Smallpox

疫苗一词是“疫苗之父”巴斯德( Louis Pasteur) 为纪念先驱者琴纳( Edward Jenner) 发明牛痘苗( vaccine) 而创造，指由减毒或灭活微生物制成、能够针对疾病产生免疫力的生物制品。疫苗作为人类与疾病斗争的有力武器，消灭或控制了许多传染病。脊髓灰质炎、鼠疫、麻疹、狂犬病、百日咳、破伤风、乙型病毒性肝炎(乙肝) 等发病率也通过接种疫苗大幅降低。自 18 世纪天花疫苗诞生至今，疫苗研发经历了数百年的发展其技术发展经历了 3 次革命。第一次始于 19 世纪末，巴斯德研制成功鸡霍乱疫苗、羊炭疽疫苗和狂犬疫苗，并利用生物传代和物理化学方法处理病原体，得到减毒和灭活疫苗; 第二次发生在 20 世纪 80 年代，其标志是以酵母制造乙肝疫苗。这一阶段，以重组 DNA 技术为代表的分子生物学技术的发展，使疫苗的研究从整体病原体水平进阶到分子水平; 第三次是 20 世纪 90 年代研制成功核酸疫苗，该技术最早由美国的沃夫( Wolff) 等发明。人类使用疫苗预防疾病已有200多年的历史，疫苗作为人类与疾病斗争的有力武器，消灭或控制了许多传染病。今天我们就来回顾一下，疫苗经历了怎样的发展轨迹？疫苗发展历程梳理一、萌芽期疫苗的横空出世首先得从天花病毒说起。天花是一种烈性传染病，不论什么人，一旦与患者接触，几乎都会传染，并且死亡率极高。但是在长时间的医疗中发现，有两种人是对天花有抵抗力的：一是从天花中康复的人，二是曾经护理过天花病的人。我们的前人在这种现象的启发下，研究出了用人痘接种预防天花的方法。该方法是将沾有疤浆患者的衣服给正常儿童穿戴，或将天花愈合后局部皮肤组织研磨成细粉，经鼻使儿童吸入。我们的前人在这种现象的启发下，研究出了用人痘接种预防天花的方法。该方法是将沾有疤浆患者的衣服给正常儿童穿戴，或将天花愈合后局部皮肤组织研磨成细粉，经鼻使儿童吸入。不过因为风险太大，这个技术一直没有推广开来，但这个技术的发展却给了人们很大的启发，让他们找到了对抗天花的方法。在18世纪末，一名英国的乡下大夫爱德华-琴纳接待一名妇女，她患有发烧、腰疼、呕吐等症状，他从中意识到接种牛痘可以预防天花。为了证实这一设想，他于1796年5月14日从一名正患牛痘的挤奶女工身上的脓疤里取少量脓液注射至八岁男孩詹姆斯费普臂内。六周后，男孩的牛痘反应消退，所以正如琴纳所说：“尽管假性天花接种小孩手臂出现类似的脓疤，除此之外几乎不可觉察。”琴纳为了证实其效果，先后多次给费普接种，但费普却安然无恙。2个月后，再接种天花患者来源的痘液，费普仅局部手臂出现疤疹，未引起全身天花。据此，琴纳于1798年出版其专著《探究》，称此技术为疫苗接种。在琴纳那个时代，人们根本不知道天花是由一种病毒引起的，也不知道种痘能让身体产生一种对抗天花的免疫。但是，经过他的实际观察，经过试验，确定了一种新的疫苗接种法，它不仅安全，而且很有效，是一个划时代的发明。琴纳（公元1749年—公元1823年）二、第一次疫苗革命这一阶段疫苗的发展归功于路易·巴斯德于19世纪末在疫苗研制领域的先锋作用和卓越贡献。被誉为疫苗之父的巴斯德的伟大贡献在于：他选用免疫原性强的病原微生物经培养，用物理或化学方法将其灭活后，再经纯化制成。灭活疫苗使用的毒种一般是强毒株，但使用减毒的弱毒株也有良好的免疫原性，如用萨宾减毒株生产的脊髓灰质炎灭活疫苗。减毒活疫苗是采用人工定向变异的方法，或从自然界筛选出毒力高度减弱或基本无毒的活的微生物制成疫苗，并以此给人接种而达到预防传染病的目的。在19世纪末，科赫发明了在固体培养基上分离细菌培养物的方法，该法为巴斯德研制疫苗奠定了基础。巴斯德首次发现，长期在人工培养基上，如将鸡霍乱弧菌置于两个星期后，这种菌种对雏鸡不会造成致病性。还有一点很重要：即使再次给这些被注射过的雏鸡注射了霍乱，他们也不会感染。巴斯德提出，这可能是因为在老的培养基中，鸡霍乱弧菌的毒性降低，但是其免疫原性保持不变，从而导致雏鸡对霍乱弧菌有了免疫力。以此理论巴斯德将炭疽杆菌在42~43℃的环境下培养两周后，制成人工减毒炭疽活疫苗。在巴斯德光辉成就的启发下，1908年卡麦特和古林将一株牛型结核杆菌在含有胆汁的培养基上连续培养13年213代，终于在1921获得减毒的卡介苗(BCG)。最初卡介苗为口服，20世纪20年代末改为皮内注射，卡介苗在新生儿抵御粟粒性肺结核和结核性脑膜炎方面具有很好的效果。自1928年至今，卡介苗仍在全世界广泛地被用于儿童计划免疫接种，已有40多亿人接种过卡介苗。这一阶段疫苗革命中还包括白喉、破伤风类毒素、鼠疫疫苗、伤寒疫苗和黄热病等30多种疫苗的成功研制。巴斯德三、第二次疫苗革命第二次疫苗革命主要是从分子水平上制备基因工程亚单位疫苗。由于分子生物技术、生物化学、遗传学和免疫学的迅速发展，使得研制新疫苗和改进旧疫苗的工作能 够在分子水平上进行。以酵母制备乙肝疫苗作为二次疫苗革命的分水岭。采用重组DNA技术、蛋白质化学技术开创了疫苗研制的第二次革命。1.重组核酸技术美国斯坦福大学于1972年提出重组核酸技术，并以迅雷不及掩耳之势风靡世界，开创了生命科学的新局面，其中包括疫苗的研制。基因重组技术的运用，为疫苗的研发提供了一条崭新的道路。该技术不仅可以获得几乎所有的免疫原，还可以让病原微生物的研究者和疫苗的接种者变得更加安全。例如，乙肝疫苗最初是从人乙型肝炎表面抗原(HBsAg)携带者血浆中提取，对健康人来说，其接种的危险性显而易见。20世纪80年代，又有研究报道了 HBsAg的基因在酵母和真核细胞中的表达，该方法既可获得类似于血液疫苗的免疫效果，又可获得简单、快速、廉价、高效的 HBsAg的抗体，对接种人群具有较高的安全性。当前，在不改变疫苗抗原性的前提下，利用重组核酸技术，以病毒、细菌作为载体，将目标基因导入到疫苗菌株及其质粒的基因组中，从而在不改变其抗原性的情况下，实现对疫苗菌株的高表达。所以，该疫苗对人体所起到的免疫作用是双向的。例如，第一次疫苗革命产生的卡介苗，现在采用重组核酸技术将γ-干扰素(IFN-γ)、白细胞介素2(IL-2)等细胞因子基因导入卡介苗中，成为重组卡介苗(γBCG)。重组卡介苗不仅保留传统卡介苗的特性，同时还分泌γ-干扰素和白细胞介素2，这样重组卡介苗既可用于结核病的预防，又能用于肿瘤或其他免疫性疾病的治疗。2.蛋白质化学和化学技术由于疫苗中的保护性抗原大部分为蛋白质，所以要得到特异性的蛋白质抗原，必须先对其进行分离纯化，由此可见蛋白质化学技术的发展对疫苗的研制起着重大作用。另外，可根据骨髓依赖性(B)淋巴细胞表位或胸腺依赖性(T)淋巴细胞表位直接采用蛋白质化学和化学技术合成多肤抗原，用来制备多肤疫苗。四、第三次疫苗革命核酸疫苗的开发研制，标志着第三次疫苗革命的到来。1995年美国纽约科学院召开专门研讨核酸疫苗会议，称之为疫苗学的新纪元和疫苗的第三次革命。1.核酸疫苗的发现和研制沃夫等人偶然的研究成果以及阿瑟的基因递送体系，为发展新型核酸疫苗奠定了基础。20世纪80年代后期，90年代初期，人们利用表达基因的核酸进行基因疗法，发现不经任何处理的裸露基因，可以在肌肉细胞内表达蛋白质，并且可以在肌肉细胞内持续两个月，引起人体产生免疫反应，由此引发了一场核酸疫苗的研发。在最初的动物实验中有两个令人欣喜的结果:第一是A型流感病毒核酸疫苗注射给小鼠，结果诱发了小鼠产生抗体和细胞毒性T细胞。然后用A型流感(PR/8) 攻击，100%小鼠健康存活，而对照组100%在9天后死亡。几乎同时，费南(Fynan)等人使用基因枪和编码红细胞凝集素的核酸，其结果也使小鼠获得 保护性免疫应答。另一个重要的研究结果是乙肝表面抗原的核酸疫苗。该疫苗不但能诱导动物产生相应的抗体，还能让转基因动物体内的 HBV表面抗原呈阴性。因此，可以用核酸疫苗来预防和治疗疾病，特别是对乙型肝炎的核酸疫苗。该结果对目前国内乙型肝炎疫苗的研发具有一定的指导意义。2.核酸疫苗的应用前景核酸疫苗的研究进展令人鼓舞，核酸疫苗因其独特的优势，在免疫防治中发挥了重要作用。因此，自1994年以来，美国 FDA先后批准了包括 AIDS，流感，乙肝，单纯疤疹，疟疾，Cancer在内的几种核酸疫苗的临床试验。欧美各国都投入了大量的人力物力，对核酸疫苗进行了研发。核酸疫苗已用于淋巴瘤、黑色素瘤、结肠癌及前列腺癌的临床前治疗研究。据统计，1989年至2004年，全球得到认可的基因治疗临床试验共9987例，仅肿瘤治疗占66%。然而，由于其高致死率，迄今尚无针对肝癌 DNA疫苗进行临床研究的相关报道。因此，开展肝癌核酸疫苗临床应用的研究具有重要意义。核酸疫苗也被广泛应用于基因缺陷导致的免疫缺陷疾病的治疗，其中以 ADA基因为代表的基因治疗是目前最有效的一种。mRNA 疫苗技术在新冠疫情应对中市场前景得到较大提升。2020年是 mRNA 技术平台的突破元年，新冠 mRNA 疫苗的推出和广泛使用极大提升了mRNA 疫苗的融资和市场活力。目前开发中的 mRNA 制剂有3个主要应用：预防性疫苗、治疗性疫苗和治疗药物。复星与拜恩泰科研发的mRNA新冠疫苗样品人类在200多年前就开始应用疫苗，它为我们构筑了一道强有力的生物屏障，使我们免受病毒的攻击。在这次疫情之后，疫苗是人类的“保护神”，这一点是毋庸置疑的。随着技术的进步，经过科学家们的不懈努力，将会有更多的治疗性和预防性疫苗被研制出来。疫苗对于人体的作用，无论怎样夸张也不为过，因为每一种新型疫苗的出现，都代表着一场人类对某种疾病的胜利！参考：[1]许丽丽,陈艳,陈征宇等.疫苗的发展与创新：从天花疫苗到新型冠状病毒疫苗[J].医药导报,2021,40(07):876-881.[2]贾冰冰,李卫国.疫苗技术发展的历史与展望[J].生物学通报,2016,51(06):1-3.[3]https://www.nobelprize.org/prizes/lists/all-nobel-prizes/[4]https://www.nature.com/immersive/d42859-020-00005-8/index.html识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

SHREVEPORT, La.--(BUSINESS WIRE)-- Morris & Dickson is proud to announce it is the first U.S. distributor of Bavarian Nordic’s newly launched mpox vaccine, JYNNEOS®. As the only FDA-approved mpox vaccine, JYNNEOS is now commercially available in the U.S., marking a significant expansion for access. Bavarian Nordic announced its commercial entry into the US on April 2, noting the ongoing need for the vaccine. Mpox (also known as monkeypox) is a viral disease that is part of the same family of viruses that causes smallpox. Mpox is rarely fatal, and its symptoms are similar to smallpox but milder. According to the Centers for Disease Control and Prevention (CDC), while mpox no longer constitutes a public health emergency, infections are still occurring throughout the U.S., with around 200 cases every month on average. Since the beginning of the outbreak in 2022, more than 32,000 cases have been reported in the U.S., representing a third of all cases reported globally. Morris & Dickson is receiving the first U.S. shipment of JYNNEOS, which must be safely stored at negative 20 degrees Celsius (-20°C). This storage and transport capability is also a unique feature of Morris & Dickson’s state-of-the-art distribution techniques. “We are proud to be a key partner in expanding access to this first-to-market vaccine,” says Layne Martin, head of Specialty at Morris & Dickson. “JYNNEOS meets a critical public health need and helps ensure equitable access to healthcare, which in turn helps significantly prevent the spread of mpox to at-risk populations.” About Morris & Dickson Morris & Dickson is the industry’s largest independent full-line and specialty pharmaceutical distributor with a singular focus of reliable, next-day delivery of drugs and related products to health systems, independent pharmacies, specialty pharmacies, and alternative care facilities across 27 states (and counting). Doing business the right way since 1841, Morris & Dickson continues to grow to meet customers’ needs with over 30,000 SKUs of pharmaceutical and healthcare products found in our state-of-the-art, 12-acre automated distribution center, located in Louisiana. For more information, please visit .

Mpox last gained national attention during a 2022 outbreak. After years relying on the U.S. government to stockpile and distribute Jynneos, Bavarian Nordic is launching the mpox vaccine into the commercial market. Jynneos, the only FDA-approved mpox vaccine, is now commercially available in the U.S., Bavarian Nordic announced Tuesday. The commercial rollout means that interested individuals can access the shot at local pharmacies and physician offices, in addition to the limited number of clinics designated by health authorities. The launch builds on Jynneos’ availability through public health channels since an mpox—then known as monkeypox—outbreak in 2022. It also follows a unanimous decision in October from the U.S. CDC’s Advisory Committee on Immunization Practices to recommend Jynneos as a routine vaccination in adults at risk of mpox infection, backing the shot’s use beyond an outbreak. People at risk of mpox include men who have sex with men and others who engage in risky sex practices, according to the CDC. About 2 million individuals in the U.S. are eligible for Jynneos under the CDC’s new recommendation, Bavarian Nordic said, citing CDC estimates. About 60% of those people remain completely unvaccinated, and 15% have received only one of the two vaccine doses. A real-world case-match study conducted in 12 U.S. jurisdictions previously showed that Jynneos, when given in two doses, was estimated to be 85.9% effective against mpox. At one dose, the vaccine was found to be 75.2% effective. Back in 2022, when initial supplies were constrained, the FDA issued an emergency use authorization (EUA) allowing intradermal administration of Jynneos at a lower dose so that a single vial could be used on up to five people. The EUA prioritized sparing doses, while the regular FDA-approved dosing of Jynneos calls for an entire 0.5mL vial given subcutaneously, Peter Costa, the North America medical director at Bavarian Nordic, explained in an interview. Although mpox is no longer considered an emergency, infections still occur at an average monthly rate of about 200 cases in the U.S., with reports across most of the states so far this year. More than 32,000 mpox cases have been reported in the U.S. since the last outbreak in 2022. Jynneos was developed with support from the Biomedical Advanced Research and Development Authority as part of the U.S.’s preparedness efforts. The vaccine got its FDA approval for the prevention of smallpox and mpox in 2019 and has been supplied to the government for national stockpiling. Jynneos was Bavarian Nordic’s first revenue-generating product until the Danish company in 2020 decided to add more commercial products under a deal with GSK. Last year, Jynneos, which is also known as Imvamune or Imvanex outside the U.S., nearly tripled its prior-year sales to reach more than DKK 5 billion ($720 million). The revenues came from contracts with various governments, including the U.S. The mpox shot also received immunization recommendations from authorities outside the U.S., including Germany, which could potentially also enable a commercial launch in those countries, according to Bavarian Nordic. Despite setting a company revenue record in 2023, Bavarian Nordic realized that Jynneos’ sales wouldn’t be sustainable as the number of mpox cases declines in part thanks to the protection provided by the vaccine, CEO Paul Chaplin said on the company’s fourth-quarter earnings call in March. Still, Bavarian Nordic expects its total 2024 revenue to come in a range between DKK 5 billion to DKK 5.3 billion. This guidance includes contribution from travel vaccines, which contributed nearly DKK 1.9 billion in sales last year. The Danish company last year beefed up its offerings with the acquisition of Emergent BioSolutions’ travel health business, which includes the typhoid vaccine Vivotif and the cholera vaccine Vaxchora. For Jynneos, Chaplin touted additional customers in the public preparedness sector that the company signed on during the mpox outbreak, as well as “concrete discussions” with other governments for more contracts. The U.S. private market will give the Jynneos franchise another boost, he said. Jynneos is the first vaccine that Bavarian Nordic is taking through the entire U.S. commercial process, including signing reimbursement deals with payers, Lee Ann Kimak, the company’s U.S commercial lead, noted during the interview.  After the free government-run Jynneos program winds down, Bavarian Nordic will work to make sure that uninsured people also have access to Jynneos, including by working with the CDC’s Vaccines for Adults program, which offers recommended vaccinations to people at no cost, Kimak said. Jynneos isn't expected to be a seasonal vaccine like flu shots, but Kimak said the company expects some spikes in demand prior to pride events. Bavarian Nordic has partnered with organizations such as the National Coalition of STD Directors and the National Coalition of LGBTQ Health to raise awareness and promote access to Jynneos. Editor's Note: The story was updated with additional information from an interview with Bavarian Nordic's Peter Costa and Lee Ann Kimak.