依然是讲述美国应对新冠疫情发明疫苗的故事。美方的曲速行动计划动用了近300亿美元，完成了疫苗的研发、生产、分配和使用，才有了今天疫情的彻底终结。这段有趣的历史，不应该被遗忘。照例做些摘录。
“There were about 120 viruses known to pose a potential risk to people. Those viruses could be divided into twenty-five different families. There were licensed vaccines for viruses in just thirteen of those families. Most global-health efforts focused on the troubling pathogens that had emerged in the past—but that left a whole swath of the viral landscape unknown, unprobed, unprotected against”
25个家族的120个病毒中，真正有疫苗的才13个家族，人类依然任重道远。
“Back at the NIH, Graham thought he had an inside line on the coronavirus sequence, which he would need for the vaccine work to begin. At Fauci’s suggestion, he reached out to George Gao, the head of China’s CDC, a scientist whom Graham had met at several international meetings. Days went by without a response. In the end, the NIH obtained the sequence when it went global on Virological.org on January 10. “It’s online so everyone has it now,” McLellan griped in a message to a member of his lab in Texas.”
不得不感叹老美的速度。
“Big Pharma had, by and large, concluded that there was no upside to going after emerging infectious diseases. As Merck and Sanofi had learned firsthand from their own experiences with Ebola and Zika, most outbreaks are terrifying, headline-grabbing events that quickly become utterly forgettable—at least to those not directly affected. Vaccines cost hundreds of millions of dollars to develop and often take years, decades even, to bring to market. Very few vaccines share the history of Merck’s 1967 mumps vaccine, developed and approved in four years and still needed today.* ”
埃博拉和寨卡疫苗的折翼让大公司对新病毒疫苗的研发兴趣不大。
“He discovered that Moderna could manufacture a pilot lot for a safety trial in humans using the small-scale equipment the company used for personalized cancer treatments. This brought the cost down from three to five million dollars to less than a million—a veritable bargain.”
Moderna的个性化疫苗设备让早期新冠疫苗从3-5百万美元的生产费用降低到一百万以下。
“If Moderna was the Apple of the vaccine world, an envy-inspiring company that was oozing with cool and bursting with capital, Novavax was Nokia, a has-been that was still selling something but you weren’t entirely sure who was buying it. Novasomes, the company’s trademarked encapsulation technology, were microscopic bubbles of fat developed as a timed-release mechanism for chicken vaccines. But they proved to be more valuable as a moisturizer in a skin-care line, Nova Skin Care. And thanks to their oh-so-creamy mouth-feel, novasomes ended up in low-fat Girl Scout cookies and in Richard Simmons’s Slimmons, 97 percent fat-free cookies. Thirty years later, Novavax had dropped the novasomes but was still trying, unsuccessfully, to get a human vaccine onto the market.”
The company focused on protein-subunit vaccines. Unlike Moderna’s mRNA vaccine, which delivered instructions to the body’s cells on how to produce the spike protein, Novavax’s vaccine delivered the spike protein itself. Protein-subunit vaccines were invented during the genetic-engineering revolution in the 1980s, and though they took longer to make than mRNA vaccines, the technique had a solid track record. You could grow virus proteins inside a variety of organisms, from E. coli bacteria to tobacco plants. Back in the 1980s, long before he became Novavax’s head of vaccine development, Gale Smith had invented a technique that used one of the fastest—and strangest—platforms: caterpillar ovary cells. Whenever there was an outbreak of an infectious disease, from swine flu to Ebola, Novavax raced to produce a vaccine candidate in these cells, juicing its stock with a blitz of press releases. But every time, the company let its investors down. It let itself down. This time, Glenn and Smith hoped things would end differently.”
Apple vs Nokia。Novovax的坏运气值得深入研究。看起来只是运气背后实际往往是实力不足。
“He soon discovered that when the antibody response went off the rails, the rest of the immune system malfunctioned as well. You might say the immune system was confused about the size of the threat it was facing. A healthy immune response to a virus, as we’ve seen, involves, among other things, sending in killer T cells to destroy infected cells. But for larger interlopers that, unlike viruses, remain outside of cells—like bacteria, pollens, or parasitic worms—the body produces mucus, inflammation, and fighting cells known as eosinophils. This is the type of response we associate with allergies. That response cuts back on the killer T cells and generally makes it more difficult for the body to clear viruses from small airways.”
“Using a technique called X-ray crystallography, Graham and McLellan produced three-dimensional images of the antibody-bound protein, and the difference between the prefusion and postfusion structures was obvious. Prefusion, the protein was a squat triangle. Postfusion, it was like the Eiffel Tower, 50 percent taller. When the protein changed shape, it exposed different nooks and crannies, known as epitopes. This explained why so many of the antibodies people produced to the postfusion form were not neutralizing the virus.”
抗体和免疫系统的相互作用、相爱相杀。抗体的结构特征也影响其消灭病毒的效率。
“Going back to the old platform Smith had developed, Novavax was planning to grow its spike proteins inside cells plucked from caterpillar ovaries. Although the concept had proven itself over and over again, every new protein you made in those cells required time-consuming tweaks to the purification and manufacturing processes, a big difference from the plug-and-play approach of Moderna’s mRNA vaccines.
Novavax’s general process began by harnessing the power of another virus, one that infected insects rather than people. ”
mRNA技术相比蛋白苗的优势：即插即用 vs 繁琐的细胞培养、纯化体系，在速度上拥有压倒性的优势。
Emergency use authorization, or EUA, the agency just needed to be convinced that a product “may be effective” and that the potential benefits outweighed the safety risks. The agency had issued EUAs for antiviral drugs during the swine flu pandemic, but it had never authorized a vaccine in that manner in its history. Because vaccines are meant for the healthy, everyone knew the risk-benefit calculus was going to be stacked against an EUA for a vaccine.”
疫苗的EUA居然是历史上的头一回。这个也是人类和病毒斗争的巨大进步，感染期一年内就搞出来疫苗了。
“Congress, meanwhile, had upped the administration’s meager request for a funding supplement, passing a bill to give HHS nearly eight billion dollars to fight the coronavirus. Trump signed it a day later, at 9:05 a.m. on Friday, March 6.”
美国的拨款效率也是够快的，2020/3/6，投入80亿美元。
With the rise of molecular biology in the 1980s, the concept of gene-based vaccines began to take shape. The biggest hurdle was that DNA on its own didn’t generate much of an immune response. When Weissman tested Karikó’s mRNA in his lab, he found it had the opposite problem that DNA did: It caused too much of a reaction. His cell cultures looked like the aftermath of a bombing raid. He had a hunch about what was happening. To a cell, a strand of foreign mRNA is indistinguishable from an RNA virus. The cell will issue a red alert and stop expressing any and all RNA. A cell that senses it is under attack for long enough will self-destruct. Weissman told Karikó that her mRNA produced such an overwhelming immune reaction, it would not only be challenging as a vaccine, it might never work as a therapy either.”
DNA疫苗的问题在于其免疫反应过大。mRNA这方面的问题最初要更大。
Moderna became a patent-filing machine, building up a fortress of intellectual property, but it couldn’t outrun the need for the Karikó and Weissman technology. Their patent was officially approved in October 2012, and it was broad enough that it was going to be hard to build a business on modified mRNA without infringing on it. The following year, Moderna signed a $420 million deal with AstraZeneca to collaborate on an mRNA-based drug to repair damaged heart tissue, along with possible cancer drugs. A breakthrough seemed imminent. With each passing year, the price of the Karikó patent crept upward. The license holder, Gary Dahl, was now unwilling to sublicense the mRNA technology for less than $30 million.”
“In 2016, the company was forced to abandon a clinical trial on what was going to be the company’s first therapy, a treatment for a rare disease called Crigler-Najjar syndrome. Patients with the disease are missing a single liver enzyme, and in its most severe form, the disorder can lead to brain damage in infants. As a single-gene disorder that could be treated with only a small amount of enzyme, it seemed like the perfect target. Moderna, however, could never find the correct dose during animal studies. Too much of the drug induced liver toxicity; too little of the drug wasn’t potent enough. In Moderna’s first two clinical trials of flu vaccines, a significant number of people suffered from pain and swelling at the injection site, and the levels of antibodies produced were middling, possibly due to the type of fat Moderna had used to stabilize its mRNA and shuttle it into cells.Moderna agreed to pay seventy-five million dollars for a license to the UPenn patent on top of future royalties.
Modena的创业也不容易，还好拿到了大厂的资金，但专利上问题也很明显，授权费还一下子高到离谱了。几个临床也进展不顺，肝上的临床始终在动物实验上找不到何时的剂量；转疫苗也不容易，流感疫苗遇到了效果一般但副作用更大的问题，成不了。最后的专利授权花了7500万美元。
Project Warp Speed：Maximally expediting a safe effective vaccine， A safe, effective, broadly-administered vaccine is the single most important solution to COVID-19 pandemic
MISSION: Maximally expedite the development of a safe and effective vaccine with sufficient scale to inoculate all Americans who need it
DEADLINE: Enable broad access to the public by October 2020
PLAN: Modeled after the Manhattan Project approach, a multi-disciplinary, multi-sector team that brings the numerous in-flight efforts under a single authority to drive relentless coordination, barrier elimination, and accountability for mission success”
新时代的曼哈顿计划：曲速计划。
“Working closely with BARDA, Marks was narrowing down the list of ninety-two vaccine candidates the MP 2.0 team was considering. The Defense Department, for instance, had been funding the biotech firm Inovio, which was developing a DNA-based vaccine that required a special device, known as a gene gun, in order to be injected. Marks didn’t think it was practical, but he wasn’t quite ready to write it off. “Beam me up, Scotty,” he said, adding it to the portfolio.”
也是惊了，前阵子居然还能看到这个DBA疫苗公司的项目，东方高圣引入了国内，注定要完蛋。
“Marks began again, describing how he and his team had come up with a scheme to prioritize fourteen vaccines using a five-point scale under five different criteria, including the status of development and the likelihood of success with a particular manufacturing platform. At the top of the list, with fourteen points, he ranked the vaccine Merck was developing using the same platform as its Ebola vaccine, which had received FDA approval six months earlier. This coronavirus vaccine was a chimera; it would use a weakened strain of the vesicular stomatitis virus outfitted with a functional coronavirus spike that did the dirty work of infecting cells. Unlike the Oxford vaccine, which generated a onetime burst of spike proteins inside cells, the viruses in Merck’s live-attenuated vaccine made copies of themselves, producing multiple generations of spike-covered viruses. Next up was Sanofi’s protein-subunit vaccine, which earned thirteen points. Tied for third place were the mRNA vaccines from Moderna and Pfizer, with ten points each. Johnson and Johnson and Novavax were in fourth place, while the Oxford vaccine, with just five points, was tied for last place with an obscure company in California. “About half of those vaccines had already received some support from the federal government, but Marks had a few long-shot candidates on the list, including an oral vaccine made by a company called VaxArt.”
十四种疫苗的打分方式，满分25分居然最高的只有14分，最低才几分。
“In April 2004, two researchers studying the first SARS virus at the Beijing Institute of Virology were infected in separate incidents and they spread the virus to seven others. Hundreds were quarantined and one person died.”
泄露说果然还是有原因的。
The other four companies that had, at least in principle, joined Operation Warp Speed would have to undertake the same process to get sign-offs on their trial protocols. AstraZeneca was aiming for a July start to its trial; Johnson and Johnson was gearing up for early fall; cash-poor Novavax and venerable Sanofi were a distant fourth and fifth place. Notably absent from Operation Warp Speed’s harmonized trials: Pfizer. The unstoppable multinational was likely going to be the second company to enter phase 3 clinical trials in the United States, but, as chief scientific officer Mikael Dolsten had already made clear to Francis Collins, Pfizer would be taking no money for development. The company would be assuming all the risk and, it hoped, reaping all the reward. It would soon offer Operation Warp Speed a chance to lock in its two-dose mRNA vaccine at an exorbitant one hundred dollars per dose—that meant ten billion dollars to vaccinate fifty million people, less than a sixth of the U.S. population. That was more than double the sum Moderna had floated. Moncef Slaoui and General Perna declined.
曲速计划下，大家的进展起初还是不错的。辉瑞倒是猴子不够用了。
“In reality, convalescent plasma wasn’t going to save the lives of thirty-five people out of a hundred. It was going to reduce the relative risk of death in this subgroup by 35 percent, from, say, ten out of every hundred patients to around seven out of a hundred. No self-respecting cancer doctor would ever talk in terms of absolute-risk reductions! Marks thought. That would be a miracle.
血浆疗法的帮忙可能没那么大，有趣的统计游戏。
Mascola rang Graham, but he wasn’t answering. After a few minutes, Graham called him back. He listened intently but expressed little emotion. “I can’t believe it worked so well,” he said, his scientist hat firmly on his head. It was only later, after he set down the phone, that he recognized the heft of it, and once again he grew emotional. Two vaccines, both mRNA, both with his stabilized spike design, had worked extraordinarily well. The shock of it all turned to exuberance, and he realized that, beyond a shadow of a doubt, this vaccine truly had the potential to end the pandemic.
It couldn’t come soon enough.”
mRNA的效果好的令科学家都惊讶。
“AstraZeneca-Oxford vaccine was unlikely to gain approval in the United States anytime soon. The company had, as Moncef Slaoui anticipated, overhyped the results from the Oxford-run clinical trials in Brazil and the United Kingdom. It touted a result showing that it was 90 percent effective, but this was based on an analysis of a subset of subjects who had accidentally received a half dose as their first dose. When participants received two full doses, as they had in the Operation Warp Speed trial in the United States, the efficacy dropped to 62 percent. It was a passing grade, but not by much. Johnson and Johnson would top that with just one dose.”
牛津疫苗的问题是范围以扩大，有效性就从90掉到了62，刚刚及格。
“Based on the agreements the company had already inked with governments around the world for its COVID-19 vaccine, Bancel said it was on track to bring in at least $11.7 billion in revenue by the end of 2021. With its growing war chest, the company was investing in a major way in eight other vaccines, including one against that diabolical virus that Barney Graham had studied so long ago, RSV. Also in its pipeline were additional vaccines being developed with the NIH for HIV and emerging disease-causing viruses, such as Nipah, which, like the novel coronavirus, was endemic to bats. But that was not all, Bancel said. The company was also working to propel more mRNA therapeutics onto the market, including those against cancers, rare diseases, autoimmune diseases, and heart disease. He told viewers that he could not wait to see what the next ten years was going to look like. “I believe this is just the beginning,” he said.”
mRNA时代刚刚开启。从疫苗到治疗性药物等等。