Kati Kariko Helped Shield the World From the Coronavirus

She grew up in Hungary, daughter of a butcher. She decided she wanted to be a scientist, although she had never met one. She moved to the United States in her 20s, but for decades never found a permanent position, instead clinging to the fringes of academia.

Now Katalin Kariko, 66, known to colleagues as Kati, has emerged as one of the heroes of Covid-19 vaccine development. Her work, with her close collaborator, Dr. Drew Weissman of the University of Pennsylvania, laid the foundation for the stunningly successful vaccines made by Pfizer-BioNTech and Moderna.

For her entire career, Dr. Kariko has focused on messenger RNA, or mRNA — the genetic script that carries DNA instructions to each cell’s protein-making machinery. She was convinced mRNA could be used to instruct cells to make their own medicines, including vaccines.

But for many years her career at the University of Pennsylvania was fragile. She migrated from lab to lab, relying on one senior scientist after another to take her in. She never made more than $60,000 a year.

was published, in Immunity, it got little attention.

Dr. Weissman and Dr. Kariko then showed they could induce an animal — a monkey — to make a protein they had selected. In this case, they injected monkeys with mRNA for erythropoietin, a protein that stimulates the body to make red blood cells. The animals’ red blood cell counts soared.

25 years of work by multiple scientists, including Pieter Cullis of the University of British Columbia.

Scientists also needed to isolate the virus’s spike protein from the bounty of genetic data provided by Chinese researchers. Dr. Barney Graham, of the National Institutes of Health, and Jason McClellan, of the University of Texas at Austin, solved that problem in short order.

Testing the quickly designed vaccines required a monumental effort by companies and the National Institutes of Health. But Dr. Kariko had no doubts.

On Nov. 8, the first results of the Pfizer-BioNTech study came in, showing that the mRNA vaccine offered powerful immunity to the new virus. Dr. Kariko turned to her husband. “Oh, it works,” she said. “I thought so.”

To celebrate, she ate an entire box of Goobers chocolate-covered peanuts. By herself.

Dr. Weissman celebrated with his family, ordering takeout dinner from an Italian restaurant, “with wine,” he said. Deep down, he was awed.

“My dream was always that we develop something in the lab that helps people,” Dr. Weissman said. “I’ve satisfied my life’s dream.”

Dr. Kariko and Dr. Weissman were vaccinated on Dec. 18 at the University of Pennsylvania. Their inoculations turned into a press event, and as the cameras flashed, she began to feel uncharacteristically overwhelmed.

A senior administrator told the doctors and nurses rolling up their sleeves for shots that the scientists whose research made the vaccine possible were present, and they all clapped. Dr. Kariko wept.

Things could have gone so differently, for the scientists and for the world, Dr. Langer said. “There are probably many people like her who failed,” he said.

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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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Virus Variants Can Infect Mice, Scientists Report

Bats, humans, monkeys, minks, big cats and big apes — the coronavirus can make a home in many different animals. But now the list of potential hosts has expanded to include mice, according to an unnerving new study.

Infected rodents pose no immediate risk to people, even in cities like London and New York, where they are ubiquitous and unwelcome occupants of subway stations, basements and backyards.

Still, the finding is worrying. Along with previous work, it suggests that new mutations are giving the virus the ability to replicate in a wider array of animal species, experts said.

“The virus is changing, and unfortunately it’s changing pretty fast,” said Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill, who was not involved in the new study.

only animals known to be able to catch the coronavirus from humans and pass it back. In early November, Denmark culled 17 million farmed mink to prevent the virus from evolving into dangerous new variants in the animals.

More recently, researchers found that B.1.1.7 infections in domesticated cats and dogs can cause the pets to develop heart problems similar to those seen in people with Covid-19.

To establish a successful infection, the coronavirus must bind to a protein on the surface of animal cells, gain entry into the cells, and exploit their machinery to make copies of itself. The virus must also evade the immune system’s early attempts at thwarting the infection.

Given all those requirements, it is “quite extraordinary” that the coronavirus can infect so many species, said Vincent Munster, a virologist at the National Institute of Allergy and Infectious Diseases. “Typically, viruses have a more curtailed host range.”

Mice are a known reservoir for hantavirus, which causes a rare and deadly disease in people. Even though the coronavirus variants don’t seem to be able to jump from mice to people, there is potential for them to spread among rodents, evolve into new variants, and then infect people again, Dr. Munster said.

black-footed ferrets. “This virus seems to be able to surprise us more than anything else, or any other previous virus,” Dr. Munster said. “We have to err on the side of caution.”

Dr. Sheahan said he was more concerned about transmission to people from farm animals and pets than from mice.

“You’re not catching wild mice in your house and snuggling — getting all up in their face and sharing the same airspace, like maybe with your cat or your dog,” he said. “I’d be more worried about wild or domestic animals with which we have a more intimate relationship.”

But he and other experts said the results emphasized the need to closely monitor the rapid changes in the virus.

“It’s like a moving target — it’s crazy,” he added. “There’s nothing we can do about it, other than try and get people vaccinated really fast.”

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Getting One Vaccine Is Good. How About Mix-and-Match?

In January, Britain made a change to its vaccine guidelines that shocked many health experts: If the second dose of one vaccine wasn’t available, patients could be given a different one.

The new rule was based on sheer guesswork; there was no scientific data at the time demonstrating that mixing two coronavirus vaccines was safe and effective. But that may change soon.

In February, researchers at the University of Oxford began a trial in which volunteers received a dose of the Pfizer-BioNTech vaccine followed by a dose of AstraZeneca’s formulation, or vice versa. This month, the researchers will start analyzing the blood of the subjects to see how well the mix-and-match approach works.

As growing numbers of vaccines are being authorized, researchers are testing other combinations. A few are in clinical trials, while others are being tested in animals for now.

created an Ebola vaccine whose first dose contained a virus called an adenovirus. The second shot used another virus, called vesicular stomatitis virus.

When the Covid-19 pandemic began last year, the Gamaleya researchers used a similar strategy to create vaccines against the new coronavirus. The first dose used the same adenovirus as in their Ebola vaccine, called Ad5. The second dose contained a different human adenovirus, Ad26. The researches inserted a gene into both viruses for the protein on the surface of the coronavirus, called spike.

Studies revealed that the vaccine, now known as Sputnik V, provided a strong defense against Covid-19. In clinical trials, the researchers found that it had an efficacy of 91.6 percent. Sputnik V is now in use in Russia and 56 other countries.

Recently, the Gamaleya institute joined forces with AstraZeneca, which makes its own Covid-19 vaccine. AstraZeneca’s consists of two doses of a chimpanzee adenovirus called ChAdOx1. Last week, the company reported that its vaccine had an efficacy of 76 percent.

found that the mixture worked better than two doses of the spike or of the R.B.D.

The researchers suspect that the first dose produces a broad range of antibodies that can stick to spots along the length of the spike protein, and that the second dose delivers a big supply of particularly potent antibodies to the tip of the spike. Together, the assortment of antibodies does a better job of stopping the coronavirus.

held back exports of vaccines to other countries as it grappled with a surge of Covid-19. For countries that were counting on those vaccines, a safe alternative for second doses could save lives.

After Britain was criticized in January for suggesting that vaccines could be mixed, researchers at the University of Oxford set out to put the idea to a formal test. In a trial called Com-Cov, they recruited 830 volunteers to test the two vaccines authorized by the British government: AstraZeneca’s adenovirus-based vaccine and the vaccine by Pfizer-BioNTech.

Pfizer-BioNTech’s vaccine uses a fundamentally different technology to produce spike proteins in the body. It contains tiny bubbles with genetic molecules called RNA. Once the bubbles fuse to cells, the cells use the RNA to make spike proteins.

stronger immune responses than mice that received the same vaccine for both doses.

Whether scientists carry out more experiments on other vaccines will depend on the willingness of the vaccine manufacturers. “You’re requiring quite large pharmaceutical companies to play nice together,” Dr. Wheatley said.

Dr. Bernard Moss, a virologist at the National Institute of Allergy and Infectious Diseases, suspects that a number of companies will be willing to let their vaccines be tested in combinations. “It’s always better to be a part of something that is going to be used,” he said, “than to wholly own something that isn’t.”

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Scientists Grow Mice Embryos in a Mechanical Womb

The mouse embryos looked perfectly normal. All their organs were developing as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute.

But these embryos were not growing in a mother mouse. They were developed inside an artificial uterus, the first time such a feat has been accomplished, scientists reported on Wednesday.

The experiments, at the Weizmann Institute of Science in Israel, were meant to help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.

In a study published in the journal Nature, Dr. Jacob Hanna described removing embryos from the uteruses of mice at five days of gestation and growing them for six more days in artificial wombs.

Two other papers published in Nature on Wednesday report on attempts that edge near creating early human embryos in this way. Of course, Dr. Meissner said, creation of human embryos is years away — if it is permitted at all. And for now, international regulations prohibit studying human embryos beyond 14 days of fertilization.

In the future, Dr. Tesar said, “it is not unreasonable that we might have the capacity to develop a human embryo from fertilization to birth entirely outside the uterus.”

Of course, even the suggestion of this science fiction scenario is bound to horrify many. But it is early days, with no assurance human fetuses could ever develop entirely outside the womb.

Even assuming they could, Dr. Tesar noted, “whether that is appropriate is a question for ethicists, regulators and society.”

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