The diagnosis of cancer shows a large spike at age 65.The doctor guesses the reason


New York Times

Researchers are hatching a low-cost coronavirus vaccine

The new COVID-19 vaccine, which is in clinical trials in Brazil, Mexico, Thailand and Vietnam, could change the way the world fights pandemics. The vaccine, called NVD-HXP-S, is the first in a clinical trial using a new molecular design that is widely expected to produce antibodies that are stronger than current-generation vaccines. And new vaccines are much easier to make. Existing vaccines from companies such as Pfizer and Johnson & Johnson must be manufactured in specialized factories using hard-to-find ingredients. In contrast, new vaccines can be mass-produced in chicken eggs. This is the same egg that produces billions of flu vaccines each year in factories around the world. If NVD-HXP-S proves safe and effective, influenza vaccine makers can produce well over a billion doses annually. Low- and middle-income countries that are currently struggling to get vaccines from wealthy countries may make NVD-HXP-S themselves or get it from neighboring countries at low cost. Sign up for The New York Times The Morning Newsletter. “It’s amazing. It’s going to be a game changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center. However, first, clinical trials need to confirm that NVD-HXP-S actually works on humans. The first phase of the clinical trial will end in July and the final phase will take several more months. However, experiments with vaccinated animals have raised expectations for the outlook for vaccines. “This is a home run for protection,” said Dr. Bruce Inis of the PATH Center for Vaccine Innovation and Access, which coordinated the development of NVD-HXP-S. “I think it’s a world-class vaccine.” 2P to the Rescue Vaccines works by making the immune system well aware of the virus and promoting defense. Some vaccines contain the entire killed virus. Others contain only one protein from the virus. Yet others contain genetic instructions that our cells can use to make viral proteins. When exposed to the virus or parts of it, the immune system can learn to make antibodies that attack the virus. Immune cells can also learn to recognize infected cells and destroy them. In the case of coronavirus, the best target of the immune system is the protein that covers its surface like a crown. A protein known as a spike latches on a cell and allows the virus to fuse with the cell. However, simply injecting people with coronavirus spelomers is not the best way to vaccinate them. This is because the peaplomers can take the wrong shape and encourage the immune system to make the wrong antibodies. This insight appeared long before the COVID-19 pandemic. In 2015, another coronavirus emerged, causing a fatal pneumonia called Middle East Respiratory Syndrome. Jason McLellan, then a structural biologist at Dartmouth College of Medicine, and his colleagues set out to produce a vaccine against it. They wanted to use the spike protein as a target. However, they had to take into account the fact that peplomer is a shape shifter. When a protein prepares to fuse with a cell, it distorts from a tulip-like shape to something more similar to javelin. Scientists call these two shapes the pre- and post-fusion morphologies of the spikes. Antibodies to the pre-fused shape act strongly against the coronavirus, but post-fused antibodies do not stop it. McClellan and his colleagues used standard techniques to make the MERS vaccine, but ended up with many post-fusion spikes that didn’t serve their purpose. Then they found a way to fix the protein in a tulip-like pre-fusion form. All they had to do was change two of the more than 1,000 building blocks of protein to a compound called proline. The resulting spikes (called 2P for the two new proline molecules contained) are much more likely to take the shape of the tulip of interest. Researchers injected 2P spikes into mice and found that animals could easily fight off the MERS coronavirus infection. The team filed a patent for the modified spike, but the world was barely aware of the invention. Although deadly, MERS has proven to be a relatively small threat, less contagious. Since the first appearance of MERS in humans, less than 1,000 people have died from MERS. However, in late 2019, the new coronavirus SARS-CoV-2 emerged and began to devastate the world. McClellan and his colleagues took action and designed the SARS-CoV-2 specific 2P spikes. Within a few days, Moderna used that information to design a vaccine for COVID-19. It contained a genetic molecule called RNA with instructions for making 2P spikes. Other companies soon followed suit, adopting 2P spikes in their vaccine designs and starting clinical trials. All three US-approved vaccines to date, including Johnson & Johnson, Moderna, and Pfizer-BioNTech, use 2P spikes. Other vaccine makers are also using it. Novavax has achieved strong results with 2P spikes in clinical trials and plans to apply for an emergency use authorization from the Food and Drug Administration within the next few weeks. Sanofi is also testing a 2P spike vaccine and plans to complete clinical trials later this year. Two prolines are good. Six Are Better McLellan’s ability to find life-saving clues in the structure of proteins has given him deep praise in the world of vaccines. “This guy is a genius,” said Harry Crianthus, senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he did for humanity.” But after McClellan and his colleagues handed the 2P spikes to the vaccine maker, he went back to protein and scrutinized. .. If simply exchanging two prolines improves the vaccine, further adjustments should improve the vaccine. “It makes sense to try a better vaccine,” said McClellan, now an associate professor at the University of Texas at Austin. In March, he joined forces with two biologists at the University of Texas, Ilya Finkelstein and Jennifer Maynard. Their three labs each created 100 new spikes with modified building blocks. Funded by the Gates Foundation, they tested each and combined promising changes in the new spike. Ultimately, they created a single protein that met their aspirations. The winner contained two prolines in the 2P spike, as well as four additional prolines found elsewhere in the protein. McClellan called the new spike Hexa Pro in honor of a total of six prolines. The team found that the structure of Hexa Pro is even more stable than 2P. It was also elastic and could withstand heat and harmful chemicals. McClellan wanted its rugged design to be powerful with vaccines. McClellan also hoped that HexaPro-based vaccines would reach more parts of the world, especially low- and middle-income countries that have received only a fraction of the total first-wave vaccine distribution so far. “The share of the vaccines they have received so far is terrible,” McClellan said. To that end, the University of Texas has set up a HexaPro license agreement that allows companies and laboratories in 80 low- and middle-income countries to use proteins in vaccines without paying royalties. Meanwhile, PATH’s Innisfree and his colleagues were looking for ways to increase production of the COVID-19 vaccine. They wanted a vaccine that non-wealthy countries could make on their own. The first wave of COVID-19 vaccine, approved with a little help from eggs, requires special and expensive ingredients to make. For example, Moderna’s RNA-based vaccines require genetic components called nucleotides and custom-made fatty acids to create bubbles around them. These ingredients need to be assembled into a vaccine in a dedicated factory. In contrast, the method of making influenza vaccines is research. Many countries have huge factories where the flu virus is injected into chicken eggs for cheap flu shots. The egg produces a large number of new copies of the virus. Factory workers then extract the virus, weaken or kill it, and then vaccinate it. The PATH team wondered if scientists could make a COVID-19 vaccine that could be cheaply grown on chicken eggs. That way, the same factory that vaccinates against the flu can also vaccinate against COVID-19. In New York, a team of scientists at Mount Sinai School of Medicine knew how to make just such a vaccine using a bird virus called the Newcastle disease virus, which is harmless to humans. Scientists have been experimenting with the Newcastle virus for years to create vaccines for a variety of diseases. For example, to develop an Ebola vaccine, researchers added the Ebola gene to the Newcastle virus’ own gene set. Scientists then inserted the genetically engineered virus into chicken eggs. Because it is a bird virus, it proliferated rapidly in eggs. Researchers have arrived at the Newcastle disease virus, which is coated with Ebola protein. At Mount Sinai, researchers tried to do the same with the coronavirus peplomer instead of the Ebola protein. When they learned about the new HexaPro version of McClellan, they added it to the Newcastle disease virus. The virus became bristle with peplomer, many of which had the desired pre-fusion shape. In favor of both the Newcastle virus and the HexaPro spike, they called it NDV-HXP-S. PATH has arranged to produce thousands of NDV-HXP-S at a factory in Vietnam that normally produces influenza vaccines from chicken eggs. In October, the factory sent the vaccine to New York for testing. Researchers at Mount Sinai have discovered that NDV-HXP-S provides strong protection for mice and hamsters. “I can honestly say that every hamster and every mouse in the world can be protected from SARS-CoV-2,” said research leader Peter Parese. “But the jury hasn’t yet discussed what it does in humans.” The efficacy of the vaccine has provided additional benefits: researchers needed less virus for effective doses. One egg may yield 5-10 NDV-HXP-S compared to one or two doses of influenza vaccine. “We’re very excited about this because I think it’s a cheap way to make a vaccine,” Parese said. Later, PATH linked the Mount Sinai team with the flu vaccine maker. On March 15, Vietnam’s Vaccine Medical and Biology Institute announced the start of clinical trials for NDV-HXP-S. A week later, the Thai government pharmaceutical organization followed. On March 26, the Butantan Institute in Brazil said it would seek permission to begin its own clinical trials of NDV-HXP-S. Meanwhile, the Mount Sinai team has licensed the vaccine as an intranasal spray to Mexican vaccine maker Avi-Mex. The company will begin clinical trials to see if the vaccine is even more potent in its form. The prospect of producing the vaccine entirely on its own was appealing to the countries involved. “The production of this vaccine is produced by Thai people for Thai people,” Thai health minister Anutin Charnviracle said in a statement in Bangkok. In Brazil, the Butantan Institute has exaggerated its version of NDV-HXP-S as a “Brazilian vaccine”. It is “produced entirely in Brazil, independent of imports”. Taylor at the Duke Global Health Innovation Center was sympathetic. “I understand why it’s a really fascinating outlook,” she said. “They have been at the mercy of the global supply chain.” Georgetown Law School intellectual property expert Madhaby Thunder said the NDV-HXP-S is tackling the current wave of COVID-19 infections. He warned that he would not help a country like Brazil immediately. “We’re not talking about 16 billion doses in 2020,” she said. Instead, this strategy is important for long-term vaccine production, not only for COVID-19, but also for other pandemics that may occur in the future. “It sounds very promising,” she said. Meanwhile, McClellan went back to the molecular drawing board and tried to create a third version of Spike, which was even better than Hexa Pro. “There is no end to this process,” he said. “The number of permutations is almost infinite. At some point, we would have to say,” This is the next generation. ” This article was originally published in The New York Times. © 2021 The New York Times Company

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