性价比更高的无针贴片疫苗！

屈泰龙

       自1853年苏格兰人亚历山大和法国人普拉沃兹发明注射器及针头以来，直至目前我们还在大量的使用注射器，甚至在未来很长远的日子里，注射器依然是我们不可或缺的医疗用品。已走过163年历史的注射器和针头，是不是该变革了？ 生物医学工程师Mark Kendall率领的团队发明了一种1cm*1cm的正方形的可贴于皮肤表面的纳米疫苗贴片。这一微小的硅片能够解决现今使用的针和注射器进行免疫的疫苗所面临的四大主要问题：对注射器及针头的恐惧，尤其儿童；针刺伤后带来的感染风险；疫苗需要冷链运输和新一代疫苗免疫反应的限制（如DNA疫苗用注射方式其效果大打折扣）。除了解决以上问题，纳米贴片制作成本更低廉。
       说了这么多，一起来听听Mark Kendall的精彩演讲吧！没有WIFI，没关系，小编连夜将其进行了翻译，并配上关键图片，让你也看的过瘾。只是若有词不达意的地方，还请您多多见谅呗！

        It's a pleasure to be here in Edinburgh, Scotland, the birthplace of the needleand syringe. Less than a mile from here inthis direction, in 1853 a Scotsman filed his very first patenton the needle and syringe.His name was Alexander Wood, and it was at the RoyalCollege of Physicians. This is the patent. What blows my mind when Ilook at it even today is that it looks almost identical to the needle in use today. Yet,it's 160 years old.

       很高兴能来到注射器和针头诞生地-苏格兰首府爱丁堡和大家进行交流。1853年，在距这里不到1英里的地方，一个苏格兰人申请了他的第一个专利：注射器及针头。他就是亚历山大-伍德， 他当时是伦敦皇家内科医学院的一名医生。（编者注：根据文献记载，苏格兰人亚历山大-伍德和法国人普拉沃兹同一年的发明注射器及针头，详见：EVOLUTIONOF MEDICAL APPLICATION OF SYRINGE）。令我感到不可思议的是，自注射器发明160年以来，他的这个发明和现在的注射器几乎还是一样（下图C所示）。

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注射器构造发展图，来自于EVOLUTION OF MEDICAL APPLICATION OF SYRINGE

So we turn to the field ofvaccines. Most vaccines are deliveredwith the needle and syringe, this160-year-old technology. And credit where it's due -- on many levels, vaccines are a successfultechnology. After clean water and sanitation, vaccines are the onetechnology that has increased our life span the most. That's a pretty hard act tobeat.

我们来谈一下疫苗。大多数的疫苗需要通过已有160年历史的器材—注射器和针头进行免疫。从很多个层面来讲，疫苗接种是一个很成功的技术。疫苗接种是继清洁水和环境设施之后又一个延长人类寿命贡献最大的技术，这一点很难被超越。

But just like any othertechnology, vaccines have theirshortcomings, and the needle and syringe is a key part within thatnarrative -- this old technology. So let's start with theobvious: Many of us don't like theneedle and syringe. I share that view. However, 20 percent of thepopulation have a thing called needlephobia. That's more than dislikingthe needle; that is actively avoidingbeing vaccinated because of needle phobia. And that's problematic interms of the rollout of vaccines.

但是，和其他任何一项技术一样，疫苗接种也存在其不足之处，而针头注射，这个具有悠久历史的技术，便是其关键问题所在。让我们从在明显的事例说起：我们中的很多人都不喜欢针和注射器，我深有同感。全世界有20%的人有针头恐惧症（needle phobia）。更深层次的问题是因为恐惧注射器而排斥免疫，毫无疑问，这对疫苗的普及接种带来了极大问题。

Now, related to this isanother key issue, which is needle stick injuries. And the WHO has figures that suggest about 1.3million deaths per year take place due to cross-contamination with needlestick injuries. These are early deaths thattake place。

与此相关的另一个问题就是针头接种时带来的伤害（needle stick injuries）。WHO有数据报道因为针头接种带来的交叉污染可导致每年130万人失去生命，这造成了很多人的早死。

Now, these are two thingsthat you probably may have heard of, but there are two othershortcomingsof the needle and syringe you may not have heard about. One is it could be holdingback the next generation ofvaccines in terms of their immuneresponses. And the second is that itcould be responsible for the problem of the cold chain that I'll tell you about aswell.

这两个问题大家可能听说过，但是还有另外两个因注射器和针头带来缺陷，你们可能还没听说过。其中一个是阻碍了新一代疫苗的研制（编者理解为比如DNA疫苗的免疫，若用注射器方式免疫，则大大降低了疫苗的效果）。第二个问题就是稍后我会给大家讲到的疫苗冷链运输问题。

I'm going to tell you aboutsome work that my team and I are doingin Australia at the University ofQueensland on a technology designed totackle those four problems. And that technology is called the Nanopatch. Now, this is a specimen ofthe Nanopatch. To the naked eye it just looks like asquaresmaller than a postage stamp, but under a microscope what you see are thousands oftiny projectionsthat are invisible to the human eye. And there's about 4,000projections on this particular squarecompared to the needle. And I've designed those projections to serve a key role, which isto work with the skin's immune system. So that's a very importantfunction tied in with the Nanopatch.

现在我跟大家讲讲我和我的团队在澳大利亚昆士兰大学为了解决这四个问题所做的研究。我们称这个技术为纳米贴片（Nanopatch）。这是一个纳米贴片的样品（视频内Mark拿起）。肉眼看上去，他是一个比邮票还要小的方片，但是在显微镜下你将会看肉眼无法看到的成千个微小突起。与针头相比，这个小方片内有4000个微小的突起。我们设计这些微小的突起有一个关键作用-刺激并激活皮肤的免疫系统。这是纳米贴片一个非常重要的作用。

Now we make the Nanopatch with a technique called deep reactive ionetching. And this particular techniqueis one that's been borrowed from the semiconductor industry, and therefore is low cost and can be rolled out inlarge numbers.

在制作贴片时，我们选用了一项技术-深反应离子刻蚀技术（deep reactive ion etching原谅小编，我不懂这个，只能是Google翻译了）。这项特别的技术借鉴于半导体工业技术，因此非常便宜，且可以大规模的生产。

Now we dry-coat vaccines tothe projections of the Nanopatch and apply it to the skin. Now, the simplest form ofapplication is using our finger, but our finger has somelimitations, so we've devised anapplicator. And it's a very simple device-- you could call it asophisticated finger. It's a spring-operated device. What we do is when we applythe Nanopatch to the skin as so -- (Click) -- immediately a few things happen. So firstly, the projectionson the Nanopatch breach through the tough outer layer and the vaccine is veryquickly released -- within less than a minute, in fact. Then we can take theNanopatch off and discard it. And indeed we can make areuse of the applicator itself.

我们将疫苗涂布在这些纳米贴片上，并将其贴于皮肤上。最简单的方式就是用我们的手指将其贴于皮肤，但是我们的 手指具有局限性，因此我们设计了这样一个辅助器。这个设备用起来很简单，你可以称之为高级手指。（然后是使用方法，可见视频，再次不做详述）在用“高级手指”将纳米贴片贴在皮肤上时，纳米贴片表面的突起可穿透皮肤表层，疫苗被迅速释放，实际上不到1min。然后就可以将纳米贴片撕掉并丢弃，你可以用“高级手指”继续进行接种。

So that gives you an idea ofthe Nanopatch, and immediately you can seesome key advantages. We've talked about it being needle-free -- these are projections thatyou can't even see -- and, of course, we get around the needle phobia issue aswell.

我们可以从中看到几个优势：他没有针头，你看不到这些微小的突起，因此也解决了针头恐惧症。

Now, if we take a step backand think about these other two really important advantages: One is improved immuneresponses through delivery, and the second is getting rid of the cold chain。

现在我们退后一步想一想另外两个非常重要的优势：其一改变免疫途径提高了免疫反应，其二对疫苗不再要求冷链运输。

So let's start with the firstone, this immunogenicity idea. It takes a little while to get our heads around, but I'll try toexplain it in simple terms. So I'll take a step back and explain to you how vaccines work in a simpleway. So vaccines work byintroducing into our body a thing called an antigen which is a safe form of agerm. Now that safe germ, thatantigen, tricks our body into mountingan immune response,learning and remembering how to deal with intruders. When the real intruder comesalong the body quickly mounts animmune response to deal with that vaccine and neutralizes theinfection. So it does that well.

我们先从第一个讲起，及免疫原性问题。这是一个难于理解的概念，但是我会用简单的话将其解释清楚。首先简单跟大家讲一下疫苗的工作原理：疫苗是将一种抗原注入到我们的体内，而疫苗是一个“病原”的安全形式。抗原刺激机体产生免疫反应，并使机体学习和记忆如何对抗入侵者。当真正的入侵到来的时候，机体便会迅速的调动免疫反应去处理这些感染。他就是这么有效。

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Now, the way it's donetoday with the needle and syringe, most vaccines are deliveredthat way -- with this old technology andthe needle. But it could be argued thatthe needle is holding back our immune responses; it's missing our immune sweetspot in the skin. To describe this idea, we need to take a journeythrough the skin, starting with one of those projections and applying the Nanopatch tothe skin.And we see this kind of data. Now, this is real data -- that thing that we can seethere is one projectionfrom the Nanopatch that's been applied to the skin and those colors aredifferent layers. Now, to give you an idea of scale, if the needle was shown here,it would be too big. It would be 10 times bigger than the size of that screen,going 10 times deeper as well. It's off the grid entirely. You can see immediately thatwe have those projections in the skin. That red layer is a toughouter layer of dead skin, but the brown layer and the magenta layer are jammed full of immunecells. As one example, in the brownlayer there's a certain type of cell called a Langerhans cell -- every square millimeter ofour body is jammed full of thoseLangerhans cells, those immune cells, and there's others shown as well that we haven't stained inthis image. But you can immediately seethat the Nanopatch achieves that penetration indeed. We target thousands uponthousands of these particular cells just residing within a hair'swidthof the surface of the skin.

由于大多数的疫苗需要通过针和注射器来完成疫苗接种，然而也恰恰是由于针阻碍了免疫反应，因为他无法到达皮肤上最好的免疫位置。为了更好的说明这个问题，我们先来了解下皮肤的构造。从这个途中我们可以看到，一个纳米贴片的突起穿刺与皮肤表层，不同的颜色代表皮肤不同的组织层。如果给你一个注射器穿插皮肤层的图片作为参照 ，它将会是屏幕的十倍大，并且10倍深，他完全超出坐标了。你可以立刻看到这些微小突起已经穿插于皮肤内。红色的部分是坏死皮肤的最外层，但是棕色和紫色的那两层却充满了免疫细胞。在棕色层内含有一种免疫细胞-朗罕氏细胞。我们身体里充满了这种免疫细胞，同样也含有其他的细胞，只是未在这个图片中体现出来。但是你可明了的看到纳米贴片确实延伸了需要达到的深度。我们只占用了皮肤表层约一跟头发直径的宽度，便触及和覆盖了无数这样的细胞。

Now, as the guy that'sinvented this thing and designed it to do that, I found that exciting. But sowhat? So what if you've targeted cells? In the world of vaccines,what does that mean? The world of vaccines is getting better. It's getting more systematic. However, you still don'treally know if a vaccine is going to work until you roll your sleevesup and vaccinate and wait. It's a gambler's game eventoday.

作为这项技术的发明者和设计者，我觉得这是令人兴奋的。但是又怎样？即便是你触及到了这些免疫细胞，在疫苗免疫的角度来看，这意味着什么呢？如今疫苗领域发展迅速，变得更好更具系统性。但是，当你挽起袖子，露出胳膊准备接种疫苗时，你依然不知道疫苗是否有效。即便是现在看来，这也似乎是一种赌博。

So, we had to do that gamble. We obtained an influenzavaccine, we applied it to ourNanopatches and we applied theNanopatches to the skin, and we waited -- and this is in the live animal. We waited a month, and this is what we foundout. This is a data slide showingthe immune responses that we've generated with a Nanopatch compared to the needle andsyringe into muscle. So on the horizontal axis we have the dose shown innanograms. On the vertical axis we havethe immune response generated,and that dashed line indicates the protectionthreshold. If we're above that line it'sconsidered protective; if we're below that line it's not. So the red line is mostlybelow that curve and indeed there's only one point that is achieved with theneedle that's protective, and that's with a high dose of 6,000 nanograms. But notice immediately thedistinctly different curve that we achieve with the blue line.That's what's achieved withthe Nanopatch; the delivered dose of theNanopatch is a completely differentimmunogenicity curve. That's a real fresh opportunity. Suddenly we have a brand newlever in the world of vaccines. We can push it one way, where we can take a vaccinethat works but is too expensive and can get protection with a hundredth of the dosecompared to the needle. That can take a vaccine that's suddenly 10 dollars down to 10cents, and that's particularlyimportant within the developing world.

因此，我们也需要这样的赌博。当我们得到一个流感疫苗，我们将其图不再纳米贴片上，并贴在皮肤表面，然后就是等待。因为我们是应用在活体内，我们等了一个月，然后对比纳米贴片和注射器免疫的数据。在这个坐标图上，横坐标是免疫抗原剂量，纵坐标是免疫反应值。红线为注射器方式产生的免疫值，蓝色表示纳米贴片的免疫值，虚线为保护临界值，高于这个值则具有保护性，反之低于这个线则布局保护性。我们可以看到，蓝色线都处在临界值之上，而蓝线大部分均在临界值之下，仅有一个点具有保护效果即抗原量高达6000 ng，而对比明显的是红色线所需抗原量远远低于蓝色线，这是一个前所未有的机会，我们突然有了一个疫苗领域全新的杠杆。当一个疫苗有效但是很贵的前提下，我们免疫注射方式的1/100当量的抗原便可达到目的。这就可以使原本10美元的疫苗降价至10美分，这对发展中国家意义重大。

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But there's another angle tothis as well -- you can take vaccines that currently don't work and get them over that line and get them protective. And certainly in the world ofvaccines that can be important. Let's consider the big three: HIV, malaria, tuberculosis. They're responsible for about7 million deaths per year, and there is no adequate vaccination method for any of those. So potentially, with this newlever that we have with the Nanopatch, we can help make that happen. We can push that lever tohelp get those candidate vaccines over the line. Now, of course, we've workedwithin my lab with many other vaccines that have attained similar responses and similarcurves to this, what we've achieved with influenza.

我们也可以从另外一个角度来看，即一个现在看来无效的疫苗，使其超过临界值，并具有保护性。这对于疫苗领域来说是很重要的。看看困扰世界的三大疾病：艾滋病，疟疾和结核病。由于没有合适有效的疫苗，每年造成约700万人失去生命。现在有了纳米贴片这个杠杆，合适有效的疫苗将不再是可望不可及的事。我们可以使候选的疫苗产生的免疫反应值跨过临界值，从而具有保护性。当然，我们在实验室还研究了很多其他的疫苗，都得出了和流感纳米贴片疫苗反应结果类似的曲线。

I'd like to now switch totalk about another key shortcoming oftoday's vaccines, and that is the need to maintain the cold chain. As the name suggests -- thecold chain -- it's the requirements ofkeeping a vaccine right from production all the way through to whenthe vaccine is applied, to keep it refrigerated.Now, that presents some logisticalchallenges but we have ways to do it. This is a slightly extremecase in point but it helps illustrate thelogistical challenges, in particular in resource-poor settings, of what's required to getvaccines refrigerated and maintain thecold chain. If the vaccine is too warmthe vaccine breaks down, but interestingly it can be too cold and the vaccine can breakdown as well.

现在我讲一下当今疫苗的另一个主要缺陷，就是需要冷链运输。顾名思义，就是在疫苗从生产，到流通，保存的过程中都要保持低温处理。我们有条件去解决他。下图是一个极端环境条件下储存疫苗的方式。如果疫苗处于过高或者过低的温度，疫苗都将失去效果。

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Now, the stakes are veryhigh. The WHO estimates that withinAfrica, up to half the vaccines usedthereare considered to not be working properly because at some point thecold chain has fallen over. So it's a big problem, and it's tied in with the needle andsyringe because it's a liquid formvaccine, and when it's liquid it needs the refrigeration.

疫苗的失效率非常高，WHO的统计显示在非洲有高达一半的疫苗并没有发挥相应的效果，因为在冷链的某一个环节出现了问题。这就是使用注射器和针头免疫带来的巨大缺陷，因为液体的疫苗，需要低温保存。

A key attribute of ourNanopatch is that the vaccine is dry, and when it's dry it doesn'tneed refrigeration. Within my lab we've shown that we can keep the vaccine stored at 23degrees Celsius for more than a year without any loss in activity at all. That's an importantimprovement. (Applause) We're delighted about it aswell. And the thing about it isthat we have well and truly proven the Nanopatch within thelaboratory setting. And as a scientist, I love that and I love science. However, as an engineer,as abiomedical engineer and also as a human being, I'm not going to be satisfied until we've rolled this thingout, taken it out of the lab and got it to people in large numbers and particularly the peoplethat need it the most.

纳米贴片的一个关键性的技术就是疫苗是干粉形式，因此就无需冷藏。在我们的实验室室内进行的实验结果显示：纳米贴片疫苗在23℃条件下存放超过一年，其免疫效果没有任何丧失的现象。这是非常重要的结果。但是，尽管在实验室内做出的结果令人激动万分，作为一个科学家，我热爱这样的结果，我也热爱科学。但是作为一名生物医学工程师，同时也是一名普通人。除非能够将这项技术应用于实际中，能让大多数人从中获益，尤其需要这样技术的人们，否则我将不会对这一发现感到满意。

So we've commenced thisparticular journey, and we've commenced this journey in an unusual way. We'vestarted with Papua New Guinea.

Now, Papua New Guinea is anexample of a developing world country. It's about the same size asFrance, but it suffers from many ofthe key barriers existing within the world of today's vaccines. There's thelogistics: Within this country there areonly 800 refrigerators to keep vaccines chilled. Many of them are old, likethis one in Port Moresby, many of them are breaking down and many are not in theHighlands where they are required. That's a challenge. But also, Papua New Guineahas the world's highest incidence of HPV, human papillomavirus, thecervical cancer [risk factor]. Yet, that vaccine is not available in large numbers because it's too expensive. So for those two reasons,with the attributes of the Nanopatch, we've got into the field andworked with the Nanopatch, and taken it to Papua New Guinea and we'll be following thatup shortly.

所以我们以一种不同寻常的方式开始从事了下面的这一项事业，我们巴布新几内亚开始这项事业。巴布新几内亚是一个典型的发展中国家，他和法国具有相当的国土面积，但是却面临着当今疫苗领域存在的诸多问题。他们的物流是这样一种状况：全国仅有800台冰箱用于存放疫苗。许多已经老化到不能使用。巴布新几内亚是世界上乳头瘤病毒（宫颈癌致病因素）发病率最高的国家。但是针对此疾病的疫苗还未能大量使用，因为他太贵了。因此基于这两个原因和纳米贴片自身的优点，我们将纳米贴片带到了巴布新几内亚，并对其结果进行跟踪。

Now, doing this kind of workis not easy. It's challenging, but there's nothing else inthe world I'd rather be doing. And as we look ahead I'd like to share with you athought: It's the thought of a futurewherethe 17 million deaths per year that we currently have due toinfectious disease is a historical footnote.And it's a historical footnote that hasbeen achieved by improved, radicallyimproved vaccines. Now standing here today in front of you at the birthplace of theneedle and syringe, a device that's 160 years old, I'm presenting to you analternative approach that could really help make that happen -- and it's the Nanopatch withits attributes of being needle-free, pain-free, the ability for removing thecold chain and improving the immunogenicity. Thank you. (Applause)

做这样的事业并不是件容易的事情。他极具挑战性，但是没有其他任何的事情比这件事更值得去做。我们展望未来，我跟大家分享一个预见：在未来每年有1700万人死于传染病的事情将被封存于历史中。这是因为我们拥有了更有效，更安全的疫苗。现在我站在这个注射器和针头的诞生地，向大家讲述一种将颠覆疫苗领域的技术—纳米贴片技术，他没有针头，不会带来疼痛，无须冷藏并且提升免疫原性。

屈泰龙

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