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新冠疫苗剂量是否可以减少?专家这样说...

  • 责任编辑:siyu.zhang
  • 来源:互联网
  • 时间:2021-07-22 14:25:13

  新冠疫苗的供应一直是个问题,那么可以考虑减少新冠疫苗剂量吗?看看世界卫生组织如何回答。

  我们能否将现有的新冠疫苗扩展到更多人?专家有分歧

  海伦·布兰斯韦尔2021年7月8日

  由于全球Covid-19疫苗供应仍然严重不足,疫苗制造商正在制药行业寻找合作伙伴,以增加生产,民间社会团体正在向政界人士施压,要求他们放弃知识产权保护,以刺激更多的生产。

  但如果有更简单的方法呢?如果目前的疫苗供应可以被拉长,以更快的速度为更多的人接种疫苗,会怎么样?如果世界对每个接种疫苗的人使用的疫苗超过需要,剥夺了排队等待接种的人获得保护的机会,那会怎么样?

  一些科学家认为,减少新冠疫苗剂量是一种以前已经成功使用过的方法,应该加以探索。

  近年来,世界卫生组织多次建议“分段”——在关键疫苗供应有限的情况下使用部分或部分剂量。当安哥拉和刚果民主共和国爆发危险的黄热病疫情,可能耗尽世界上的黄热病疫苗储备时,世卫组织指示各国在紧急疫苗接种工作中使用正常剂量的五分之一。(2016年那次疫情期间进行的研究表明,较低的剂量保护了接种者。)世卫组织还建议在疫苗缺乏期间使用部分剂量的灭活脊髓灰质炎疫苗和脑膜炎球菌结合疫苗。

  然而,并不是所有人都支持分剂量接种新冠疫苗的想法;一些专家认为,疫苗应该按照临床试验期间测试的剂量大小使用,并得到监管机构的批准。他们坚持认为,这种方式为接种疫苗的人提供了最好的保护。拉里·科里(Larry Corey)是美国政府支持的新冠疫苗试验设计的共同负责人,他说:“我的问题是,你必须证明部分剂量是有效的。”这还没有发生。

  但是,香港大学传染病研究员Ben Cowling认为,公共卫生方法——关注对整个人群而不是个人最好的方法——是大流行所需要的。本周早些时候,他和香港健康数据发现实验室(Laboratory of Data Discovery for Health)的林伟文(Wey Wen Lim)以及芝加哥大学(University of Chicago)病毒生态学与进化副教授莎拉·科比(Sarah Cobey)在《自然》(Nature)杂志上发表的一篇评论文章中,为使用小剂量的Covid疫苗提出了理由。

  考林在接受STAT采访时表示,如果生产商在测试新冠疫苗时,将研究集中于寻找最小的可能保护剂量,“想想可以挽救多少生命”。

  重要的是要理解,制药公司在2020年初开始开发Covid疫苗时,它们是在与时间赛跑,SARS-CoV-2病毒席卷全球,感染和死亡人数迅速上升。在这种情况下,没有时间去寻找一种“金发姑娘”剂量——即使用刚好足够保护被接种者的抗原,但不超过所需的剂量。

  在这种情况下确定疫苗剂量既是一门艺术也是一门科学。大多数制造商测试的是两剂方案,因为积累的大量疫苗经验表明,免疫系统需要两次引入新病原体才能对其产生良好的反应。(唯一的例外是强生公司(Johnson & Johnson),该公司测试了一剂和两剂疫苗。前者已被授权使用;对后者的研究仍在继续。)

  在需要多少抗原(构成每剂疫苗的液体)的问题上,每家制造商迅速测试了一小部分选择。例如,辉瑞(Pfizer)和生物技术公司(BioNTech)是第一个将疫苗推向美国市场的合作伙伴,它们在两剂方案中测试了10、20和30微克的剂量,在剂量发现研究中测试了单一100微克的剂量;Moderna测试了25、100和250微克的剂量。两家公司都选择了双剂量方案,辉瑞选择了30微克剂量,Moderna选择了100微克剂量。(Moderna的250微克剂量产生了过多的副作用,因此被放弃了。)

  过去的研究认为,这些剂量不够大,不足以表明低剂量是否具有保护作用。他们只记录了剂量的可耐受程度——它们是否引发了太多不愉快的反应?——以及接种疫苗的人的可测量免疫反应。对于制造商来说,当务之急是找到一种有效的疫苗剂量,促使他们提高剂量,以确保安全。

  (当世界上最大的疫苗制造商赛诺菲在其一次试验中意外地给人剂量不足时,错误的代价就显而易见了。去年12月,当辉瑞和Moderna寻求紧急使用许可时,赛诺菲宣布将不得不重新进行2期试验。虽然辉瑞和Moderna已经销售了数亿剂疫苗,但赛诺菲仍然没有获得授权的产品。)

  一些科学家注意到,对一些疫苗的剂量发现研究表明,可以使用低剂量的疫苗。事实上,“扭曲速度行动”(Operation Warp Speed)——特朗普政府快速追踪新冠疫苗、药物和诊断的项目——的领导层几个月前要求Moderna研究是否可以将疫苗剂量减半;今年1月,Warp Speed的前首席顾问蒙塞夫·斯拉维(Moncef Slaoui)在哥伦比亚广播公司(CBS)上表示,50微克剂量产生的反应与Moderna选择的100微克剂量相同。

  斯拉维没有引用具体的研究报告,公司也回避了有关是否履行了“曲速行动”要求的问题。Moderna发言人通过电子邮件表示:“100[-微克]剂量被选择用于关键的3期研究,这仍然是我们唯一证明具有临床疗效的剂量水平。”

  考林、林和科比指出,辉瑞测试的最低剂量10微克引发的免疫反应与该公司选择的剂量相当,后者含有三倍于前者的抗原。

  一些科学家注意到,对一些疫苗的剂量发现研究表明,可以使用低剂量的疫苗。事实上,“扭曲速度行动”(Operation Warp Speed)——特朗普政府快速追踪新冠疫苗、药物和诊断的项目——的领导层几个月前要求Moderna研究是否可以将疫苗剂量减半;今年1月,Warp Speed的前首席顾问蒙塞夫·斯拉维(Moncef Slaoui)在哥伦比亚广播公司(CBS)上表示,50微克剂量产生的反应与Moderna选择的100微克剂量相同。

  斯拉维没有引用具体的研究报告,公司也回避了有关是否履行了“曲速行动”要求的问题。Moderna发言人通过电子邮件表示:“100[-微克]剂量被选择用于关键的3期研究,这仍然是我们唯一证明具有临床疗效的剂量水平。”

  考林、林和科比指出,辉瑞测试的最低剂量10微克引发的免疫反应与该公司选择的剂量相当,后者含有三倍于前者的抗原。

  和免疫学家拉霍亚免疫学研究所的一项研究,本周公布的预印本服务器报道,那些收到25微克的现代化的疫苗,最低剂量公司研究,有免疫反应与人从Covid感染中恢复过来。

  这篇论文的一位资深作者Daniela Weiskopf警告说,因为世界上还不知道免疫系统武器的水平和组合——中和抗体?绑定的抗体吗?激活的是B细胞还是T细胞?-是预防SARS-2病毒所需的,目前还不清楚这是否是一种有效的疫苗。

  (包括Moderna的科学家在内的多个研究小组正在努力建立所谓的保护相关物——受保护的免疫系统是什么样子。该公司表示,如果能确定保护作用的相关因素,可能会考虑降低剂量,但这需要得到监管部门的批准。)

  “我们不知道的是……这是否足够好,”Weiskopf说,他是拉霍亚大学的助理研究教授,主要研究T细胞在病毒免疫中的作用。“这种程度的免疫反应足以保护人体吗?”

  拉霍亚大学的免疫学家、论文的资深作者谢恩·克罗蒂(Shane Crotty)说,他认为,如果Moderna选择了最低的测试剂量,而不是最高的测试剂量,药效会有可测量的差异。但对于一种在第三阶段试验中显示94%功效的疫苗来说,这种差异是否足以显著削弱疫苗的功效呢?

  “从科学上讲,它成功的可能性是合理的,但我们进行第三阶段临床试验也有很好的理由。这些结果很难预测。

  他说,有几个国家在获得足够的疫苗供应方面遇到了困难,他们询问了Crotty关于他们是否可以使用小剂量疫苗的建议。“我没有向任何人推荐它。”

  当世界卫生组织推荐小剂量的黄热病疫苗时,它是基于在巴西进行的一项研究,该研究表明这种方法是有效的。克罗蒂说,目前还没有对新冠病毒疫苗进行类似的研究。

  世界卫生组织免疫、疫苗和生物制品司司长Kate O 'Brien说:“我们对任何现有的证据都非常感兴趣,这些证据表明,任何疫苗在[当前]剂量以外的剂量下的效果。”“最重要的是,我们不会在没有数据的情况下提出任何建议——你知道,这只是没有数据的建议。”

  科里是弗雷德·哈钦森癌症研究中心的病毒学家,他承认他不喜欢分数剂量的想法。“这可能行得通,但也可能行不通,”他直截了当地说。

  他说:“当然,最好的方法是用有效剂量接种最好的疫苗。”他说:“难道你想放弃95%的(疫苗效力)来达到80%吗?它还能抵抗严重疾病吗?一样长吗?”

  就连考林也承认,鉴于需要测试较低剂量的疫苗,在这场大流行中采取这种做法的机会可能正在从世界的掌控中消失。他担心,即使这个想法被采纳,部分剂量疫苗可能在一些国家被认为是不可接受的;他们可能会认为这是次品。

  “我的一个具体担忧是,现在,如果[世卫组织的疫苗专家]开会讨论非洲、南美洲或亚洲部分地区的疫苗分离,这些地区目前的疫苗供应相对较低,当发达国家一直在使用全额剂量时,这些国家会对使用少量剂量的想法感到不满。”

  关于作者

  海伦现在

  高级作家,传染病

  海伦涵盖与传染病广泛相关的问题,包括疫情爆发、防范、研究和疫苗开发。

  @HelenBranswell

  附上原文,以供参考,拒绝转载,侵权必删:

  Can we stretch existing Covid vaccines to inoculate more people? Experts are divided

  By Helen Branswell July 8, 2021

  With the global supply of Covid-19 vaccine still woefully inadequate, vaccine makers are scouring the pharmaceutical landscape for partners to ramp up manufacturing, and civil society groups are pressing politicians to waive intellectual property protections in a bid to spur still more production.

  But what if there was a simpler way? What if current supplies could be stretched, to vaccinate more people more quickly? What if the world is using more vaccine than it needs to on each person immunized, depriving people in the queue of a chance to be protected?

  Reducing the size of a vaccine dose is an approach that has been used successfully before and ought to be explored, some scientists argue.

  Several times in recent years the World Health Organization has recommended “fractionation” — using partial or fractional doses when supplies of critical vaccines have been limited. When a dangerous yellow fever outbreak in Angola and the Democratic Republic of the Congo threatened to exhaust the world’s stores of yellow fever vaccine, the WHO instructed countries to use one-fifth of a normal dose in their emergency vaccination efforts. (Research done during that 2016 outbreak suggested the lower dose protected those who received it.) The WHO has also recommended use of fractional doses of inactivated polio vaccine and meningococcal conjugate vaccines during periods of scarcity of those shots.

  The idea of splitting doses of Covid vaccines is not universally supported, however; a number of experts contend that the vaccines should be used in the dose size tested during clinical trials and cleared for use by regulatory agencies. That route offers the best protection for individuals who are vaccinated, they insist. “The problem where I’m coming from is you have to prove fractional dosing works,” said Larry Corey, who co-led design of the trials of the Covid vaccines supported by the U.S. government. That hasn’t happened yet.

  But Ben Cowling, an infectious diseases researcher at Hong Kong University, believes that a public health approach — one that focuses on what’s best for whole populations, not individuals — is what’s needed in a pandemic. He and two colleagues, Wey Wen Lim, of Hong Kong’s Laboratory of Data Discovery for Health, and Sarah Cobey, an associate professor of viral ecology and evolution at the University of Chicago, argued the case for using fractional doses of Covid vaccine in a commentary in Nature earlier this week.

  “Think of the lives that would have been saved” if manufacturers geared their research to finding the smallest possible dose that was protective when they were testing their Covid vaccines, Cowling told STAT in an interview about fractionation.

  It’s important to understand that when pharmaceutical companies set out to develop Covid vaccines in early 2020, they were in a race against time, with the SARS-CoV-2 virus sweeping the globe and infections and deaths rising rapidly. In such a scenario, there was no time to find a Goldilocks dose — the one that used just enough antigen to protect a person being vaccinated, but no more than was needed.

  Settling on a vaccine dose in a situation like this is as much an art as it is a science. Most manufacturers tested a two-dose regimen, because the accumulated body of vaccine experience suggests that an immune system will need two introductions to a new pathogen to mount a good response against it. (The sole exception was Johnson & Johnson, which tested both a one-dose and a two-dose vaccine. The former has been authorized for use; study of the latter continues.)

  On the question of how much antigen — the fluid that comprises each vaccine dose — was needed, each of the manufacturers quickly tested a small range of options. For instance, Pfizer and BioNTech, the partnership that brought the first vaccine to market in the U.S., tested doses of 10, 20, and 30 micrograms given in a two-dose regimen, and a single 100-microgram dose in its dose-finding study; Moderna tested doses of 25, 100 and 250 micrograms. Both opted for two-dose regimens with Pfizer selecting the 30-microgram dose and Moderna opting for 100 micrograms. (Moderna’s 250-microgram dose had caused too many side effects and was abandoned.)

  The studies used to decide on those doses weren’t large enough to show whether the lower doses would have been protective. They only charted how tolerable the doses were — did they trigger too many unpleasant reactions? — and what the measurable immune responses were in the people who were vaccinated. For manufacturers, the priority was to find a vaccine dose that was effective, pushing them toward higher doses to be on the safe side.

  (The cost of getting this wrong was evident when Sanofi, one of the world’s biggest vaccine makers, accidentally under-dosed people in one of its trials. Its Covid vaccine was not adequately protective and when Pfizer and Moderna were seeking emergency use authorizations last December, Sanofi announced it would have to redo its Phase 2 trial. While Pfizer and Moderna have been selling hundreds of millions of doses of vaccine, Sanofi still does not have an authorized product.)

  A number of scientists have noted that the dose-finding studies for some of the vaccines suggest lower doses could have been used. In fact, the leadership of Operation Warp Speed — the Trump administration’s program to fast-track Covid vaccines, drugs and diagnostics — asked Moderna months ago to study whether it could halve its vaccine dose; Moncef Slaoui, the former chief adviser to Warp Speed, said on CBS in January that the responses generated by a 50-microgram dose was identical to that of the 100-microgram dose Moderna chose.

  Slaoui didn’t cite a specific study, and the company sidesteps questions about whether it followed through on the Operation Warp Speed request. A Moderna spokesperson said via email that “the 100[-microgram] dose was selected for the pivotal Phase 3 study and this remains the only dose level for which we have demonstrated clinical efficacy.”

  Cowling, Lim, and Cobey noted that the lowest dose Pfizer had tested, 10 micrograms, elicited immune responses that were comparable to the dose the company chose, which included three times as much antigen.

  A number of scientists have noted that the dose-finding studies for some of the vaccines suggest lower doses could have been used. In fact, the leadership of Operation Warp Speed — the Trump administration’s program to fast-track Covid vaccines, drugs and diagnostics — asked Moderna months ago to study whether it could halve its vaccine dose; Moncef Slaoui, the former chief adviser to Warp Speed, said on CBS in January that the responses generated by a 50-microgram dose was identical to that of the 100-microgram dose Moderna chose.

  Slaoui didn’t cite a specific study, and the company sidesteps questions about whether it followed through on the Operation Warp Speed request. A Moderna spokesperson said via email that “the 100[-microgram] dose was selected for the pivotal Phase 3 study and this remains the only dose level for which we have demonstrated clinical efficacy.”

  Cowling, Lim, and Cobey noted that the lowest dose Pfizer had tested, 10 micrograms, elicited immune responses that were comparable to the dose the company chose, which included three times as much antigen.

  And a study from immunologists at La Jolla Institute of Immunology that was posted this week to a preprint server reported that people who received 25 micrograms of Moderna’s vaccine, the lowest dose the company studied, had immune responses that were on a par with people who had recovered from Covid infection.

  One of the senior authors of that paper, Daniela Weiskopf, cautioned that because the world doesn’t yet know what levels and combinations of immune system armaments — Neutralizing antibodies? Binding antibodies? Activated B cells or T cells? — are needed to protect against the SARS-2 virus, it’s not clear if that would have been an effective vaccine.

  (Multiple research groups, including scientists at Moderna, are working to try to establish so-called correlates of protection — what a protected immune system looks like. If the correlates of protection can be determined, a move to a lower dose might be considered, the company said, thought it would require regulatory approval.)

  “What we don’t know … is if that is good enough,” said Weiskopf, an assistant research professor at La Jolla whose work focuses on the role of T cells in viral immunity. “Is that level of immune response enough to protect?”

  Shane Crotty, an immunologist at La Jolla who was also a senior author of the paper, said he believes there would have been a measurable difference in efficacy if Moderna had opted for its lowest, rather than its highest, tested dose. But for a vaccine that showed 94% efficacy in its Phase 3 trial, would the difference have been great enough to significantly erode the effectiveness of the vaccine?

  “Scientifically, there’s a reasonable chance it would be successful, but there’s also a really good reason we run Phase 3 clinical trials. It’s hard to predict those outcomes,” Crotty said.

  Several countries that were having trouble accessing sufficient supplies of vaccine have asked Crotty’s advice about whether they could use fractional doses, he said. “I didn’t recommend it to anybody.”

  When the WHO recommended fractional doses of yellow fever vaccine, it did so based on a study done in Brazil, which suggested the approach would work. Similar studies of Covid vaccines haven’t been conducted, Crotty said.

  “We’re very interested in any evidence that is available on the performance of any of the vaccines at a dose other than the [current] dose,” said Kate O’Brien, director of the WHO’s department of immunization, vaccine, and biologicals. “The most important thing is we don’t make any recommendations that are absent data — you know, that are just data-free recommendations.”

  Corey, a virologist at the Fred Hutchinson Cancer Research Center, admitted he isn’t a fan of the fractional dose idea. “It might work, but it may not work,” he said flatly.

  “The best approach, of course, is to give the best vaccine at the effective dose,” he said. “Do you want to throw away 95% [vaccine efficacy] to get something to 80%? Will it still be as good against severe disease? Last as long?”

  Even Cowling acknowledged that given that lower doses would need to be tested, the opportunity to go this route in this pandemic may be slipping from the world’s grasp. And he worries that even if the idea was adopted, fractional dose vaccines might be deemed as unacceptable in some countries; they might see it as sub-par product.

  “One of my specific concerns is that, right now, if [WHO’s vaccine experts] were to convene to discuss fractionation for places like Africa or South America or parts of Asia that have had relatively low supply so far, that those places would be unhappy about the idea of using fractional doses when the developed world has been using full doses,” he said.

  About the Author

  Helen Branswell

  Senior Writer, Infectious Disease

  Helen covers issues broadly related to infectious diseases, including outbreaks, preparedness, research, and vaccine development.

  @HelenBranswell

  Source of articles:https://www.statnews.com/

  Author:Helen Branswell


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