探寻天外天

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。

3月份读完的书，辉瑞CEO讲述的开发新冠疫苗的故事，可以说是当下最好的医药投资类读物了。疫苗的发明远不只是科学研究、和临床试验，生产也是巨大的门槛。需要巨大的资金、极度的好运气和持续的加班加点才可能把不可能变为可能。这是今天的登月工程，毫不夸张。照例做些摘录。

Kennedy said he chose the moon, not because it was easy, but because it was hard: “Because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win.”

More recently, Mariana Mazzucato, professor in the economics of innovation and public value at University College London, in her book Mission Economy: A Moonshot Guide to Changing Capitalism, writes that we saw many “spillovers” from Kennedy’s moonshot affecting life on Earth—technological and organizational innovations that could never have been predicted at the beginning. It was a “massive exercise in problem-solving.” These are the reasons I felt it appropriate to name this book Moonshot. Like Kennedy’s moonshot, the work to develop our novel vaccine against COVID-19 was indeed a massive exercise in problem-solving, an exercise that allowed us to consolidate scientific knowledge of a decade within nine months and that will have spillover effects in many other scientific areas, affecting life on Earth more than we thought at the beginning.”

明知山有虎、偏向虎山行。当年肯尼迪登月工程带来了巨大的技术溢出效应，相信这次的mRNA也一样。

What matters is not what happens to you, but how you react to it. Epictetus, AD 50–135”

You will never do anything in this world without courage. It is the greatest quality of the mind next to honor. Our problem is not that we aim too high and miss, but we aim too low and hit. — Aristotle, 384–322 BC

先哲的经典语录。关键的不是发生了什么，而是如何应对= 放下执念，认真应对；没有勇气什么都干不成，勇气是最大的美德。人类的问题不是目标太远大，往往是目标太渺小！

Clearly this is not business as usual. If we miss our budget for a year, no one will remember it the year after. If we miss the opportunity to do something for the world now, we will all remember it forever.

At the end of the meeting I went through the room to each of my executive leadership team members and assigned them specific tasks related to what we had agreed. I sensed the team’s resolve.”

危难到来时，即是难得的担当，也是对良机的充分把握，身在其中不错过。

And as usual in life, the most critical decisions were the most challenging to make. When I look back, the one that clearly stood out was the decision to use the mRNA technology to develop a COVID-19 vaccine. Not only because a different choice would have yielded very different outcomes. It was also because that particular decision was the most counterintuitive. The obvious option was not to use mRNA. It required a lot of forward thinking and eventually a lot of courage, but this is what gave us the vaccine.”

“In 2012, Phil and others published an article showing that self-amplifying RNA encapsulated within a lipid nanoparticle potently elicited antibody and T-cell responses. These findings were early signals of what was to come. Pfizer has been interested in RNA in part because of its ability to respond quickly to changes and be consistent. Although molecules of RNA also can vary in their behavior, one piece of RNA behaves a lot more like another piece of RNA in general than either viruses or proteins do. We liked the flexibility of the technology compared with traditional vaccine technologies. This flexibility includes the ability to alter the RNA sequence in the vaccine to potentially address new strains of the virus, if one were to emerge that is not well covered by the current vaccine.”

“Are you sure about this?” I asked. He was. Mikael was convinced through our work with flu that the technology was the right choice.“The technology is ideal for something like this. It is fast, and capable of being edited quickly for updates and boosters. Adenovirus or other viral vectors technologies could have difficulties with boosters because the immune system will create antibodies not only against the coronavirus but also against the adenovirus,” he said. Mikael knew from previous discussions that the speed of development and the ability to boost frequently were very high priorities for me.”

“What about using protein technology?” I asked. “We are good with proteins, and we could certainly make a vaccine with this platform, but with mRNA we would have both humoral and cellular immune responses. With proteins, we will have good antibodies, but I am not sure we would have T-cells,” he replied.”

选择mRNA技术对辉瑞来说要比Moderna等难得多，大公司更倾向选择成熟的技术路线，比如GSK、AZ和Sanofi等等。辉瑞的选择小心谨慎，也充满智慧，还没有依仗自己的资源多头并进。

“On April 9, we signed a collaboration agreement to codevelop a first-in-class, mRNA-based coronavirus vaccine, aimed at preventing COVID-19 infection. BioNTech received from us a $72 million up-front payment and was eligible for future milestone payments of an additional $563 million for a total consideration of about $636 million. In addition, we were going to provide $113 million in cash to them by buying equity from the company (bringing our total ownership of the company to about 2.3 percent at that time). Under the collaboration agreement, the two parties agreed to share all development costs and profits fifty-fifty, but Pfizer agreed to cover all these costs up front. If the project failed, Pfizer would bear all the losses alone. If the project succeeded, BioNTech would pay back to Pfizer its share of development costs from its profits from the commercialization of the product. ”

惊人、大方的合作条款了。

“I knew that a century ago, during the 1918 influenza pandemic, the second wave was much more lethal than the first. I also knew that during the coming fall we would face the double danger of a flu season amid the pandemic.“It is not good enough,” I told the teams. “We must have it by this October. And we must have hundreds of millions of doses by next year, not tens of millions.”

病毒的第二波冲击要比第一波狠，原来并非首次。

“The design of the Phase 1 and 2 programs was done in a very clever way. Instead of waiting to have all candidates released from the lab before they started the program, they would start the study immediately, when the first vaccine candidate became available. They would test it on multiple combinations at different doses, in different regimens, and with different age groups so they could develop a good understanding of how the candidate interacted with the immune system. Once the second candidate became available, they would follow a smart plan of targeted tests, comparing it with the first one. These tests would allow us to draw conclusions for the second candidate without repeating the entire set of tests we had done for the first. We would repeat the same with the third and fourth candidates. The idea was to quickly terminate the less promising candidates, concentrate on the best two, and with a few additional tests select the final candidate that would move to a Phase 3 study. ”

从构建的12个疫苗到选出4个候选进入临床，再到3期选中1个，每一步都要过关。

“The FDA had set a limit of at least 50 percent efficacy for a vaccine to be approved. Our team had designed the study to be able to demonstrate vaccine efficacy of 60 percent, an even higher internal standard. The FDA usually asks for two months of safety data for Emergency Use Authorization and six months of safety data for full approval. Regardless, our team would follow up with the enrolled participants for two years. The statistical analysis that our mathematicians performed indicated that for this level of efficacy (60 percent), they would need a total of at least 164 events of COVID-19 (participants who get the disease) to demonstrate statistically significant efficacy. A study size of ten thousand to fifteen thousand participants could potentially generate these results in less than a year (dependent on incidence rate of disease/infection). They decided to blow out the study size and go for thirty thousand participants so they could accumulate COVID-19 events faster (later we increased this number to over forty-six thousand).”

早期仅仅是60%的有效率预估。为了加速，只能扩大临床规模，都是钱啊。

“I told the global presidents of these business units that they should each consider their unit like an entrepreneurial biotech company, with the presidents of each business unit acting as CEOs and with me in the role of the CEO of a private equity firm that owns them.

“A private equity firm does three things with the biotechs they own,” I told them.”“First, it appoints their management. I have appointed you. Second, it agrees with their management on the strategic direction. We have discussed and have clear alignment on the strategic direction that each one of you should follow. Third, it allocates capital to them. You will have to compete for that. The best proposals will get the funding.”

不得不说这种灵活的组织安排犹如创业公司。

“We had developed four vaccine candidates, each representing a unique mRNA format and target antigen combination. Two of the four vaccine candidates included a nucleoside-modified mRNA (modRNA), one included a uridine containing mRNA (uRNA), and the fourth vaccine candidate utilized self-amplifying mRNA (saRNA). Each mRNA format was combined with a lipid nanoparticle formulation. Two of the vaccine candidates encoded an optimized full-length spike protein, and the other two candidates encoded the receptor binding domain (RBD) of the spike protein. The RBD-based candidates contain a piece of the spike that was thought to be important for eliciting antibodies that could inactivate the virus, while the longer spike protein was thought to be important for eliciting a broader or more differentiated antibody response. The first studies in humans were meant to compare the four candidates at different dose levels. The dose escalation portion of the Phase 1/2 trial included approximately two hundred healthy subjects ages eighteen to fifty-five and targeted a dose range of one microgram (µg) to one hundred µg, aiming to determine the optimal dose for further studies as well as evaluate the safety and immunogenicity of the vaccine candidates.

“We had two promising final candidates, two different vaccine formulations. The first (known as b1) was the one that used only the RBD of the SARS-CoV-2 spike protein. This candidate had the most data and appeared to be an excellent choice. The second (known as b2) was the one that used the full-length spike protein. It appeared to have a broader immune response with fewer tolerability issues, fewer chills, and fewer headaches. Very preliminary data was also indicating that it might be potentially more potent in older adults, who were more susceptible to severe COVID-19 in the first place and whose immunity was more difficult to boost.”

艰难的四选二、二选一，最难的成功了。

“From the ninety-four cases of confirmed COVID-19, ninety belonged to the placebo group.” I was shocked and felt I’d misheard, so I abruptly interjected.“Did you say Nineteen? One–nine?”“No. Ninety. Nine–zero!”“But what is the efficacy?”“Ninety-five-point-six percent, sir.”

Doug and I remained speechless for a few moments.“How conclusive is this number?” I asked.“The statistical significance is very high, sir,” one of them replied. “We do not expect this number to change much when we have all the one hundred sixty-four cases accumulated and proceed to the final readout.”

中期见到了95.6%的有效率，难以置信。当初的预估只有60%。

“For context, total vaccine production at Pfizer at this point, before COVID-19, was two hundred million doses per year, including Prevnar, a pneumococcal flu vaccine to protect infants, kids, and adults. Prior to the pandemic, Prevnar was our largest-volume vaccine, and it had taken ten years to get to that level of production. I knew that we would need to double our overall vaccine production in just nine months. And we would need to do so on an mRNA platform that had not been used at any scale, ever.”

“The key ingredient in our COVID-19 vaccine would prove to be lipids. Remember that our vaccine uses lipid nanoparticles to transport mRNA to instruct cells to make the SARS-CoV-2 spike protein. Lipids, which are chemically synthesized, became the most important constraint to solve for. They were a new ingredient, not used at scale in other vaccines.

To make matters even more complex, there are four different lipids needed. Two are proprietary and two are commodity. And so where does one go to buy large volumes of diverse lipids? It turns out, not many places. On the commodity side, niche chemical companies became critical partners. The term “working together” does not sufficiently describe the extreme collaboration we had with the entire biopharma ecosystem.”

关键原料：脂质体，还需要4种，供应链就很关键了。

“As we set our sights on producing larger and larger volumes of vaccine, we became concerned about the capacity of our already overburdened suppliers. The solution we landed on was to build our own capacity. This meant replicating the pumps and T-mixers dozens and dozens of times into lipid nanoparticle skids. The tech industry has seen warehouse-sized data centers with hundreds and hundreds of racks of network computers. Those racks of computers combine to form cloud computing. It’s a similar idea with our lipid nanoparticle skids. Combined, they can produce massive doses of vaccine. ”

“Of course, we are doing aseptic formulation and we cannot host our new formulation suites under a tent. But the concept is what is important here. We can order prefabricated modules that we can install in our Kalamazoo manufacturing site within months, not years. There is a producer in Texas that makes them. We can give him specifications, build them there, and transfer them to Michigan with special large trucks. We will have to do the transfer at night, and we would need the police forces of several states to cooperate with us for this operation, but it can be done. It would take us months instead of years,” Mike said.”

“This breakthrough in logistics will become increasingly useful in the future as we explore new mRNA technologies.

Vaccines have always faced a last-mile problem. We can ship the vaccine thousands and thousands of miles by planes, trains, boats, and automobiles, but that last mile into the center of a city or a remote community—all the while preserving a subfreezing cold chain—requires solving a snarl of complications. Inventing a therapeutic drug or a vaccine is the first mile, but there remain many miles to go. Medicines have always faced this challenge, which is why some companies and philanthropies have invested in mobile refrigeration. Cool.”

“Another challenge we recognized early on was to reduce waste and increase the number of doses per vial.”“Another challenge we recognized early on was to reduce waste and increase the number of doses per vial.

At the time we submitted our first regulatory applications, we knew that we were filling our vials with enough vaccine volume so that after dilution each vial would have approximately 2.25 ml. For each dose we needed 0.3 ml, so inside every vial we had volume for at least six doses. The challenge was that you cannot use all the volume all the time. After injection, some volume will remain unused, typically in the space between the needle and the tip of the syringe, as “dead volume.” There”

“He had noticed that we were significantly overfilling our vials and told me that according to his calculations we were wasting 40 percent.

“Albert, we must find a solution to this,” Ugur told me.

I brought it up to the team, and we started exploring solutions. We agreed to a plan that would allow us to test many different combinations of syringes and needles and find how many doses could be extracted with each. But at the time of the submission, we hadn’t done the work to determine the maximum number of doses that we could safely extract from each vial, and for this reason, we filed our application indicating only five doses per vial.”

“The way we price our medicines is by calculating the value they bring to patients, to the healthcare system, and to society. Unlike what some may believe, good medicines reduce, rather than increase, the cost of a healthcare system. We try to calculate this economic value. For example, if one hundred people take a heart medicine and as a result we have five fewer heart attacks, we calculate the cost that these five heart attacks would generate to the healthcare system (ambulance rides, hospital stays, tests, doctors, caregivers, work days lost, etc.) and compare it to the cost of the medicine for one hundred people. Of course, there are many more nuances to this economic value. How does one put a price on the avoidance of human pain? This, in my opinion, is truly invaluable.

I asked our pricing team to calculate the usual economics of the global COVID-19 crisis, and they came back with staggering numbers. For an assumed 65 percent efficacy, the reduction of hospitalization costs alone would be hundreds of billions of dollars. We could price the vaccine at $600 per dose, and still the healthcare system would pay less than it saves—not counting the value of human lives saved. I realized that this could become a gigantic financial opportunity for us but also that in the middle of a pandemic we could not use the standard value calculation for setting the price. I asked for a different approach. I told the team to bring me the current cost of other cutting-edge vaccines like for measles, shingles, pneumonia, etc. In the US they were priced between $150 and $200 per dose. It sounded fair to me to match the low end of the already existing vaccine prices. No one could say that we were using the pandemic as an opportunity to set prices at unusually high levels.”

“In the US, pharmaceuticals ranked near the bottom of all sectors, right next to the government, in terms of reputation. I again asked the pricing team to give me the current prices of the cheapest commodity vaccines. In the US, flu vaccines cost up to $70, but they also offered a low protection rate of around 50 percent. Their low end is around $20 to $30.

“We are changing course,” I told them. “For the high-income countries, the starting point should be the low end of flu pricing. We can still offer discounts for high-volume commitments.”

“Equity doesn’t mean that we give everyone the same. Equity means that we give more to those who need more. Therefore, we couldn’t have a single price for all. Instead, we decided to implement a three-tiered pricing approach. We used the World Bank’s classification of economies for our own analytical purposes. ”

“Most of the high-income countries were among the first to place orders to reserve doses of our vaccine through 2021. Europe, the US, Japan, and the UK were among the many that included us in their bets. Unfortunately, many other countries, particularly middle- and low-income, decided to go exclusively with other vaccines, either because mRNA technology was untested at that time or because other companies had promised local manufacturing options. ”

不容易的定价。特别时刻特殊定价，商业化要卖到600，为了大家最后实际美国采购价只有19.5。

“In the meantime, the US Trade Representative, Katherine Tai, announced suddenly that the US would support a waiver of the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement for COVID-19 vaccines at the World Trade Organization (WTO). The TRIPS agreement is an international legal agreement that was signed in April of 1994 and became effective on January 1, 1995. The agreement introduced intellectual property law into the multilateral trading system for the first time. India and South Africa had requested such a waiver from the WTO, but there was no traction for this request so far. Interestingly enough, both countries are among the largest generic medicine manufacturers in the world, and for many people the request looked quite self-serving.”

“The US made this a condition to COVAX and decided to purchase five hundred million doses with an option to procure more. It was a major step toward vaccine equity, and I was proud that we were leading the way. There was, however, one stubborn issue that needed to be resolved first with respect to liability-related provisions. ”

“ I called Netanyahu back. A few hours later, he returned my call. Ron Dermer, Israel’s ambassador to the US, was already on the line, together with Israel’s national security advisor. I looked at my watch and calculated the time in Israel. I was shocked. “Prime minister, it is two thirty in the morning!”

“Don’t worry about that. I don’t need much sleep,” he replied. “Look, Albert. If we leave this just to the lawyers, we will never get it done. I will conference our head lawyer now. Can you do the same?”

I felt a little bit uncomfortable, but I was also intrigued by his decisiveness and sense of urgency. ”

“The rise in infections was occurring with the introduction of the more infectious delta variant, and what we needed to determine quickly was whether the upsurge in cases was caused by lack of efficacy of the vaccine against this variant or the gradual loss of efficacy over time. This had critical implications not just for Israel but also for the world, because if the former was true, then a new vaccine tailor-made to prevent the delta variant needed to be developed immediately. Our analysis revealed that the efficacy of the vaccine was waning over time and most specifically among the individuals vaccinated in large numbers beginning in December. ”

“New mRNA technology could drive prevention and early detection of disease.

The breakthroughs we have made with mRNA vaccine technology may allow for one vaccine to provide protection for multiple diseases, decreasing the number of shots needed for common vaccine-preventable diseases. In addition, cancer research is studying how to use mRNA to trigger the immune system to target specific cancer cells. ”

“At the time of this writing, cumulative global mortality from COVID-19 has surpassed five million, a horrifying toll, and it will continue to rise. But each and every year, about seventeen million people die from cardiovascular disease and ten million from cancer. Are these patients somehow less deserving?”

“The first truth is that our breakthrough vaccine was the result of the rare combination of brilliant, cutting-edge science powered by the private sector alongside collaborative engagements with governments. It’s fascinating to see that in the last year “mRNA” became a household word. Laypeople followed the science as if it were a popular sport. It’s imperative that our society continues to respect and honor science. ”

“Let us always remember that businesses have the power to make a positive difference. Corporations play a vital role as engines of creativity and avenues of opportunity. Commercial pressures require businesspeople to quickly discover and adapt new technologies and boost efficiency and productivity. Entrepreneurship and innovation go hand in hand.”

“This culture that we created gave us the appropriate mindset and allowed Pfizer to move with the agility and speed of a small biotech and bring to the world a breakthrough vaccine that is dramatically changing the lives of so many. Whether you are a leader or a team member, I would encourage you to ask yourself the following three questions during every step of your journey:

Am I being true to my purpose?

Have I aimed high enough?

Do I have the right mindset?”