money manager, earning solid returns on the Gateses’ and the foundation’s combined $174 billion investment portfolio through a secretive operation called Cascade Investment. Cascade owned assets like stocks, bonds, hotels and vast tracts of farmland, and it also put the Gateses’ money in other investment vehicles. One was a venture capital firm called Rally Capital, which is in the same building that Cascade occupies in Kirkland, Wash.

Rally Capital had an ownership stake in a nearby bicycle shop. In 2017, the woman who managed the bike shop hired a lawyer, who wrote a letter to Mr. Gates and Ms. French Gates.

The letter said that Mr. Larson had been sexually harassing the manager of the bike shop, according to three people familiar with the claim. The letter said the woman had tried to handle the situation on her own, without success, and she asked the Gateses for help. If they didn’t resolve the situation, the letter said, she might pursue legal action.

The woman reached a settlement in 2018 in which she signed a nondisclosure agreement in exchange for a payment, the three people said.

While Mr. Gates thought that brought the matter to an end, Ms. French Gates was not satisfied with the outcome, two of the people said. She called for a law firm to conduct an independent review of the woman’s allegations, and of Cascade’s culture. Mr. Larson was put on leave while the investigation was underway, but he was eventually reinstated. (It is unclear whether the investigation exonerated Mr. Larson.) He remains in charge of Cascade.

published an article detailing Mr. Gates’s relationship with Mr. Epstein. The article reported that the two men had spent time together on multiple occasions, flying on Mr. Epstein’s private jet and attending a late-night gathering at his Manhattan townhouse. “His lifestyle is very different and kind of intriguing although it would not work for me,” Mr. Gates emailed colleagues in 2011, after he first met Mr. Epstein.

(Ms. Arnold, the spokeswoman for Mr. Gates, said at the time that he regretted the relationship with Mr. Epstein. She said that Mr. Gates had been unaware that the plane belonged to Mr. Epstein and that Mr. Gates had been referring to the unique décor of Mr. Epstein’s home.)

The Times article included details about Mr. Gates’s interactions with Mr. Epstein that Ms. French Gates had not previously known, according to people familiar with the matter. Soon after its publication she began consulting with divorce lawyers and other advisers who would help the couple divide their assets, one of the people said. The Wall Street Journal previously reported the timing of her lawyers’ hiring.

The revelations in The Times were especially upsetting to Ms. French Gates because she had previously voiced her discomfort with her husband associating with Mr. Epstein, who died by suicide in federal custody in 2019, shortly after being charged with sex trafficking of girls. Ms. French Gates expressed her unease in the fall of 2013 after she and Mr. Gates had dinner with Mr. Epstein at his townhouse, according to people briefed on the dinner and its aftermath. (The incident was reported earlier by The Daily Beast.)

For years, Mr. Gates continued to go to dinners and meetings at Mr. Epstein’s home, where Mr. Epstein usually surrounded himself with young and attractive women, said two people who were there and two others who were told about the gatherings.

Ms. Arnold said Mr. Gates never socialized or attended parties with Mr. Epstein, and she denied that young and attractive women participated at their meetings. “Bill only met with Epstein to discuss philanthropy,” Ms. Arnold said.

On at least one occasion, Mr. Gates remarked in Mr. Epstein’s presence that he was unhappy in his marriage, according to people who heard the comments.

Leon Black, the head of Apollo Investments who had a multifaceted business and personal relationship with Mr. Epstein, according to two people familiar with the meeting. The meeting was held at Apollo’s New York offices.

It is unclear whether Ms. French Gates was aware of the latest meetings with Mr. Epstein. A person who recently spoke to her said that “she decided that it was best for her to leave her marriage as she moved into the next phase of her life.”

Steve Eder and Jodi Kantor contributed reporting.

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The Gateses’ Public Split Spotlights a Secretive Fortune

The fortune of Bill Gates and Melinda French Gates exceeds the size of Morocco’s annual economy, combines the value of Ford, Twitter and Marriott International and is triple the endowment of Harvard. While few know how their wealth will be divided in the divorce, one thing is clear: breaking it up can’t be easy.

Mr. Gates built one of the great fortunes in human history when he founded Microsoft in 1975 with Paul Allen. The Gateses’ net worth is estimated to be more than $124 billion, and includes assets as varied as trophy real estate, public company stocks and rare artifacts.

There’s a big stake in the luxury Four Seasons hotel chain. There are hundreds of thousands of acres of farmland and ranch land, including Buffalo Bill’s historic Wyoming ranch. There are billions of dollars’ worth of shares in companies like AutoNation and Waste Management. There’s a beachfront mansion in Southern California. And one of Leonardo da Vinci’s notebooks.

“The amount of money and the diversity of assets that are involved in this divorce boggles the imagination,” said David Aronson, a lawyer who has represented wealthy clients in divorce cases. “There have rarely been cases that are even close to this in size.”

2019 divorce between the Amazon founder Jeff Bezos and his now ex-wife, the novelist and philanthropist MacKenzie Scott, was bigger. Mr. Bezos had an estimated fortune of $137 billion, though mostly in Amazon stock, and Ms. Scott kept 4 percent of Amazon’s shares, worth $36 billion at the time.

But Mr. Gates has for decades been diversifying his holdings; he owns just 1.3 percent of Microsoft. Instead, his stock portfolio includes stakes in dozens of publicly traded companies. He is the largest private owner of farmland in the country, according to The Land Report. In addition to the Four Seasons, he has stakes in other luxury hotels and a company that caters to private jet owners. His real estate portfolio includes one of the largest houses in the country and several equestrian facilities. He owns stakes in a clean energy investment fund and a nuclear energy start-up.

Forbes, or $146 billion, according to the research firm Wealth-X. Including the Gates Foundation’s endowment and the Gates personal fortune, Cascade most likely oversees assets that put it on par or beyond some of the world’s biggest hedge funds in size.

Mr. Larson operates Cascade with an obsessive level of secrecy, going to great lengths to cloak the firm’s transactions so that they can’t easily be traced back to the Gateses. In a 1999 interview with Fortune magazine, Mr. Larson said he chose the name “Cascade” because it was a generic-sounding name in the Pacific Northwest.

that questions about the future of the Gates Foundation immediately arose following news of the divorce. The foundation directs billions to 135 countries to help fight poverty and disease. As of 2019, it had given away nearly $55 billion. (In 2006, Mr. Buffett pledged $31 billion of his fortune to the Gates Foundation, greatly increasing its grant making.)

Since he stepped down from day-to-day operations at Microsoft in 2008, Mr. Gates has devoted much of his time to the foundation. He also runs Gates Ventures, a firm that invests in companies working on climate change and other issues. Over the decades, Mr. Gates shed the image of a ruthless tech executive battling the United States government on antitrust to be viewed as a global do-gooder. And he appears to be keenly aware of the stark contrast between the scale of his wealth and his role as a philanthropist. “I’ve been disproportionately rewarded for the work I’ve done — while many others who work just as hard struggle to get by,” he acknowledged in a year-end blog post from 2019.

told The New York Times last year. “There’s just none.”

Matthew Goldstein contributed reporting.

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The Week in Business: Where Are the Jobs?

Good morning and happy Mother’s Day. (Hi, mom!) Here’s the news you need to know for the week ahead in business and tech. — Charlotte Cowles

Credit…Giacomo Bagnara

Economists expected the April jobs report to be full of great news — lower unemployment, robust hiring, confetti! And by most measures, they were disappointed. The pace of hiring actually slowed, and the unemployment rate rose slightly, to 6.1 percent, for the first time in a year. What’s going on? It’s complicated. Some lawmakers say that the government’s supplemental unemployment benefits are discouraging people from re-entering the work force, particularly in lower-wage positions. Others point to the millions of Americans who aren’t able to work because they’re managing child care, as many schools still aren’t yet back to normal operations. Either way, the country’s economic recovery isn’t going to be simple.

It’s been five months since Facebook barred former President Donald J. Trump indefinitely for his role in inciting the Jan. 6 insurrection at the Capitol. As for when to allow him back, the platform kicked the question over to its independent oversight board, a group of about 20 academics, human rights leaders and political figures from around the globe. Last Wednesday, the group upheld Facebook’s ban, but ruled that the company had to establish a clearer policy for it. Facebook now has six months to make a long-term decision about Mr. Trump’s account and create community standards that justify it.

are divorcing. Their eponymous foundation has an endowment of about $50 billion and spent over $1 billion to combat the coronavirus pandemic in the past year alone. The organization released a statement saying that the couple intends to remain co-chairs and trustees, and no changes are expected. Still, the divorce will affect their shared fortune, much of which has been pledged but not yet donated to the foundation. Mr. Gates, 65, co-founded Microsoft and is one of the richest people in the world.

Credit…Giacomo Bagnara

President Joseph R. Biden will hold a meeting with the four top House and Senate leaders, from both sides of the aisle, for the first time since taking office. House Speaker Nancy Pelosi, the Senate majority leader Chuck Schumer, and their Republican counterparts, Kevin McCarthy and Mitch McConnell, are expected to discuss Mr. Biden’s $4 trillion economic agenda and his plans to fund it by taxing the rich. Republican lawmakers have fought the proposals from day one. Sounds like a fun conversation.

Warren Buffett, the chief executive of Berkshire Hathaway, says inflation is rising. The price of building materials and other consumer goods is going up as demand grows and production costs increase. But the Federal Reserve has repeatedly encouraged investors not to fret. Is the economy going to overheat, with interest rates so low? Probably a bit. But slightly higher prices for a temporary period is in step with the Fed’s general aim for an inflation rate of 2 percent on average over time, to make up for exceptionally weak gains over the past several years.

The Biden administration has backed a temporary suspension of intellectual property rights for coronavirus vaccines, which would allow third-party drugmakers around the world to manufacture and distribute them to nations that need them. But the U.S. pharmaceutical industry is not happy about this, particularly those who hold the patents on these vaccines. (Pfizer alone generated $3.5 billion in revenue from its Covid-19 vaccine in the first three months of this year.) Representatives of the companies argue that suspending those patents will discourage future innovation and potentially decrease the safety standards of vaccine manufacturing and efficacy. Support from the White House does not guarantee that a waiver will happen, but it adds momentum.

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The Separate Worlds of Bill and Melinda Gates

“It was a constant tension point of the foundation. It was Warren who limited it, but Bill’s appetite is always, ‘We should do this, we should do this.’ Teams end up with this massive to-do list,” the former executive said.

Mr. Buffett acknowledged in an interview with The Times last year that he opposed institutional bloat. “That’s the one piece of advice I don’t shut up on, ever, because it’s the natural tendency of every organization,” he said.

Employees at the foundation often have to wear multiple hats to keep up with the demands. For instance, one staff member, Anita Zaidi, serves in the highly technical role of director of vaccine development and surveillance but also serves as president for gender equality.

Mr. Gates famously gave a TED Talk in 2015 warning about the global threat posed by contagious respiratory viruses. The foundation was packed with top talent working on developing new vaccines. It did not, however, have a single person out of roughly 1,600 staff members devoted full time to pandemics before the Covid-19 outbreak began.

For all the workarounds with contract employees and consultants, there was only so much bandwidth, and the decision was made not to have a dedicated team working on the matter. Instead the foundation threw its weight behind the Coalition for Epidemic Preparedness Innovations, which helped develop vaccines to combat outbreaks.

When the pandemic struck, the foundation put its resources and expertise to work. It has dedicated $1.75 billion to combating the pandemic so far and played a key role in shaping the global response.

Even without the divorce, the foundation was in the midst of change. Mr. Buffett, the third trustee, turns 91 this summer. Mr. Gates’s father, Bill Gates Sr., who was co-chair and a guiding hand at the foundation, died this past September. Some observers have wondered if the couple’s three children could get involved soon. The elder two are already in college and medical school. Others have raised the possibility that this is the moment to loosen the family’s grip and install a board drawn from professionals outside the inner circle.

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Bill and Melinda Gates’ Divorce Has a Lot at Stake

Bill and Melinda Gates are divorcing after 27 years of marriage, raising questions about the fate of their vast fortune. Their split could yield the biggest divorce settlement on record, according to Forbes’s calculations, surpassing the $35 billion breakup of Amazon’s Jeff Bezos and MacKenzie Scott. Given the likely sums involved, what happens with the Gateses’ extensive investments and charity work will be monitored at the highest levels of government, business and the nonprofit sector.

What’s at stake: Mr. Gates is the fourth-richest person in the world, according to Forbes, with wealth estimated at $124 billion. The family is the largest owner of farmland in the U.S. His personal investment firm, Cascade Investment, owns big stakes in assets like the Four Seasons, the Canadian National Railway and the AutoNation chain of car dealerships.

The two have faced relationship struggles in recent years, Andrew, David Gelles and Nick Kulish report in The Times. Mr. Gates stepped down from the boards of Microsoft and Berkshire Hathaway in part to spend more time with his family.

What will happen to the Gates Foundation? The $50 billion nonprofit is one of the biggest philanthropies in the world, giving away about $5 billion each year to causes like global public health and childhood education. Most recently, it was instrumental in forming Covax, the global coronavirus vaccination program. For now, the foundation says little will change in how it is run day to day, but people in its orbit worry that an acrimonious split by its founders could cloud the nonprofit’s plans. “Together they have assured me of their continued commitment to the foundation that they have worked so hard to build together,” the foundation’s chief executive, Mark Suzman, told employees in an email.

Ms. Gates could separately become a big philanthropic force. She has already used her own investment office, Pivotal Ventures, to donate money to causes like women’s economic empowerment, and could use any settlement to amplify her giving to preferred groups. “You could imagine Melinda Gates being a much more progressive giver on her own,” said David Callahan, the founder of Inside Philanthropy. “She’s going to be a major force in philanthropy for decades to come.”

The Tristate area will reopen sooner than expected. The governors of New York, New Jersey and Connecticut said they would ease most Covid-19 capacity limits on businesses starting on May 19, thanks to declining coronavirus case numbers.

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What the Gates Divorce Means for the Gates Foundation

The Bill and Melinda Gates Foundation started with ambitions that, by its lofty standards today, appear almost quaint: providing free internet access to public libraries in the United States. As its founders’ objectives grew in scope, so did the foundation’s reach, until it achieved its current position as the pre-eminent private institution in global public health.

With 1,600 staff members directing $5 billion in annual grants to 135 countries around the globe, the Gates Foundation set a new standard for private philanthropy in the 21st century.

All of that was thrown into question on Monday when the world learned that the foundation’s co-chairs, who had been married for 27 years, filed for divorce in Washington State. Grant recipients and staff members alike wondered what would happen and whether it might affect the mission.

The message from the headquarters in Seattle was clear: Bill and Melinda Gates may be splitting up, but the Bill and Melinda Gates Foundation isn’t going anywhere. Their roles as co-chairs and trustees are not changing, and they will still set the agenda for the organization that bears their names. In an email on Monday, the Gates Foundation’s chief executive, Mark Suzman, reassured the staff that both Mr. and Ms. Gates remained committed to the organization.

observers noted that Ms. Gates had added her maiden name, French, to her Twitter profile.

The couple deployed their connections last year in response to the pandemic, calling leaders like Chancellor Angela Merkel of Germany and Crown Prince Mohammed bin Zayed of Abu Dhabi to drum up support for their plans. The foundation has committed $1.75 billion so far to its Covid-19 response, and played a key role in shaping the global deal to bring vaccines to poor countries.

That prominence has also brought a fair share of scrutiny, throwing a spotlight on Mr. Gates’s robust defense of intellectual property rights — in this case, specific to vaccine patents — even in a time of extreme crisis, as well as the larger question of how unelected wealthy individuals can play such an outsize part on the global stage.

“In a civil society that is democratic, one couple’s personal choices shouldn’t lead university research centers, service providers and nonprofits to really question whether they’ll be able to continue,” said Maribel Morey, founding executive director of the Miami Institute for the Social Sciences.

reported earlier by Bloomberg.

Before the news of the divorce broke, the Gates Foundation had been in the midst of a period of upheaval. The pandemic shuttered its headquarters in Seattle even as staff members drawn from the top ranks of government health agencies and the pharmaceutical industry worked to muster a response to the deadly, rapidly spreading new coronavirus.

And as his public profile during the pandemic grew, so did spurious conspiracy theories such as that the global immunization effort was a cover for Mr. Gates to implant microchips to track people, blatantly false but still damaging as misinformation increased vaccine hesitancy.

Then Mr. Gates’s father, Bill Gates Sr., also a foundation co-chair, died in September. The elder Mr. Gates had initially taken the lead on his son’s charitable endeavors while the younger Mr. Gates was still at the helm of Microsoft. Bill Gates Sr. was viewed by many as a calm voice and a moral compass within the organization, even as he had stepped back in recent years.

The third trustee, the billionaire investor Warren E. Buffett, turned 90 last year and has begun to discuss succession plans at his company, Berkshire Hathaway.

Dr. Morey said the recent changes could also present an opportunity to create a large, diverse board while increasing visibility into the foundation’s decision-making. “Part of the anxiety is coming from the lack of transparency in the day-to-day activities of the Gates Foundation,” she said.

Forbes estimates at $124 billion. The divorce won’t affect the money that has already been given to the foundation trust, but the couple may devote less money to it over time than they would have if they had stayed together.

“People are right to feel unmoored in terms of the direction of the foundation,” said Ms. Tompkins-Stange of the University of Michigan. “There’s a lot of ambiguity, as there might be in any divorce situation, but they seem committed to co-parenting the foundation.”

David Gelles contributed reporting.

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Bill and Melinda Gates Are Divorcing

Bill and Melinda Gates, two of the most influential philanthropists in the world, said on Monday that they were divorcing.

The couple have together emerged as leading figures in the global fight against Covid-19, and their separation is likely to send shock waves through the worlds of philanthropy, public health and business.

The divorce will create new questions about the fate of the Gates fortune, much of which has not yet been donated to the Bill and Melinda Gates Foundation. Mr. Gates, who co-founded Microsoft, is one of the richest people in the world, worth an estimated $124 billion, according to Forbes.

“After a great deal of thought and a lot of work on our relationship, we have made the decision to end our marriage,” the couple said in a statement that was posted to Mr. Gates’s Twitter account.

This is a developing story. Check back for updates.

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Researchers Are Hatching a Low-Cost Covid-19 Vaccine

A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make.

Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world.

If NVD-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NVD-HXP-S for themselves or acquire it at low cost from neighbors.

“That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center.

Vaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.

Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them.

spike, latches onto cells and then allows the virus to fuse to them.

But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies.

The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus.

The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans.

But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike.

Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike.

Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year.

Dr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.”

But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more.

HexaPro, in honor of its total of six prolines.

The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine.

Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines.

“The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said.

To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties.

Meanwhile, Dr. Innes and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own.

experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes.

The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins.

At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S.

announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S.

Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form.

To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok.

In Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.”

Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.”

Madhavi Sunder, an expert on intellectual property at Georgetown Law School, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said.

Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said.

In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro.

“There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’”

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Researchers Are Hatching a Low-Cost Coronavirus Vaccine

A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make.

Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world.

If NVD-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NVD-HXP-S for themselves or acquire it at low cost from neighbors.

“That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center.

Vaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.

Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them.

spike, latches onto cells and then allows the virus to fuse to them.

But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies.

The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus.

The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans.

But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike.

Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike.

Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year.

Dr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.”

But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more.

HexaPro, in honor of its total of six prolines.

The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine.

Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines.

“The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said.

To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties.

Meanwhile, Dr. Innes and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own.

experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes.

The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins.

At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S.

announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S.

Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form.

To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok.

In Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.”

Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.”

Madhavi Sunder, an expert on intellectual property at Georgetown Law School, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said.

Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said.

In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro.

“There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’”

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In a Crucial South African Vaccine Trial, a Cautionary Tale

In a year that has seesawed between astonishing gains and brutal setbacks on Covid-19, few moments were as sobering as the revelation last month that a coronavirus variant in South Africa was dampening the effect of one of the world’s most potent vaccines.

That finding — from a South African trial of the Oxford-AstraZeneca shot — exposed how quickly the virus had managed to dodge human antibodies, ending what some researchers have described as the world’s honeymoon period with Covid-19 vaccines and setting back hopes for containing the pandemic.

As countries adjust to that jarring turn of fortune, the story of how scientists uncovered the dangers of the variant in South Africa has put a spotlight on the global vaccine trials that were indispensable in warning the world.

“Historically, people might have thought a problem in a country like South Africa would stay in South Africa,” said Mark Feinberg, the chief executive of IAVI, a nonprofit scientific research group. “But we’ve seen how quickly variants are cropping up all around the world. Even wealthy countries have to pay a lot of attention to the evolving landscape all around the world.”

a recent lab study, the Oxford-AstraZeneca vaccine protected hamsters exposed to the variant from becoming ill, even if the animals’ immune responses were somewhat weaker. The human trial in South Africa was too small to say definitively whether the vaccine prevented severe disease. But the finding that it provided minimal protection against milder cases was itself discouraging, given that the shot remains the backbone of many poorer countries’ rollouts.

announced the discovery of the variant a week later. The serendipitous placement of the trials gave scientists what they almost never have: an open-air laboratory for watching, in real time, as a vaccine and a variant faced off.

Since the Oxford results were announced last month, Dr. Koen said, volunteers have been trying to console her: “I’m getting a lot of messages of condolence, and ‘I’m sorry,’” she said.

So long as that vaccine and others prevent severe disease, even in cases of the variant, the world can live with the virus, scientists said. But the trial in South Africa nevertheless underscored the need to stamp out the virus before it mutates further. Without it, scientists said, the world could have been blind to what was coming.

“We would anticipate these variants are not the end of the story,” said Andrew Pollard, the Oxford scientist in charge of its trials. “For the virus to survive, once populations have good immunity against the current variants, it must continue to mutate.”

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