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连“战时法”都搬出来了,为什么美国疫苗依然一支难求

连“战时法”都搬出来了,为什么美国疫苗依然一支难求

Rachana Pradhan, Arthur Allen, Kaiser Health News 2021年02月27日
按照当前的生产速度,辉瑞和Moderna在3月底无法完成各自供应至少1亿支疫苗的目标。

美国政府已经投资了数十亿美元用于制造疫苗,并且通过数十次使用战时法令来提振产量。然而,新冠疫苗的生产速度依然难以满足需求,甚至连美国政府自身的全国性接种目标都未实现。

美国总统乔·拜登本月在美国国家卫生研究院(National Institutes of Health)的致辞中表示,美国“如今有望在7月底之前为3亿美国人提供充足的疫苗供应”。然而按照当前的生产速度,辉瑞(Pfizer)和Moderna在3月底无法完成各自供应至少1亿支疫苗的目标,更不用提各自在7月之前提供2亿多支疫苗了。

要履行其合同义务,Moderna必须将其1月的疫苗生产率(约1900万支)提升至少一倍。辉瑞在2月17日之前供应了4000万支疫苗。距离其承诺的交付1.2亿支疫苗的日期仅剩下约六周的时间。

拜登以及来自于这两家公司的高管称,他们正在迅速扩张产能。然而,评论家们已经等不及了,他们希望了解政府是否迅速采取了足够的措施,来保证这些公司能够应对新冠疫情的紧急挑战。至于那些收到大量税金提振的制造商,它们为什么不更早地分享科技与知识,或者在达成战略生产合作关系方面更快地采取行动?

专家称,整个过程比较复杂,并表示原材料的生产以及组装线不是说按个键就可以增至之前的1万倍,而且能够做到当前这个水平几乎就是奇迹。他们指出瓶颈至少存在三个方面:特种脂质体的生产,这种脂肪材料是Moderna和辉瑞-BioNTech疫苗的重要组件;数亿个用来盛放疫苗的玻璃小瓶;以及无菌自动生产线,疫苗在这里从大型容器分装至小瓶,然后发货。

美国官员开始频繁利用《国防生产法案》(Defense Production Act)的各种限制,该法案诞生于朝鲜战争时期,可以让联邦政府在国家紧急状态时期提高关键材料的供应。疫苗加工流程需要一套复杂的供应链,从采购原材料和设备,到设计化学流程、打造生产线以及聘请和培训员工等。

此外,专家还表示,没有人知道哪种疫苗能够发挥作用。

Biologics Consulting公司的高级咨询师、美国生物医学高级研究与发展管理局(Biomedical Advanced Research and Development Authority)的前官员凯文·吉利干说:“一年前,mRNA产品没有商业市场,仅用于科研和医药公司生产的小批量临床用药。如今,我们需要数十亿支疫苗,这个数字让供应基础设施处于超负荷状态。”美国生物医学高级研究与发展管理局是一个于2006年创建的联邦机构,用于应对疫情和生物恐怖主义。

今年1月,美国政府问责办公室(Government Accountability Office)的报道显示,截至去年12月,特朗普政府通过其“曲速行动”(Operation Warp Speed)疫苗计划划拨了近140亿美元用于疫苗开发和生产,其中包括扩张美国产能的投资。Kaiser Health News在查看了联邦合约数据库、非营利机构Knowledge Ecology International获得的合约以及政府新闻稿之后表示,当局在至少23个与疫苗相关的合同中调用了《国防生产法案》,部分原因是为了让政府的合约优于其他合约。

这些合约包括去年12月美国卫生与公共服务部(Department of Health and Human Services)与辉瑞签署的额外供应1亿支疫苗的协议,此前双方已经在去年夏天签署了供应1亿支疫苗的合约。该部门的一位前任官员称,这个合约价值19.5亿美元,其中融合了《国防生产法案》的条款,旨在让公司可以优先获取原材料以及工厂的备用部件。

与Moderna、强生(Johnson & Johnson)和其他医药公司签署的涉及数亿药剂的疫苗合约中亦出现了《国防生产法案》的条款。除此之外,在与针头和针管制造企业签署的合约中,至少有10个合约亦调用了该法案的内容。该法案还被用于要求玻璃制造商康宁(Corning)和SiO2 Materials Science优先生产疫苗用玻璃瓶,同时亦写入了与Emergent BioSolutions、Fujifilm Diosynth Biotechnologies和Grand River Aseptic Manufacturing公司签署的与制造相关的合约当中。

“曲速行动”疫苗计划于去年向Emergent BioSolutions拨款6.48亿美元,以便其产能能够达到与强生和阿斯利康(AstraZeneca)进行签约所需的水平,以帮助其生产疫苗。这两笔合约至少分别价值6.15亿美元和2.61亿美元。Grand River Aseptic Manufacturing从美国生物医学高级研究与发展管理局手中拿到了1.6亿美元的合同,而且与强生签署了合约,灌封其单次注射新冠疫苗。该疫苗有望在本月获得美国食品与药品管理局(Food and Drug Administration)的紧急授权,但其初始供应量只有数百万支。

拜登政府扩大了其对战时法案的使用范围,以优先生产辉瑞所需的填充泵和过滤系统等设备。负责政府新冠疫苗供应举措的白宫官员提姆·曼宁在2月的新闻发布会上表示:“我们说过,只要听到与疫苗供应相关的所需设备、供应物资或技术出现瓶颈,那么我们就会介入并提供帮助。”

然而,医疗供应链的专家称,它的作用亦是有限的。哈佛大学全球发展中心(Center for Global Development at Harvard University)的高级研究员普拉山特·雅达福说,《国防生产法案》的举措需要数月的时间才可以发挥其效用,因为购买设备以及安装需要一定的时间,而且其每一步都受到了严格监管。

约翰斯·霍普金斯大学凯瑞商学院(Johns Hopkins University’s Carey Business School)的副教授戴定龙(音译)称,美国在产能方面不大可能出现实质性的增长,“除非我们能够探讨联合生产模式”,也就是允许制药公司生产其竞争对手的疫苗。

到目前为止,这类安排已经在欧洲广泛使用,而欧洲本身的医药产能也低于美国。与其他首要疫苗生产商进行这类交易在美国并不是很常见。

Moderna的发言人雷·乔丹在一封电子邮件中说:“虽然我们没有与其他大型制药公司进行合作,但我们已经与多家对于我们扩大规模、实现供应和商业化规划有着重要意义的机构建立了战略合作伙伴关系。”

Moderna于本月表示,其制造流程在未来数周内将迅速扩大,而且公司将在2月和3月向美国提供3000支至3500万支疫苗,从4月到7月每月提供4000支至4500万支疫苗。公司拒绝透露产能提振的具体原因。

专注于专利权的非盈利机构Knowledge Ecology International的总监詹姆斯·拉夫表示,疫苗制造商在很久以前就应该通过分享技术和专长来提振美国和欧洲的产能,尤其是发展中国家的产能。

他说:“很明显,有很多事情是应该做而没有做,而且我们为此浪费了一年的时间。其言外之意是,虽然事情很紧急,但我们在提升产能方面什么都没有发生。”

其他人认为事情并没有这么简单。深度参与“曲速行动”计划的美国卫生与公共服务部的前任官员保尔·曼戈在谈论疫苗时说:“一年前美国没有任何可用的剩余产能。美国正在购买设备,进行质量控制,招兵买马。这件事情在很多人眼中十分容易。这个并不是招400名员工来干活就能够解决的问题。”

每一支Pfizer-BioNTech或Moderna针剂含有数十亿个脂质纳米颗粒,每一个颗粒含有4个脂质体和一段核酸RNA,这五种成分的组合方式可以让RNA进入我们的细胞,并打造能够激发免疫系统的分子,从而防御新冠病毒。

仅有少数工厂生产的脂质体一直都是供应方面的首要问题。雅达福说:“没有人想过我们会使用数十亿剂量的脂质纳米颗粒药剂。我们还没有发明一个可以大规模生产脂质纳米颗粒的流程。”

疫苗中的两种脂质体——胆固醇和DSCP,一直都被工业用于化学药剂的塑造和缓释。第三种脂质体能够预防这些分子相互凝结。第四种脂质体可以让疫苗的脂质外壳与人类细胞进行融合,而且一旦它进入细胞之后就会打开,这样RNA便能够进入名为核糖体的构架,并制造可以激发免疫力的蛋白。

所有这些原材料都是在规范的条件下生产,这些由Moderna、辉瑞或Acuitas Therapeutics授权的生产商位于马萨诸塞州、密苏里州、科罗拉多州和阿拉巴马州。Acuitas Therapeutics由英属哥伦比亚大学(University of British Columbia)的教授皮耶特·库里斯共同创建,而皮耶特被誉为脂质纳米颗粒技术的鼻祖。

在疫情之前,这些公司的产量并不高,其供应对象是小型临床试验、实验室实验或某个授权药物(例如用于治疗罕见基因疾病的patisiran,全球仅有数千名患者)。脂质体生产商Evonik的副总裁史蒂芬·兰德尔称,如今这些公司生产了上万公斤的脂质体。Evonik最近宣布,公司可能会在今年下半年扩大其两个德国工厂的产能,这些脂质体将被用于辉瑞-BioNTech疫苗。公司去年在美国阿拉巴马州收购了一家脂质体生产商。

兰德尔说:“突然间,公司不得不把产量提升数千倍以上。这是最大的瓶颈。”

Precision NanoSystems的首席科学官安德鲁·吉尔称,疫苗中的多种材料,包括制作mRNA的脂质体和酶,在最近之前一直使用动物产品生产,例如羊毛。Precision NanoSystems从事设计用于混合mRNA与脂质体的设备。动物产品,哪怕只是微小剂量,都可能会引发污染或疾病,因此制造商目前已经改为使用合成材料。

Evonik的发言人茱莉亚·伯恩表示,幸运的是,化妆品行业在最近几十年中也在逐渐放弃动物产品。作为脂质体的使用大户,化妆品行业也会使用一些疫苗用脂质体。

Acuitas的首席执行官及联合创始人托马斯·梅登称,然而,全球仅有少数公司拥有制作脂质体的专长和设施。从实验室所需用量提升至工业规模生产给他们带来了不小的麻烦。他说,例如,在工业流程中应该避免使用实验室流程中使用的危险溶剂和化学品,这些物品可能会增加工厂的安全隐患。

梅登说:“这是一个超级复杂的供应链。一旦你解决了某一点的瓶颈之后,你会发现流程中的下一个瓶颈。有点像游戏‘打地鼠’。”

英属哥伦比亚大学教授的库里斯说,尽管疫苗用脂质体的制作并不是特别困难,但大规模生产工厂设施获得美国食品与药品管理局的批准需要一定的时间。他说,从零开始建这样一座工厂需要两到三年的时间,因此,Moderna与辉瑞-BioNTech选择与现有生产商开展合作,并让他们转而生产脂质体。

另一个瓶颈是“灌/封”,也就是将做好的疫苗装入小瓶或针筒里,以便将注射液运给客户。Moderna子公司Valera的前总裁迈克·沃森称,疫苗灌装线要求极高的效率和无菌环境,全球有这个能力的公司并不多。Moderna聘请Catalent(这家合约生产商最近出现的拖延现象放缓了一些疫苗的发货进度)在其印第安纳州布卢明顿工厂灌封美国疫苗。至少还有其他两家公司为Moderna的海外疫苗供应提供这类服务。

今年1月,法国跨国公司赛诺菲(Sanofi)同意使用其德国的灌封线生产辉瑞-BioNTech疫苗。该生产线预计要到7月才能够运营。赛诺菲的自家疫苗因为免疫激发表现欠佳而被延迟推出。

在美国,最近几周运往各州的疫苗数量有所增加,部分原因在于辉瑞称其瓶装的5剂疫苗实际上可以注射六次。Moderna正在申请美国食品与药品管理局批准,在瓶装10剂疫苗中增加不超过5剂的量。

辉瑞称,公司的原材料产于圣路易斯,疫苗的活性成分产自马萨诸塞州的安德沃,灌封则在密歇根州的卡拉马祖完成。

2月19日在卡拉马祖,站在拜登身旁的辉瑞首席执行官艾伯乐(Albert Bourla)称,公司增加了在密歇根州和康涅狄格州工厂的脂质体产能以及堪萨斯城的灌封生产线能力。他说,辉瑞已经将疫苗制作的平均时间从110天大幅削减至60天。

艾伯乐说:“在今天的这次会面中,美国总统给我们布置了一项任务,要求我们寻找其他的方式,以便他的团队可以帮助我们进一步加速疫苗生产进程,在7月之前交付所有3亿支疫苗。我们接受了这个任务,而且将会竭尽全力去完成这项工作。”(财富中文网)

KHN(Kaiser Health News)是一家报道健康新闻的非营利性新闻服务。它是KFF(Kaiser Family Foundation)旗下一个独立社论业务,与Kaiser Permanente没有关联。

译者:冯丰

审校:夏林

美国政府已经投资了数十亿美元用于制造疫苗,并且通过数十次使用战时法令来提振产量。然而,新冠疫苗的生产速度依然难以满足需求,甚至连美国政府自身的全国性接种目标都未实现。

美国总统乔·拜登本月在美国国家卫生研究院(National Institutes of Health)的致辞中表示,美国“如今有望在7月底之前为3亿美国人提供充足的疫苗供应”。然而按照当前的生产速度,辉瑞(Pfizer)和Moderna在3月底无法完成各自供应至少1亿支疫苗的目标,更不用提各自在7月之前提供2亿多支疫苗了。

要履行其合同义务,Moderna必须将其1月的疫苗生产率(约1900万支)提升至少一倍。辉瑞在2月17日之前供应了4000万支疫苗。距离其承诺的交付1.2亿支疫苗的日期仅剩下约六周的时间。

拜登以及来自于这两家公司的高管称,他们正在迅速扩张产能。然而,评论家们已经等不及了,他们希望了解政府是否迅速采取了足够的措施,来保证这些公司能够应对新冠疫情的紧急挑战。至于那些收到大量税金提振的制造商,它们为什么不更早地分享科技与知识,或者在达成战略生产合作关系方面更快地采取行动?

专家称,整个过程比较复杂,并表示原材料的生产以及组装线不是说按个键就可以增至之前的1万倍,而且能够做到当前这个水平几乎就是奇迹。他们指出瓶颈至少存在三个方面:特种脂质体的生产,这种脂肪材料是Moderna和辉瑞-BioNTech疫苗的重要组件;数亿个用来盛放疫苗的玻璃小瓶;以及无菌自动生产线,疫苗在这里从大型容器分装至小瓶,然后发货。

美国官员开始频繁利用《国防生产法案》(Defense Production Act)的各种限制,该法案诞生于朝鲜战争时期,可以让联邦政府在国家紧急状态时期提高关键材料的供应。疫苗加工流程需要一套复杂的供应链,从采购原材料和设备,到设计化学流程、打造生产线以及聘请和培训员工等。

此外,专家还表示,没有人知道哪种疫苗能够发挥作用。

Biologics Consulting公司的高级咨询师、美国生物医学高级研究与发展管理局(Biomedical Advanced Research and Development Authority)的前官员凯文·吉利干说:“一年前,mRNA产品没有商业市场,仅用于科研和医药公司生产的小批量临床用药。如今,我们需要数十亿支疫苗,这个数字让供应基础设施处于超负荷状态。”美国生物医学高级研究与发展管理局是一个于2006年创建的联邦机构,用于应对疫情和生物恐怖主义。

今年1月,美国政府问责办公室(Government Accountability Office)的报道显示,截至去年12月,特朗普政府通过其“曲速行动”(Operation Warp Speed)疫苗计划划拨了近140亿美元用于疫苗开发和生产,其中包括扩张美国产能的投资。Kaiser Health News在查看了联邦合约数据库、非营利机构Knowledge Ecology International获得的合约以及政府新闻稿之后表示,当局在至少23个与疫苗相关的合同中调用了《国防生产法案》,部分原因是为了让政府的合约优于其他合约。

这些合约包括去年12月美国卫生与公共服务部(Department of Health and Human Services)与辉瑞签署的额外供应1亿支疫苗的协议,此前双方已经在去年夏天签署了供应1亿支疫苗的合约。该部门的一位前任官员称,这个合约价值19.5亿美元,其中融合了《国防生产法案》的条款,旨在让公司可以优先获取原材料以及工厂的备用部件。

与Moderna、强生(Johnson & Johnson)和其他医药公司签署的涉及数亿药剂的疫苗合约中亦出现了《国防生产法案》的条款。除此之外,在与针头和针管制造企业签署的合约中,至少有10个合约亦调用了该法案的内容。该法案还被用于要求玻璃制造商康宁(Corning)和SiO2 Materials Science优先生产疫苗用玻璃瓶,同时亦写入了与Emergent BioSolutions、Fujifilm Diosynth Biotechnologies和Grand River Aseptic Manufacturing公司签署的与制造相关的合约当中。

“曲速行动”疫苗计划于去年向Emergent BioSolutions拨款6.48亿美元,以便其产能能够达到与强生和阿斯利康(AstraZeneca)进行签约所需的水平,以帮助其生产疫苗。这两笔合约至少分别价值6.15亿美元和2.61亿美元。Grand River Aseptic Manufacturing从美国生物医学高级研究与发展管理局手中拿到了1.6亿美元的合同,而且与强生签署了合约,灌封其单次注射新冠疫苗。该疫苗有望在本月获得美国食品与药品管理局(Food and Drug Administration)的紧急授权,但其初始供应量只有数百万支。

拜登政府扩大了其对战时法案的使用范围,以优先生产辉瑞所需的填充泵和过滤系统等设备。负责政府新冠疫苗供应举措的白宫官员提姆·曼宁在2月的新闻发布会上表示:“我们说过,只要听到与疫苗供应相关的所需设备、供应物资或技术出现瓶颈,那么我们就会介入并提供帮助。”

然而,医疗供应链的专家称,它的作用亦是有限的。哈佛大学全球发展中心(Center for Global Development at Harvard University)的高级研究员普拉山特·雅达福说,《国防生产法案》的举措需要数月的时间才可以发挥其效用,因为购买设备以及安装需要一定的时间,而且其每一步都受到了严格监管。

约翰斯·霍普金斯大学凯瑞商学院(Johns Hopkins University’s Carey Business School)的副教授戴定龙(音译)称,美国在产能方面不大可能出现实质性的增长,“除非我们能够探讨联合生产模式”,也就是允许制药公司生产其竞争对手的疫苗。

到目前为止,这类安排已经在欧洲广泛使用,而欧洲本身的医药产能也低于美国。与其他首要疫苗生产商进行这类交易在美国并不是很常见。

Moderna的发言人雷·乔丹在一封电子邮件中说:“虽然我们没有与其他大型制药公司进行合作,但我们已经与多家对于我们扩大规模、实现供应和商业化规划有着重要意义的机构建立了战略合作伙伴关系。”

Moderna于本月表示,其制造流程在未来数周内将迅速扩大,而且公司将在2月和3月向美国提供3000支至3500万支疫苗,从4月到7月每月提供4000支至4500万支疫苗。公司拒绝透露产能提振的具体原因。

专注于专利权的非盈利机构Knowledge Ecology International的总监詹姆斯·拉夫表示,疫苗制造商在很久以前就应该通过分享技术和专长来提振美国和欧洲的产能,尤其是发展中国家的产能。

他说:“很明显,有很多事情是应该做而没有做,而且我们为此浪费了一年的时间。其言外之意是,虽然事情很紧急,但我们在提升产能方面什么都没有发生。”

其他人认为事情并没有这么简单。深度参与“曲速行动”计划的美国卫生与公共服务部的前任官员保尔·曼戈在谈论疫苗时说:“一年前美国没有任何可用的剩余产能。美国正在购买设备,进行质量控制,招兵买马。这件事情在很多人眼中十分容易。这个并不是招400名员工来干活就能够解决的问题。”

每一支Pfizer-BioNTech或Moderna针剂含有数十亿个脂质纳米颗粒,每一个颗粒含有4个脂质体和一段核酸RNA,这五种成分的组合方式可以让RNA进入我们的细胞,并打造能够激发免疫系统的分子,从而防御新冠病毒。

仅有少数工厂生产的脂质体一直都是供应方面的首要问题。雅达福说:“没有人想过我们会使用数十亿剂量的脂质纳米颗粒药剂。我们还没有发明一个可以大规模生产脂质纳米颗粒的流程。”

疫苗中的两种脂质体——胆固醇和DSCP,一直都被工业用于化学药剂的塑造和缓释。第三种脂质体能够预防这些分子相互凝结。第四种脂质体可以让疫苗的脂质外壳与人类细胞进行融合,而且一旦它进入细胞之后就会打开,这样RNA便能够进入名为核糖体的构架,并制造可以激发免疫力的蛋白。

所有这些原材料都是在规范的条件下生产,这些由Moderna、辉瑞或Acuitas Therapeutics授权的生产商位于马萨诸塞州、密苏里州、科罗拉多州和阿拉巴马州。Acuitas Therapeutics由英属哥伦比亚大学(University of British Columbia)的教授皮耶特·库里斯共同创建,而皮耶特被誉为脂质纳米颗粒技术的鼻祖。

在疫情之前,这些公司的产量并不高,其供应对象是小型临床试验、实验室实验或某个授权药物(例如用于治疗罕见基因疾病的patisiran,全球仅有数千名患者)。脂质体生产商Evonik的副总裁史蒂芬·兰德尔称,如今这些公司生产了上万公斤的脂质体。Evonik最近宣布,公司可能会在今年下半年扩大其两个德国工厂的产能,这些脂质体将被用于辉瑞-BioNTech疫苗。公司去年在美国阿拉巴马州收购了一家脂质体生产商。

兰德尔说:“突然间,公司不得不把产量提升数千倍以上。这是最大的瓶颈。”

Precision NanoSystems的首席科学官安德鲁·吉尔称,疫苗中的多种材料,包括制作mRNA的脂质体和酶,在最近之前一直使用动物产品生产,例如羊毛。Precision NanoSystems从事设计用于混合mRNA与脂质体的设备。动物产品,哪怕只是微小剂量,都可能会引发污染或疾病,因此制造商目前已经改为使用合成材料。

Evonik的发言人茱莉亚·伯恩表示,幸运的是,化妆品行业在最近几十年中也在逐渐放弃动物产品。作为脂质体的使用大户,化妆品行业也会使用一些疫苗用脂质体。

Acuitas的首席执行官及联合创始人托马斯·梅登称,然而,全球仅有少数公司拥有制作脂质体的专长和设施。从实验室所需用量提升至工业规模生产给他们带来了不小的麻烦。他说,例如,在工业流程中应该避免使用实验室流程中使用的危险溶剂和化学品,这些物品可能会增加工厂的安全隐患。

梅登说:“这是一个超级复杂的供应链。一旦你解决了某一点的瓶颈之后,你会发现流程中的下一个瓶颈。有点像游戏‘打地鼠’。”

英属哥伦比亚大学教授的库里斯说,尽管疫苗用脂质体的制作并不是特别困难,但大规模生产工厂设施获得美国食品与药品管理局的批准需要一定的时间。他说,从零开始建这样一座工厂需要两到三年的时间,因此,Moderna与辉瑞-BioNTech选择与现有生产商开展合作,并让他们转而生产脂质体。

另一个瓶颈是“灌/封”,也就是将做好的疫苗装入小瓶或针筒里,以便将注射液运给客户。Moderna子公司Valera的前总裁迈克·沃森称,疫苗灌装线要求极高的效率和无菌环境,全球有这个能力的公司并不多。Moderna聘请Catalent(这家合约生产商最近出现的拖延现象放缓了一些疫苗的发货进度)在其印第安纳州布卢明顿工厂灌封美国疫苗。至少还有其他两家公司为Moderna的海外疫苗供应提供这类服务。

今年1月,法国跨国公司赛诺菲(Sanofi)同意使用其德国的灌封线生产辉瑞-BioNTech疫苗。该生产线预计要到7月才能够运营。赛诺菲的自家疫苗因为免疫激发表现欠佳而被延迟推出。

在美国,最近几周运往各州的疫苗数量有所增加,部分原因在于辉瑞称其瓶装的5剂疫苗实际上可以注射六次。Moderna正在申请美国食品与药品管理局批准,在瓶装10剂疫苗中增加不超过5剂的量。

辉瑞称,公司的原材料产于圣路易斯,疫苗的活性成分产自马萨诸塞州的安德沃,灌封则在密歇根州的卡拉马祖完成。

2月19日在卡拉马祖,站在拜登身旁的辉瑞首席执行官艾伯乐(Albert Bourla)称,公司增加了在密歇根州和康涅狄格州工厂的脂质体产能以及堪萨斯城的灌封生产线能力。他说,辉瑞已经将疫苗制作的平均时间从110天大幅削减至60天。

艾伯乐说:“在今天的这次会面中,美国总统给我们布置了一项任务,要求我们寻找其他的方式,以便他的团队可以帮助我们进一步加速疫苗生产进程,在7月之前交付所有3亿支疫苗。我们接受了这个任务,而且将会竭尽全力去完成这项工作。”(财富中文网)

KHN(Kaiser Health News)是一家报道健康新闻的非营利性新闻服务。它是KFF(Kaiser Family Foundation)旗下一个独立社论业务,与Kaiser Permanente没有关联。

译者:冯丰

审校:夏林

The U.S. government has invested billions of dollars in manufacturing, used a wartime act dozens of times to boost supplies, and yet there’s still not enough COVID vaccine on the way to meet demand—or even the government’s own goals for national immunization.

President Joe Biden, in remarks at the National Institutes of Health this month, said the nation is “now on track to have enough supply for 300 million Americans by the end of July.” But at the current rate of production, Pfizer and Moderna will miss their targets of providing at least 100 million doses each by the end of March, let alone 200 million more doses each has promised by July.

Moderna would need to more than double its vaccine production rate from January—when it made roughly 19 million doses—to meet its contractual obligations. Pfizer supplied 40 million vaccine doses by Feb. 17. It has roughly six weeks left to deliver the first 120 million doses it has promised.

Biden and officials from the two companies say they are rapidly expanding production capacity. But critics are lining up. They want to know whether the government did enough, fast enough, to guarantee that companies would meet the urgent challenges of the pandemic. As for the manufacturers bolstered by extraordinary sums of taxpayer money, why did they not share technology and know-how sooner, or move more quickly into strategic production partnerships?

Experts say it’s complicated, noting that the output of raw materials and assembly lines can’t be ratcheted up 10,000-fold at the push of a button—and that the effort thus far has been close to miraculous. They cite bottlenecks in at least three areas: the production of specialty lipids, fatty materials that are a primary component of the Moderna and Pfizer-BioNTech vaccines; the hundreds of millions of glass vials that hold the vaccine; and the sterile automated assembly lines where vaccine moves from bulk containers into vials before shipment.

U.S. officials have run headlong into the limits of the Defense Production Act, a Korean War-era law that allows the federal government to ramp up supplies of critical materials in times of national emergency. The vaccine manufacturing process relies on a complex supply chain, from sourcing raw materials and equipment to designing chemical processes, building production lines and hiring and training workers.

Also, experts note, no one knew which vaccines would prove effective.

“A year ago there was no commercial market for mRNA product. There was scientific research and pharma making small-volume clinical lots. Now we need billions of doses, in the space of a year. That’s overloading the supply infrastructure,” said Kevin Gilligan, a senior consultant with Biologics Consulting and a former official with the Biomedical Advanced Research and Development Authority, or BARDA, a federal agency created in 2006 to deal with pandemics and bioterrorism.

As of December, the Trump administration through its Operation Warp Speed initiative had obligated nearly $14 billion for vaccine development and manufacturing, including investments to expand U.S. capacity, according to a Government Accountability Office report in January. The administration invoked the Defense Production Act on at least 23 vaccine-related contracts, in part to prioritize the government’s contracts over others, according to a KHN review of the federal contracts database, contracts obtained by the nonprofit group Knowledge Ecology International and government news releases.

They include the December contract that the Department of Health and Human Services signed with Pfizer for another 100 million doses, on top of the initial 100 million it committed to last summer. That contract, worth $1.95 billion, included DPA provisions to give the company priority access to raw materials and spare parts for factories, according to a former administration official.

The DPA has also been used in vaccine contracts with Moderna, Johnson & Johnson, and other drug companies for hundreds of millions of doses. On top of that, the law has been invoked for at least 10 contracts with companies making needles or syringes. It’s been used to require glass makers Corning and SiO2 Materials Science to prioritize vial production for vaccine production, and in contracts for aspects of manufacturing with companies like Emergent BioSolutions, Fujifilm Diosynth Biotechnologies and Grand River Aseptic Manufacturing.

Operation Warp Speed awarded Emergent BioSolutions $648 million last year to boost the manufacturing capacity it needed to enter agreements with Johnson & Johnson and AstraZeneca—worth at least $615 million and $261 million, respectively—to help make their vaccines. Grand River Aseptic Manufacturing won a $160 million award from BARDA and has contracted with Johnson & Johnson to fill vials and finish packaging of its single-shot COVID vaccine, which is expected to get emergency authorization from the Food and Drug Administration as soon as this month but will only have a few million doses available initially.

The Biden administration has expanded its use of the wartime act to prioritize equipment like filling pumps and filtration systems for Pfizer. “We told you that when we heard of a bottleneck on needed equipment, supplies or technology related to vaccine supply, that we would step in and help,” Tim Manning, the White House official leading the administration’s COVID supply efforts, said during a February press briefing.

Yet it can do only so much, according to medical supply chain experts. Prashant Yadav, a senior fellow at the Center for Global Development at Harvard University, said it could take months for the impact of that DPA action to be felt because of the time it takes to procure equipment and get it installed, with each step tightly regulated.

The U.S. is unlikely to get a meaningful bump in capacity “unless we think about co-production deals,” in which a drug company agrees to manufacture a competitor’s vaccine, said Tinglong Dai, an associate professor at Johns Hopkins University’s Carey Business School.

So far, such arrangements have proliferated in Europe—which has less capacity to produce drugs than the United States does. Deals with other major vaccine manufacturers have been less common on the U.S. side of the pond.

“Though we have not partnered with, say, another large pharma for production, we have built strategic partnerships with a number of organizations that have been instrumental to our scaling up and meeting supply and commercialization plans,” Moderna spokesperson Ray Jordan said in an email.

Moderna this month said that its manufacturing process would scale up rapidly in the coming weeks, that it would provide the U.S. between 30 million and 35 million doses in February and March and between 40 million and 50 million doses monthly from April to July. The company declined to elaborate on what made the boost possible.

Vaccine manufacturers long ago should have been sharing technology and expertise to boost production in the U.S. and Europe, and especially in developing countries, said James Love, director of Knowledge Ecology International, a nonprofit focused on patent rights.

“We’ve wasted about a year by not doing some of the obvious things,” he said. “The rhetoric is that it’s an emergency. But on the scale-up of manufacturing, you just don’t see it.”

It’s not that simple, others say. “There wasn’t any excess capacity available in the United States a year ago. Zero,” Paul Mango, a former HHS official heavily involved in Operation Warp Speed, said regarding vaccines. “It’s getting the equipment. It’s quality control. It’s getting the employees. People make it sound like this is easy. You can’t just push 400 workers and say, go at it.”

Each Pfizer-BioNTech or Moderna shot contains billions of lipid nanoparticles, each particle containing four lipids and a strand of the nucleic acid RNA, the five pieces assembled in a way that allows the RNA to enter our cells and create a particle that stimulates the immune system to defend against the COVID virus.

The lipids, which are made only in a handful of factories, have been a major supply problem. “No one has ever thought of a scenario where we would use lipid nanoparticle formulation for [billions of] doses,” Yadav said. “We have not invented a process for doing lipid nanoparticles at scale.”

Two of the lipids in the vaccine, cholesterol and DSCP, have long been used in industry to shape and buffer chemical formulations. A third lipid prevents the particles from clumping together. A fourth enables the lipid shell of the vaccine to fuse with human cells and, once inside the cell, to crack open so the RNA can move to a structure called a ribosome and make proteins that stimulate immunity.

All of these raw materials are produced under regulated conditions—in Massachusetts, Missouri, Colorado, and Alabama by companies under license with Moderna, Pfizer or Acuitas Therapeutics, which was co-founded by Pieter Cullis, a University of British Columbia professor who is considered the grandfather of lipid nanoparticle technology.

Before the pandemic, these companies produced meager amounts for use in small clinical trials, laboratory experiments or in one licensed drug, patisiran, which is used to treat a rare genetic disease in perhaps a few thousand people worldwide. Now they are producing thousands of kilograms of the stuff, said Stefan Randl, a vice president at Evonik, a lipid maker. Evonik recently announced it would scale up production at two German sites, possibly in the second half of the year, to be used in the Pfizer-BioNTech vaccine. The company last year bought a U.S. lipid manufacturer in Alabama.

“All of a sudden the quantities had to be ramped up a thousand-fold or more,” Randl said. “This is the biggest bottleneck.”

Several elements of the vaccine, including lipids and enzymes used in making the mRNA, until recently were produced using animal products such as sheep’s wool, said Andrew Geall, chief scientific officer at Precision NanoSystems, which designs equipment for mixing the mRNA and lipids. Animal products could cause contamination or disease, even in minute quantities, so manufacturers now use synthetic chemicals.

Luckily, the cosmetic industry—a major user of some of the same lipids used in the vaccines—has been switching from animal products in recent decades, noted Julia Born, an Evonik spokesperson.

Still, only a limited number of companies globally have expertise and facilities to make the lipids, said Thomas Madden, CEO and a co-founder of Acuitas, and they’ve all struggled to move from quantities produced in a laboratory to industrial-scale production. For instance, he said, hazardous solvents and chemicals used in laboratory procedures need to be avoided in industrial processes, where they could give rise to workplace safety issues.

“This is a hugely complex supply chain,” Madden said. “Once you address a bottleneck at one point, you identify the next bottleneck in the process. It’s a bit of a game of whack-a-mole.”

Although it’s not particularly difficult to make the lipids used in vaccines, it takes time to get FDA authorization of a facility that can make them in high quantities, said Cullis, the UBC professor. It would take two to three years to start such a factory from scratch, so instead, Moderna and Pfizer-BioNTech have been hooking up with existing manufacturers and getting them to convert to lipid production, he said.

Another bottleneck is “fill/finish”—getting the finished vaccine into vials or syringes so the shots can be shipped to customers. Vaccine filling lines require extremely high levels of efficiency and sterility, and few companies in the world have this capacity, said Mike Watson, former president of Valera, a Moderna subsidiary. Moderna has hired Catalent, a contract manufacturer that recently experienced delays that slowed the release of some doses, to fill and finish U.S. doses at its facility in Bloomington, Indiana. At least two other companies will do the same for Moderna’s vaccine supply abroad.

In January, the French multinational Sanofi—whose own COVID vaccine has been delayed by poor performance in producing immunity—agreed to offer its fill/finish line in Germany for the Pfizer-BioNTech vaccine. That line isn’t expected to be running until July.

In the U.S., the number of vaccine doses shipped to states has ticked up in recent weeks, partly because Pfizer said its five-dose vials actually provide six shots. Moderna is seeking FDA permission to add up to five doses to its 10-dose vials.

Pfizer has said it is manufacturing raw materials in St. Louis, the active ingredients for the vaccine in Andover, Massachusetts, and filling vials in Kalamazoo, Mich.

CEO Albert Bourla, with Biden at his side in Kalamazoo on February 19, said the company added lipid production capabilities at plants in Michigan and Connecticut, as well as fill/finish lines in Kansas. He said it has significantly cut the average time it takes to make doses—from 110 days to 60 days.

“Today, during this meeting, the president challenged us to identify additional ways in which his administration could help us potentially accelerate even further the delivery of the full 300 million doses earlier than July,” Bourla said. “The challenge is accepted, and we will try to do our best.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation) that is not affiliated with Kaiser Permanente.

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