-0114-112–RBD and elucidates how 2130-1-0114-112 regains neutralization potency to Omicron VOCs. The parental COV2-2130 forms extensive interactions with the RBD through CDRH2 and CDRH3, as well as CDRL1 and CDRL2 (ref. 13) with hydrogen bond networks and hydrophobic interactions. To improve binding interactions with Omicron subvariants, 2130-1-0114-112 modifies three CDR loops: G112E in CDRH3, S32A and S33A in CDRL1, and T59E in CDRL2.

    The RBD N440K substitution, identified in the DMS as sensitizing for escape from COV2-2130 but less so for 2130-1-0114-112, is on the edge of the interface with the 2130-1-0114-112 CDRH3 loop and does not make direct contact with the CDRH3 substitution G112E. However, N440K introduces a positive charge to a local environment that has substantial hydrophobic-to-hydrophobic contact. The negative charge introduced by the CDRH3 G112E substitution (Fig. 6b) might improve the electrostatic interactions in this region. It is possible that E112 and K440 are interacting by coordinating a water molecule, but the structural resolution is not sufficient to confirm this type of interaction. These experimental structural results are also consistent with our molecular dynamics simulations, which showed this transient interaction between CDRH3 E112 and RBD K440.

    The local environment around the CDRL1 loop is mostly hydrophobic (comprising the RBD residues L452, F490 and L492, as well as the Omicron mutation E484A) with a hydrogen bond from LC N34 (Fig. 6c). The hydrophilic-to-hydrophobic CDRL1 substitutions introduced in 2130-1-0114-112, S32A and S33A, may favour the local environment and strengthen hydrophobic interactions with the RBD (Fig. 6c,e). This is supported by the DMS identification of sensitivity to hydrophobic-to-hydrophilic substitutions at RBD position 452 for both 1230-1-0114-112 and the parental COV2-2130. Finally, the T59E mutation in the CDRL2 loop establishes a new salt bridge with the RBD substitution Q498R present in Omicron RBDs. This new salt bridge probably strengthens the interaction with the RBD (Fig. 6d,e).

    2130-1-0114-112 distributes four substitutions across three of the four CDR loops comprising the parental COV2-2130 paratope. Mutations to CDRH3 loop were less fruitful than mutations in the L1 and L2 (Extended Data Fig. 7a compared with Extended Data Fig. 7d) when looking across all antibody candidates. Among successful candidates, substitutions at positions 32 and 33 in CDRL1 appear enriched—particularly with hydrophobic residues—consistent with our analysis of this region of the experimentally solved structure of 2130-1-0114-112–BA.2 spike. Another candidate, 2130-1-0104-024, achieves improved affinity and neutralization with only two substitutions: S32W in CDRL1 and T59E in CDRL2. However, full neutralization potency is not reached without the potential charge accommodation mediated by G112E. This suggests that a combination of new bonds and accommodating charge changes optimized the restored affinity and potency of 2130-1-0114-112 with Omicron variants (Extended Data Fig. 8). Altogether, the structural model of 2130-1-0114-112 with the BA.2 RBD helps explain the observed restoration of potency to early SARS-CoV-2 Omicron VOCs.

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  • US funders to tighten oversight of controversial ‘gain-of-function’ research

    US funders to tighten oversight of controversial ‘gain-of-function’ research

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    Biohazard suits hang in a Biosafety Level 4 laboratory in the U.S.

    A new US policy, which goes into effect in one year, provides stricter oversight of risky pathogen research conducted in biosafety facilities.Credit: Associated Press/Alamy Stock Photo

    After more than four years of deliberations, US officials have released a policy that outlines how federal funding agencies and research institutions must review and oversee biological experiments that could potentially be misused or spark a pandemic.

    The policy, which will apply to all research funded by US agencies and take effect in May 2025, broadens oversight of these experiments. The policy singles out work involving high-risk pathogens for special oversight and streamlines existing policies and guidelines, adding clarity that researchers have been seeking for years.

    “This is a very welcome development,” says Jaime Yassif, vice-president of global biological policy and programmes at the Nuclear Threat Initiative, a research centre in Washington DC that focuses on national security issues. “The US is the biggest funder of life sciences research [globally], so we have a moral obligation to guard against risks.”

    Balancing act

    Manipulating pathogens such as viruses inside an enclosed laboratory facility, sometimes by making them more transmissible or harmful (called gain-of-function research), can help scientists to assess their risk to society and develop countermeasures such as vaccines or antivirals. But the worry is that such pathogens could accidentally escape the laboratory or even become weaponized by bad actors.

    Policymakers have had a difficult time developing a clearly-articulated review system that evaluates the risks and benefits of this research, while ensuring that fundamental science needed to prepare for the next pandemic and to advance medicine isn’t paralyzed. The latest policy, released on 6 May by the US Office of Science and Technology Policy (OSTP), is the next chapter in a long-running balancing act in the United States between totally banning high-risk pathogen research and assessing it with standards that some say are too ambiguous.

    The shifting sands of ‘gain-of-function’ research

    In 2014, after several accidents involving mishandled pathogens at US government laboratories, the White House announced a moratorium on research that could make certain pathogens — such as influenza and coronaviruses — more dangerous, given their potential to unleash an epidemic or pandemic. At the time, some researchers said the ban threatened necessary flu-surveillance and vaccine research.

    The government ended the moratorium in early 2017 after the US National Science Advisory Board for Biosecurity (NSABB), a panel of experts that advises the US government, concluded that very few experiments posed a risk. That year, the US Department of Health and Human Services (HHS) instead implemented a review framework by which it would evaluate proposals from scientists seeking federal funding for experiments involving potential pandemic pathogens. This framework applied to proposals to any agency housed under the HHS, including the National Institutes of Health (NIH) — the largest public funder of biomedical research in the world.

    After researchers raised concerns about the transparency of this review process, the NSABB was asked to revisit these policies and guidelines in 2020, but the COVID-19 pandemic delayed any action until 2022. During that time, the emergence of the SARS-CoV-2 coronavirus and the ensuing debate over whether it had leaked from a lab in China, put biosafety at the top of researchers’ minds worldwide. The NIH, in particular, was scrutinized during the pandemic for its role in funding potentially risky coronavirus research. In response, some Republican lawmakers have — so far unsuccessfully — put forward legislation that would once again place a moratorium on research that might increase the transmissibility or virulence of pathogens.

    A ‘step forwards’

    The latest policy aims to address concerns that have arisen over the past decade about lax oversight, ambiguous wording and lack of transparency.

    It breaks potentially problematic research into two categories. The first includes research on biological pathogens or toxins that could generate knowledge, technologies or products that could be misused. The second includes research on pathogens with enhanced pandemic potential.

    Research falls into the first category if it meets several criteria. For example, it must involve high-risk biological agents, such as smallpox and anthrax, that are on a specific list, and it must have particular experimental outcomes, such as increasing an agent’s deadliness.

    Research that falls into the second category includes pathogens that could be modified in a way that is “reasonably anticipated” to make them more dangerous. That criterion means that even research on pathogens that are not typically considered dangerous — seasonal influenza, for example — can fall into the second category. Previously, pathogen surveillance and vaccine-development research were not subject to additional oversight in the United States; the latest policy eliminates this carveout, but clarifies that both surveillance and vaccine research are “typically not within the scope” of research in the second category.

    Layers of review

    Scientists and their institutions are responsible for identifying research that falls into these categories, the policy states. Once the funding agency confirms that a research proposal fits into either category, that agency will request a risk-benefit assessment and a risk mitigation plan for the research from the investigator and institution. If a proposal is deemed to fit into the second category, it will undergo an additional review before the project is greenlit. A report of all federally-funded research that fits into the second category will be made public every year.

    NIH reinstates grant for controversial coronavirus research

    This new directive also mandates that agencies funding biological research beyond the HHS, such as the US Department of Defense, must abide by the same rules — a huge step forwards, says Tom Inglesby, the director of the Johns Hopkins Center for Health Security in Baltimore, Maryland. But it applies only to federally-funded research; the policy recommends but does not require non-governmental organizations and the private sector to follow the same rules.

    Federal agencies and research institutions will now create their own implementation plans to comply with the policy by its effective date in 2025. Yassif says that the policy’s success hinges on how these stakeholders implement it.

    Nevertheless, the policy sets a worldwide standard and might inspire other countries to re-evaluate their current approaches to oversee life-sciences research, says Filippa Lentzos, a biosecurity researcher at King’s College London who chairs an advisory group for the World Health Organization (WHO) on the responsible use of life-sciences research. WHO member states will consider a proposal at the World Health Assembly in Geneva, Switzerland, later this month that would urge nations to cooperate on development of international standards for biosecurity.

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  • Virologist who was first to share COVID genome is shut out of lab in China

    Virologist who was first to share COVID genome is shut out of lab in China

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    The first person to publicly release the genome sequence of the virus that causes COVID-19 — virologist Zhang Yongzhen — appears to have resolved a public dispute with the Shanghai Public Health Clinical Center (SPHCC), Fudan University, that erupted last week.

    Zhang had been photographed camping outside his laboratory since Sunday, after the SPHCC closed the lab.

    The SPHCC did not respond to Nature’s request to comment but has released public statements saying the laboratory was one of several that needed renovations — and that it provided Zhang’s team with an alternative space.

    According to social media posts on Zhang’s personal Weibo account, the institute gave the research team two days to leave but the SPHCC did not initially specify where they should relocate. Later, Zhang said officials told his team to move to a lab that did not have the necessary biosafety conditions to store their samples, which contain unknown pathogens. Zhang’s lab is a biosafety level 3 laboratory.

    Zhang said he had been sleeping outside his laboratory since Sunday night, even in the rain. The social media posts include photos of him lying under blankets.

    Zhang told Nature on Monday that his situation was “terrible”.

    “You don’t know what I have experienced,” he said, but declined to comment further.

    According to the social media account of Chen Yanmei, a virologist at the SPHCC, and a member of Zhang’s team, their students’ incomplete experiments were now “impossible to save”. Chen said she was also camping out, inside the lab. Chen also declined to be interviewed by Nature.

    But by late Tuesday night, Zhang said in a post that a tentative agreement had been reached with the SPHCC to resume normal research activity in the laboratory. The post states that Zhang will work with the centre to relocate the laboratory and restart research.

    Virus sequence

    In 2020, Zhang was the first scientist — together with Edward Holmes, a virologist at the University of Sydney in Australia — to share the genome of SARS-CoV-2 with the world on the website virological.org. That act is widely credited as a key factor enabling the swift development of vaccines against COVID-19.

    Since 2020, Zhang has received international acclaim. That year, Zhang featured in Nature’s 10 — an annual list of people behind key developments in science, and in 2022 he was awarded the Mohammad bin Rashid Al Maktoum Knowledge Award, which carries a US$1 million bursary.

    Nature’s 10: ten people who helped shape science in 2020

    But Holmes, a long-time collaborator of Zhang’s, says that since 2020, Zhang’s research output has dwindled. Before 2020, Zhang had an extensive research network and would collect samples of animals and people to study viral evolution, says Holmes. But since 2020, Zhang’s work has largely involved analysing previously collected samples and Holmes’s own collaboration with Zhang is less prolific. “He drove that collaboration but there is nothing to collaborate on now; he hasn’t been able to get any data,” says Holmes. “All I can do is offer support from afar.”

    According to the Dimensions database, Zhang co-authored 5 research articles in 2018, 9 in 2019 and 18 in 2020. But that growing publication rate dropped to 3 in 2021 and 4 in 2022. Zhang co-authored 6 articles in 2023, none of which contained original data.

    Holmes believes the lab closure is part of an effort to sideline Zhang for unauthorized sharing of data. “It is heartbreaking to watch,” he says. “It is unfathomable to me to have a scientist of that calibre sleeping outside his lab.”

    International star

    But Yanzhong Huang, a specialist in Chinese health policy at the Council on Foreign Relations in New York City, says the true nature of the dispute and protest are “shrouded in mystery”.

    Fan Xiaohong, a physician who heads the SPHCC told reporters for Chinese newspaper Southern Weekly that Zhang’s contract had expired, but he had refused to leave. A post on Zhang’s social media said that although his own contract with SPHCC had formally ended in 2023, members of his team had renewed their contracts with the hospital, and the laboratory is still owed funding.

    Even without clarity on the details of the dispute, Dali Yang, a researcher who studies politics in China at the University of Chicago, says it’s concerning that Zhang is sleeping outside his lab. “Many people who know about him are aghast because he is truly an international star,” says Yang.

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  • Scientists tried to give people COVID — and failed

    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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  • Controversial virus-hunting scientist skewered at US COVID-origins hearing

    Controversial virus-hunting scientist skewered at US COVID-origins hearing

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    Republicans in the US House of Representatives publicly grilled infectious disease specialist Peter Daszak today during a long-awaited hearing on Capitol Hill. In their questioning they suggested that Daszak and the nonprofit organisation he heads, EcoHealth Alliance in New York City, knowingly conducted dangerous research by studying coronaviruses with a virology lab in Wuhan, China, where the first COVID-19 cases were reported during the pandemic.

    US COVID-origins hearing puts scientific journals in the hot seat

    Democrats disputed that there was any evidence that EcoHealth played a part in triggering the pandemic, but did hold Daszak’s feet to the fire over his organisation’s failure to submit a progress report on time to the federal government regarding a research grant it had been awarded by the US National Institute of Allergy and Infectious Disease (NIAID). They also called out Daszak for “questionable conduct”: inconsistencies in testimonies previously given and documents submitted to the group running the hearing, the Select Subcommittee on the Coronavirus Pandemic.

    EcoHealth “potentially misled the federal government on multiple occasions” in terms of being transparent and adhering to reporting requirements as a recipient of federal funding, said Raul Ruiz, a Democratic representative from California and the ranking member of the subcommittee.

    At the start of the hearing, subcommittee chairman Brad Wenstrup, a Republican representative from Ohio, announced the findings of a report evaluating EcoHealth’s research activities issued earlier in the day. The interim report, released by the subcommittee’s Republican members, states that EcoHealth failed to disclose high-risk, so-called gain-of-function research that it conducted in partnership with the Wuhan Institute of Virology (WIV), and recommended that the organisation be barred from receiving future federal funds and criminally investigated.

    NIH to intensify scrutiny of foreign grant recipients in wake of COVID origins debate

    Daszak disputed that the work carried out by EcoHealth and the WIV meets the definition of gain-of-function research. To meet that definition, he said, an experiment would need to have a likelihood of increasing a virus’s transmission or pathogenicity, and that the virus would already have to be known to infect humans. “Because the work we were doing was on bat coronaviruses, it was not covered by those rules,” Daszak said, referring to a definition used by the NIH to evaluate grants involving pathogen research. Wenstrup, who said the researcher had been “less than cooperative”, suggested that Daszak was using semantics to obscure the definition of gain-of-function research, which more generally confers new abilities to pathogens.

    The hearing’s intense scrutiny of Daszak and EcoHealth could disincentivize other US scientists from proposing collaborations with colleagues in China and other countries, a process that is considered essential for pandemic prevention and preparedness, says Lawrence Gostin, a health-law and policy specialist at Georgetown University in Washington DC. Researchers need to be able to study new viruses in the locations where they are emerging. “It is extraordinarily important for Western-based scientists in the United States, the UK and other places to have strong working relationships with scientists around the world, including in China,” he says.

    Angela Rasmussen, a virologist at the University of Saskatchewan in Saskatoon, Canada, says she was disappointed that the Democrats joined the Republicans in what she says was “essentially an attack on science”. “It’s a very dangerous situation because most scientists who are approaching any problem — whether it’s the origins of the pandemic, whether it’s anything else — are going to think twice: should I actually get involved in research that is high impact but potentially politically controversial?”

    A long-standing collaboration

    Daszak has been a lightning rod in the COVID-19 origins debate, in which some researchers have argued that the SARS-CoV-2 coronovirus passed to humans naturally, from animals, and others have suggested it could have escaped from the WIV. When the COVID-19 pandemic began, EcoHealth, which aims to identify pathogens that could trigger pandemics and find solutions to them, had been collaborating with researchers in China for more than 15 years, studying coronaviruses in bats.

    However, once the COVID-19 pandemic was in full force, in April 2020, the US National Institutes of Health (NIH) terminated a grant it had awarded EcoHealth for research in this vein. The WIV was a subawardee on this grant — a partner that was given funds to carry out some of the research proposed by EcoHealth. The termination was announced shortly after then-president Donald Trump, who had been publicly implying that China was to blame for the pandemic, told a reporter at a press conference that the government would stop funding the WIV.

    Peter Daszak (R), Thea Fischer (L) and other members of the World Health Organization (WHO) team investigating the origins of the COVID-19 coronavirus, arrive at the Wuhan Institute of Virology in Wuhan in China's central Hubei province on February 3, 2021.

    Daszak visited the Wuhan Institute of Virology in early 2021 as part of a team assembled by the World Health Organization to investigate the origins of the COVID-19 pandemic.Credit: Hector Retamal/AFP via Getty

    About five months earlier, Daszak and 26 other scientists published a letter in the scientific journal The Lancet1, attempting to dispel rumours about China’s involvement in the pandemic. “We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” the letter said. Although the letter declared the authors had no competing interests, critics would later point out Daszak’s close ties to scientists in China and suggest that this letter stopped the scientific community from truly considering the lab-leak hypothesis early in the pandemic.

    Later that year, his ties to China would once again become an issue when Daszak was selected by the World Health Organization (WHO) to be part of an investigative team exploring the origins of the COVID-19 pandemic. Observers at the time worried that his relationship with Chinese researchers would endanger his ability to impartially conduct the investigation, which took place in early 2021.

    At the hearing, Ruiz pressed Daszak about The Lancet letter and why he hadn’t declared competing interests. Daszak said that the letter was attempting to address specific conspiracy theories circulating early in the pandemic, including that SARS-CoV-2 contained snake DNA, rather than trying to cut off any exploration of the lab-leak hypothesis. He also pointed out that competing interests were added to the letter. They indicated that his salary is paid by EcoHealth and that the organisation works with a “range of universities and governmental health and environmental science organisations” in China – without naming the WIV specifically.

    Biosafety questions

    Another issue raised at the hearing was a grant proposal submitted in 2018 by Daszak and colleagues, including those at the WIV, to the US Defense Advanced Research Projects Agency (DARPA). The goal of the project, which DARPA did not ultimately fund, was to ‘defuse’ the threat of bat-borne coronaviruses by engineering the viruses to infect humanised mice and assess their capacity to cause disease. On the basis of a draft of the proposal obtained via a Freedom of Information Act request, politicians at the hearing suggested that Daszak attempted to downplay the role that Chinese collaborators would have in the project to increase its chances of being approved. Daszak denied this and said that he contacted DARPA to check that it was okay to include the WIV on the proposal.

    “A lot of the discussion about what was written in the marginalia of the early draft of that proposal could probably apply to anybody’s grant proposal for any agency,” Rasmussen says. “That’s the normal process of grant writing. And it’s sort of shocking to me, but also kind of hilarious, that people are reading so much into these notes.”

    NIH reinstates grant for controversial coronavirus research

    Republican representatives repeatedly questioned Daszak about whether the WIV had the appropriate biosafety levels to conduct the coronavirus research specified in the un-funded 2018 proposal.

    Gigi Kwik Gronvall, an immunologist at Johns Hopkins University in Baltimore, Maryland, says that the response to biosafety concerns in other countries shouldn’t be to avoid working with those countries, but to partner with them to provide training and promote better practices. “If we want US science to be the standard-setter for safety, for security, for social responsibility, then we have to be a leader. And that means partnering with countries to help solve their public-health problems.”

    Anthony Fauci, who was head of NIAID when EcoHealth received its grant to study bat coronaviruses with the WIV in 2014, will testify before the subcommittee on 3 June.



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