In September 1992, Deborah Fuller traveled from Wisconsin to New York for a scientific conference at the nonprofit Cold Spring Harbor Laboratory, brimming with anticipation. She was there to present early but promising research on a completely new vaccine approach that she had been working on.
1992 年 9月，黛博拉·富勒(Deborah Fuller)从威斯康星州前往纽约，在非营利性的冷泉港实验室举行了一次科学会议，充满了期待。 她在那里提出有关她一直在努力的全新疫苗方法的早期但有希望的研究。
It turned out to be a fortuitous meeting. “I go there thinking I’m going to be the only one with this new idea, and there were half a dozen other people all presenting this concept,” says Fuller, PhD, now a professor of microbiology at the University of Washington School of Medicine in Seattle who’s working on a coronavirus vaccine. If other labs were getting the same results, it meant her research wasn’t just a fluke.
原来是一次偶然的会议。 “我去那里逻辑思维能力，我会是唯一一个与这个新的想法，并有半打其他人都提出这样的理念，”富勒，博士，现在在华盛顿大学医学院微生物学教授说： 正在研究冠状病毒疫苗的西雅图医学博士。 如果其他实验室获得相同的结果，则意味着她的研究不仅仅是a幸。
The conference organizers were riveted by the new idea. They reshuffled the meeting schedule so that Fuller and the others could present their research during the same session, on the last day of the meeting. Scientists who planned to leave the conference early scrambled to reschedule their flights home so they could stick around to hear about it.
会议组织者被这个新想法所吸引。 他们重新安排了会议时间表，以便富勒和其他人可以在会议的最后一天的同一次会议上介绍他们的研究。 计划早些离开会议的科学家们争先恐后地重新安排了返程航班的时间，以便他们可以四处徘徊以了解情况。
The idea was elegant: Deliver a set of instructions that tells the body’s own cells to make a vaccine.
这个想法很优雅：提供一组指示，告诉人体自身的细胞制造疫苗。
It was a complete departure from the way vaccines were being made — and largely still are — which involves a complex and costly process. This new approach, by contrast, could be quickly adapted to virtually any infectious disease and promised to drastically shorten the timeline it took to bring a vaccine to market. “It was a revolution in the sense of vaccines at the time,” Fuller says. “We immediately recognized its potential for fighting against future pandemics.”
这与疫苗的制造方法完全不同(现在仍然是)，这涉及一个复杂且昂贵的过程。 相比之下，这种新方法可以Swift适应几乎所有传染病，并有望大大缩短将疫苗推向市场的时间表。 富勒说：“当时在疫苗意义上是一场革命。” “我们立即意识到了其对抗未来流行病的潜力。”
Now, 30 years later, none of these so-called genetic vaccines have ever been approved for human diseases. But a handful of labs and companies have kept at it, steadily improving the technology. And the coronavirus pandemic has presented itself as an opportunity to put the experimental technology to the ultimate test. Now, several genetic vaccines for Covid-19 are advancing through clinical trials and have emerged as front-runners. Moderna, Inovio Pharmaceuticals, and Pfizer are all pursuing genetic vaccines.
30年后的今天，这些所谓的基因疫苗均未获批准用于人类疾病。 但是少数实验室和公司一直坚持下去，不断改进技术。 冠状病毒大流行本身就是将实验技术进行最终测试的机会。 现在，几种针对Covid-19的基因疫苗正在通过临床试验进行开发，并已成为领先者。 Moderna，Inovio Pharmaceuticals和Pfizer都在追求基因疫苗。
Critics point out that neither Moderna nor Inovio has ever brought a drug or vaccine to market before. And before the coronavirus, genetic vaccines hadn’t been tested in large-scale clinical trials for infectious diseases.
批评人士指出，Moderna和Inovio都从未将药物或疫苗推向市场。 在冠状病毒出现之前，尚未在大规模的临床试验中测试过针对传染病的基因疫苗。
If the technology works for Covid-19, it could pave the way for more of these vaccines for other diseases, including new pathogens that emerge in the future. When the next infectious disease outbreak comes, governments could be better prepared with a safe and effective vaccine technology to quickly test, manufacture, and scale-up.
如果这项技术适用于Covid-19，则可以为更多其他疾病的疫苗铺平道路，包括将来出现的新病原体。 当下一次传染病爆发时，可以使用安全有效的疫苗技术为政府做好更好的准备，以快速测试，制造和扩大规模。
“It may actually change how other vaccines are produced,” Rahul Gupta, MD, senior vice president and chief medical and health officer at the March of Dimes, told reporters during a National Press Foundation briefing on August 7. “We may be at the cusp of very much a new technology.”
“这实际上可能会改变其他疫苗的生产方式，” 8月7日在Dimes举行的Dimes高级副总裁兼首席医学和卫生官Rahul Gupta医师在接受国家新闻基金会8月7日的简报会时对记者说。一项非常新技术的风口浪尖。”
But if it fails, it could be a major setback for stemming the tide of the deadly coronavirus.
但是，如果失败了，这可能是遏制致命冠状病毒潮流的重大挫折。
All vaccines work by essentially tricking the body into thinking it’s been infected. The immune system kicks into gear and registers the invader’s characteristics, so that if it ever encounters the real version, later on, it’s primed to attack.
所有疫苗的工作原理都是通过诱骗身体使其被感染。 免疫系统开始运转并记录入侵者的特征，因此，一旦遇到真实版本，随后便会发起攻击。
Traditional vaccines spur this immune response by injecting either a weakened or killed version of the pathogen into the body. Many of the vaccines we currently use are made this way, including those for chickenpox, polio, flu, rabies, and measles, mumps, and rubella.
传统疫苗通过将病原体的弱化或杀死形式注射入体内来刺激这种免疫React。 我们目前使用的许多疫苗都是通过这种方式制成的，包括水痘，小儿麻痹症，流感，狂犬病以及麻疹，腮腺炎和风疹的疫苗。
Weakened, or attenuated, vaccines elicit a strong and long-lasting immune response because they’re so similar to the natural infection. But because of this, people who are immunocompromised are vulnerable to get sick from an attenuated vaccine, and can’t use them. Killed or inactivated vaccines, on the other hand, don’t produce as strong of an immune response and sometimes require a booster shot.
弱化或减毒的疫苗会引起强烈而持久的免疫React，因为它们与自然感染非常相似。 但是正因为如此，免疫功能低下的人很容易从减毒疫苗中生病，无法使用它们。 另一方面，杀死或灭活的疫苗不会产生那么强的免疫React，有时需要加强注射。
The tried-and-true method of making vaccines involves growing a pathogen in chicken eggs or animal cells, then extracting it so that it can be killed or weakened. Finally, the vaccine is purified and undergoes several safety tests. The process is laborious. The flu vaccine, for instance, requires millions of eggs every year and can take six months to make. Other vaccines can take years to make and test for safety. Genetic vaccines promise to be faster and simpler.
制造疫苗的久经考验的方法包括在鸡蛋或动物细胞中生长病原体，然后将其提取以使其被杀死或削弱。 最后，将疫苗纯化并进行几次安全性测试。 这个过程很费力。 例如， 流感疫苗每年需要数百万个鸡蛋，并且可能需要六个月的时间才能制作出来。 其他疫苗可能需要数年的时间才能完成安全性测试。 基因疫苗有望更快更简单。
“Most of our vaccine development is really mired in the past,” says William Klimstra, PhD, a professor of immunology at the University of Pittsburgh. “Our ways of generating vaccines go back to the 1930s.”
匹兹堡大学免疫学教授威廉·克里姆斯特拉(William Klimstra)博士说：“我们的疫苗开发工作实际上在过去已陷入泥潭。” “我们生产疫苗的方式可以追溯到1930年代。”
Some vaccines are now made with just a piece of a pathogen — a protein or two — that best stimulates the immune system, instead of the whole germ. The hepatitis B and human papillomavirus vaccines are made with this approach. These vaccines can be safer since they only contain part of a pathogen but often have to be combined with adjuvants, substances that boost the immune response. Sometimes a second dose is needed. Starting in the late 1980s to 1990s, vaccine developers started to use genetic engineering to make synthetic versions of these proteins instead of using the real thing.
现在，有些疫苗只用一种病原体(一种或两种蛋白质)制成，它能最好地刺激免疫系统，而不是整个细菌。 乙型肝炎和人乳头瘤病毒疫苗是用这种方法制成的。 这些疫苗可能更安全，因为它们仅包含病原体的一部分，但通常必须与佐剂(可增强免疫React的物质)组合使用。 有时需要第二剂。 从1980年代末到1990年代开始，疫苗开发人员开始使用基因工程来合成这些蛋白质的合成形式，而不是使用真实的东西。
That’s when genetic vaccines entered the scene.
那就是基因疫苗进入现场的时候。
“We were starting to think about a simpler way to go about making vaccines,” says David Weiner, PhD, executive vice president of the Wistar Institute, a nonprofit biomedical research institute in Philadelphia and founder of Inovio, where he is still on the scientific advisory board. The institute is collaborating with Inovio on its DNA vaccine for Covid-19. “What if we didn’t have to depend on all this complicated machinery?”
“我们开始思考一种更简单的疫苗生产方法，”费城一家非营利性生物医学研究所Wistar研究所执行副总裁兼Inovio创始人David Weiner博士说。咨询委员会。 该研究所正在与Inovio合作开发Covid-19的DNA疫苗。 “如果我们不必依靠所有这些复杂的机器怎么办？”
Weiner was among the handful of scientists who pioneered the idea of genetic vaccines at the Cold Spring Harbor meeting back in 1992.
韦纳(Weiner)是少数在1992年的冷泉港会议上率先提出基因疫苗想法的科学家之一。
Genetic vaccines don’t contain any part of the actual pathogen. Instead, they use a small piece of genetic material — either DNA or RNA — that temporarily instructs a person’s own cells to make a piece of a pathogen.
基因疫苗不包含实际病原体的任何部分。 取而代之的是，他们使用一小部分遗传物质-DNA或RNA-暂时指示一个人自己的细胞制造某种病原体。
“They encode information,” Weiner explains. “What we’re delivering is information that encodes something that, in this case, looks like a viral protein.”
“他们对信息进行编码，” Weiner解释说。 “在这种情况下，我们提供的信息是编码某种类似于病毒蛋白的信息。”
For SARS-CoV-2, the virus that causes Covid-19, scientists have zeroed in on the “spike” protein, which is found on the virus’s surface and gives it a crown-like appearance. The virus uses the spike protein to attach to and get inside human cells. Genetic vaccines for Covid-19 carry a code that tells cells to make this protein. The hope is that the body will recognize it as foreign and mount an immune response against it.
对于导致Covid-19的病毒SARS-CoV-2，科学家已经将“尖峰”蛋白归零，该蛋白在病毒表面被发现并呈冠状。 该病毒利用刺突蛋白附着并进入人体细胞。 用于Covid-19的基因疫苗带有一个密码，告诉细胞制造这种蛋白质。 希望人体将其识别为异物并对其产生免疫React。
The allure of DNA and RNA vaccines — and what captured the imaginations of scientists at that 1992 meeting — is their adaptability. The piece of genetic code can be easily swapped out depending on the disease you want to make a vaccine for. You don’t need the actual pathogen; you just need to know its genetic code.
DNA和RNA疫苗的吸引力-以及它们的适应性，引起了1992年那次会议上科学家的想象。 这部分遗传密码可以很容易地交换出来，具体取决于要生产疫苗的疾病。 您不需要实际的病原体； 您只需要知道其遗传密码即可。
“I kind of liken it to, once you discover the recipe for ice cream, you can make different flavors of ice cream very easily,” says Margaret Liu, MD, chairman of the board of the International Society of Vaccines, who presented early work on genetic vaccines at the 1992 meeting and helped establish the field.
“我有点喜欢，一旦您发现了冰淇淋的配方，就可以很容易地制作出不同口味的冰淇淋，”国际疫苗学会董事会主席刘Mar博士说。在1992年的会议上讨论了基因疫苗，并帮助建立了该领域。
Another potential advantage is that DNA and RNA can be manufactured more quickly than traditional vaccines, and a smaller amount of genetic material is needed for each dose.
另一个潜在的优势是，与传统疫苗相比，DNA和RNA的生产速度更快，每剂所需的遗传物质数量更少。
“Production is certainly faster with genetic vaccines,” says Roxana Rustomjee, PhD, senior vice president of research and development at the nonprofit Sabin Vaccine Institute in Washington, D.C. “But scientifically, I would say the advantages are still unclear. We’re still on the fence as to whether the immune response that will develop is going to be significant enough to offer protection.”
“使用基因疫苗肯定可以更快地生产，”华盛顿特区非营利性萨宾疫苗研究所研发高级副总裁Roxana Rustomjee博士说：“但从科学上讲，我仍然不确定优势。 对于是否会产生足够的免疫React以提供保护，我们仍持保留态度。”
The idea behind genetic vaccines seemed straightforward, but getting them to work in people was another thing.
牛逼基因疫苗的背后，他想法似乎简单，但要让他们工作的人是另一回事。
Once Fuller, Weiner, and the others got home from that 1992 meeting, they raced to file patents on their technology and publish their work. But getting those early papers accepted to scientific journals wasn’t easy, Weiner says. When he tried to submit his findings, reviewers were doubtful that the approach would work. But eventually, he and others were able to get their papers published.
富勒(Fuller)，韦纳(Weiner)和其他人从1992年的会议回到家后，他们就争相为其技术申请专利并发表其著作。 但是，让那些早期的论文被科学期刊接受并不容易，Weiner说。 当他尝试提交调查结果时，审阅者怀疑该方法是否有效。 但是最终，他和其他人得以发表论文。
In animals, genetic vaccines seemed to work perfectly. In 1997, Weiner and his colleagues at the University of Pennsylvania reported that a DNA vaccine they made successfully protected two chimpanzees from HIV. But the first human trials of genetic vaccines were a flop. People didn’t mount the immune response needed to protect them against disease.
在动物中，基因疫苗似乎效果很好。 1997年，宾夕法尼亚大学的韦纳和他的同事报告说，他们制造的DNA疫苗成功保护了两只黑猩猩免受HIV感染 。 但是基因疫苗的首次人类试验失败了。 人们没有进行保护他们免受疾病侵袭的免疫React。
“It was a complete and utter failure,” Fuller says. It’s a common problem in biomedical research. Often, a drug or vaccine works in animals but isn’t effective in people.
“那是一次彻底的彻底失败，”富勒说。 这是生物医学研究中的普遍问题。 通常，药物或疫苗对动物有效，但对人无效。
A key problem to overcome was figuring out how to get the DNA or RNA into cells. Both presented their own challenges that took years to work out. By then, much of the initial excitement for genetic vaccines had fizzled out, and many companies that had gotten into the field left after early trial failures.
要克服的关键问题是弄清楚如何使DNA或RNA进入细胞。 两者都提出了自己的挑战，需要花费数年的时间才能解决。 到那时，对基因疫苗的最初许多兴奋都化为乌有，许多进入早期试验失败后进入该领域的公司也纷纷退出。
Fuller, Weiner, and some others kept at it, focusing first on DNA. They knew that DNA is more stable than RNA, which helps preserve genetic information. But cells don’t take up DNA readily, so scientists needed to devise gadgets to deliver DNA vaccine particles. One of those, created by John Sanford at Cornell University, is called a gene gun. Originally made for experiments on plants, the gun uses helium and gold particles to propel genetic material through cell walls.
富勒(Fuller)，韦纳(Weiner)和其他一些人则坚持这样做，首先关注于DNA。 他们知道DNA比RNA更稳定，这有助于保存遗传信息。 但是细胞不能轻易吸收DNA，因此科学家需要设计出能够递送DNA疫苗颗粒的小工具。 其中之一是由康奈尔大学的约翰·桑福德(John Sanford)创建的，被称为基因枪。 该枪最初是为在植物上进行实验而制造的，使用氦和金颗粒推动遗传物质穿过细胞壁。
Meanwhile, Weiner and Inovio developed an electrical device that zaps the skin and opens up cells so that the DNA vaccine particles can be taken up. Inovio’s Covid-19 vaccine uses the device to deliver the vaccine to a person’s skin. Talking to the New York Times, a volunteer in Inovio’s trial said getting zapped didn’t hurt, but “it just feels strange.” The small, hand-held device will be scaled up using $71 million from the U.S. Department of Defense.
同时，Weiner和Inovio开发了一种电子设备，可以剥开皮肤并打开细胞，从而可以吸收DNA疫苗颗粒。 Inovio的Covid-19疫苗使用该设备将疫苗运送到人的皮肤上。 在与《纽约时报》交谈时，参与Inovio审判的一名志愿者说，被拉伤并没有受伤，但是“感觉很奇怪”。 小型手持设备将使用美国国防部提供的7100万美元扩大规模。
The difficulty with RNA is that it breaks rapidly once it’s injected into the body. Scientists couldn’t get RNA vaccines to work until immunologist Drew Weissman, MD, PhD, at the University of Pennsylvania, figured out how to stabilize RNA by packaging it into tiny fatty nanoparticles. Weissman’s technology was so intriguing that a Cambridge, Massachusetts-based biotech company called Moderna ended up licensing it.
RNA的困难在于，一旦被注入体内，它就会Swift断裂。 直到宾夕法尼亚大学的免疫学家德鲁·魏斯曼(Drew Weissman)博士弄清楚如何通过将RNA包装到微小的脂肪纳米颗粒中来稳定RNA之前，科学家们才能使RNA疫苗起作用。 魏斯曼的技术如此吸引人，以至于马萨诸塞州剑桥市一家名为Moderna的生物技术公司最终获得了许可。
Though no DNA or RNA vaccines are on the market yet for human use, a veterinary DNA vaccine to protect horses from West Nile virus was approved in 2005. Liu says it’s proof that the approach can work beyond just lab animals.
尽管市场上还没有供人类使用的DNA或RNA疫苗，但2005年批准了一种保护马免受西尼罗河病毒感染的兽用DNA疫苗。
In mid-January, shortly after a mysterious respiratory virus emerged in Wuhan, China, in December 2019, Chinese researchers posted the draft genome of the virus online. Companies like Moderna and Inovio were able to start making a genetic vaccine once they had this blueprint.
在一月中旬后不久，一个神秘的呼吸道病毒在武汉，中国出现，在2019年十二月，中国的研究人员公布了病毒的基因组草图线上。 一旦有了这个蓝图，像Moderna和Inovio这样的公司就可以开始制造基因疫苗。
Scientists immediately realized that the novel virus looked a lot like two they’d seen before: the ones that cause SARS and MERS, which both have a similar spike protein. They knew that people who recovered from being infected with those viruses made antibodies to the spike protein. They reasoned that a vaccine that targets the spike protein could induce an immune response strong enough to protect against disease.
科学家们立即意识到，这种新型病毒看起来很像以前见过的两种：导致SARS和MERS的病毒，它们都具有相似的刺突蛋白。 他们知道，从那些病毒中感染后恢复过来的人会制造出刺突蛋白的抗体。 他们认为，靶向刺突蛋白的疫苗可以诱导足够强的免疫React以抵抗疾病。
Inovio, Moderna, and German firm BioNTech, the latter of which partnered with pharma giant Pfizer, were already working on medicines that involve DNA and RNA, so they were able to change gears quickly.
Inovio，Moderna和德国的BioNTech公司(后者与制药巨头辉瑞公司合作)已经在研究涉及DNA和RNA的药物，因此他们能够快速改变齿轮。
In just six weeks, Moderna designed, manufactured, and shipped a vaccine to the U.S. National Institutes of Health for an initial human safety trial, which began in mid-March. Inovio and German firm BioNTech, which partnered with Pfizer, rapidly designed their own genetic vaccines and started testing them in people in April. Now, Moderna and Pfizer are beginning large-scale trials to test vaccine efficacy. To get approved for use, a vaccine for the coronavirus will need to be at least 50% effective, according to the Food and Drug Administration. Early results show that these vaccines look safe and produce an immune response, but there’s reason to be skeptical.
在短短的六个星期内，Moderna设计，制造并向美国国立卫生研究院运送了疫苗，以进行初步的人体安全性试验，试验始于3月中旬 。 与辉瑞(Pfizer)合作的Inovio和德国公司BioNTech快速设计了自己的基因疫苗，并于4月开始在人们中进行测试。 现在，Moderna和辉瑞公司正在开始大规模试验，以测试疫苗的功效。 根据食品和药物管理局的说法，要获得批准使用，冠状病毒疫苗的有效性至少需要达到50％ 。 早期结果表明，这些疫苗看起来安全并且可以产生免疫React，但是有理由对此表示怀疑。
Moderna, historically a secretive startup, doesn’t have a track record of commercializing drugs. And over the years, Inovio has made rosy announcements about many of its vaccines, from Zika to cancer, but the company has yet to get one approved and on the market. Weiner defends the company he created, saying vaccine development just takes a long time. And that’s true; the typical timeline is a decade or more.
Moderna历来是一家秘密的初创企业，没有将药物商业化的记录。 多年来，Inovio已经宣布了从Zika到癌症的许多疫苗的乐观声明，但该公司尚未获得批准并投放市场。 韦纳为他创建的公司辩护，他说疫苗开发需要很长时间。 没错； 典型的时间表是十年或更长时间。
Despite the skepticism, all eyes are on the Covid-19 vaccine race. If genetic vaccines fail to work now, they’ll fail in a big way on the world stage.
尽管持怀疑态度，但所有人的目光都集中在Covid-19疫苗竞赛上。 如果基因疫苗现在不能起作用，它们将在世界舞台上大失败。
As much as people like Weiner and Liu are hopeful about the vaccine technology they helped spearhead, they’re also realistic about the fact that this first round of genetic vaccines might not be the most effective ones against the coronavirus.
尽管像Weiner和Liu这样的人对他们带头的疫苗技术抱有希望，但他们也很现实，认为第一轮基因疫苗可能不是针对冠状病毒的最有效疫苗。
“I’m not sure that the fastest one out of the gate will make it or that it will be the best vaccine, and maybe that’s okay,” Liu says. “A first vaccine can still make an impact and then later ones can be better.” For instance, the first vaccine for shingles, approved in 2006, reduced the risk of infection by about 51%. But a better vaccine came on the market in 2017 that’s more than 90% effective.
Liu说：“我不确定最快的疫苗会成功还是会成为最好的疫苗，也许还可以。” “第一种疫苗仍然可以产生影响，然后再接种会更好。” 例如，2006年批准的首个带状疱疹疫苗使感染风险降低了约51％。 但是2017年有更好的疫苗上市，有效率超过90％。
Different vaccines might be better suited to different populations, too. Weiner points to the example of polio to illustrate one potential future for a Covid-19 vaccine landscape. Jonas Salk is known for developing the first effective polio vaccine, which uses a killed or inactivated virus, in 1952. Salk’s rival, Albert Sabin, went on to develop an oral polio vaccine, which uses a weakened or attenuated form of the virus and became available in 1961.
不同的疫苗也可能更适合不同的人群。 Weiner指出了脊髓灰质炎的例子，以说明Covid-19疫苗前景的一个潜在未来。 乔纳斯·索尔克(Jonas Salk)于1952年以开发出第一种有效的脊髓灰质炎疫苗而闻名，这种疫苗使用一种灭活或灭活的病毒。索尔克(Salk)的竞争对手阿尔伯特·萨宾(Albert Sabin)继续开发一种口服脊髓灰质炎疫苗，该疫苗使用弱化或减毒形式的病毒，因此成为1961年上市。
While the Salk vaccine is one of the safest vaccines used today — and is arguably more famous — Sabin’s oral vaccine is widely used in developing countries because it’s easier to give to children than the inactivated injectable vaccine. Together, though, they are both used to keep polio at bay.
尽管索尔克(Salk)疫苗是当今使用的最安全的疫苗之一，并且可以说是更为著名，但萨宾的口服疫苗在发展中国家得到了广泛使用，因为它比灭活注射疫苗更容易给儿童服用。 但是，它们一起被用来阻止小儿麻痹症。
“I think that’s a very important lesson,” Weiner says. “Having more vaccine options will benefit all of us.”
“我认为这是非常重要的一课，”韦纳说。 “拥有更多疫苗选择将使我们所有人受益。”
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