Novavax：全球首款重组蛋白新冠疫苗三期临床数据披露

1、预计三季度在美递交上市申请，很可能是美国批准的第四款新冠肺炎疫苗。之前这款疫苗中和抗体水平报出来是最高的，关注度较高。

2、三期临床在美国、墨西哥入组3万人受试者，疫苗组及安慰剂组2:1分组，整体90.4%保护效力，对中重症100%保护效力。对于高危人群也有91%保护率。

共观察到77例感染，14例疫苗组、63例安慰剂组。疫苗组均为轻症，安慰剂组10例中度、4例严重病例。

3、产能：2021年3季度末预计产能1亿剂/月；4季度末产能1.5亿剂/月。看起来到2022年，疫苗的产能都不再会是瓶颈，发展中国家的物流、接种能力很重要。

4、变异株保护能力：77个病例中，54个做个基因测序。

5、安全性较好

6、王年爽博士曾在微博讲过这家公司的故事，这家公司也用到了王博士设计的S-2P构象。可谓是置之死地而后生。

微博@为格命思奔 2021年2月

这家公司成立于1987年，跟我年纪差不多。直到现在都没有产品上市（快有了哈）。

他家的黑科技Matrix-M佐剂是2013年花3000万买来的。当即决定大干一场，目标瞄向RSV（呼吸道合胞病毒）疫苗。RSV极度常见，几乎会感染每一个人。是导致2岁以内的婴儿死亡的第二重要因素（第一是疟疾）。RSV疫苗之前介绍过多次，上世纪60年代甲醛灭活疫苗引发了严重的ADE反应以失败告终，之后是半个多世纪的屡战屡败。

2016年，他们RSV疫苗ResVax的首个噩梦来临。三期临床数据显示，其RSV疫苗在老年人中几乎完全没有效果，股价跌掉85%。公司已陷入运营困难，缩减开支并裁掉1/3员工。

Novavax仍冀望东山再起。他们对RSV疫苗ResVax没有放弃，这次改变策略给孕妇注射疫苗，希望她们把抗体传递给自己的孩子。因为RSV对6个月以内的新生儿危害更大，如果能帮助婴儿熬过最初的六个月，将极大降低死亡率。盖茨基金会伸出援手，资助了8900万刀。开始了另一场豪赌。

然而迎来的是第二场噩梦。

2019年，他们的面向孕妇的RSV疫苗三期临床失败。这次失败是致命的。根据纽约时报的报道，其股价连续30天处于1美元以下，最低54美分。并险些被纳斯达克除名。Novavax只能以1800万美元打包卖掉自己的生产设施和1/3员工。公司到了崩溃的边缘。当时有传言，这家公司不久将宣布倒闭。

如果倒闭，那么新冠病毒第一梯队的疫苗当中，将不会再有重组蛋白疫苗的身影。

他们两次失败的原因，其实还是RSV F蛋白构象问题。他们自己其实也清楚，因为在当时人们对RSV的构象转变已经有了相当多的了解。多家公司也开始推进融合前构象的RSV疫苗研发。

下面图是他们自己网站上的海报。

看其中的Fig.3。他们知道他们制备的抗原不是纺锤形的融合前（pre-F）构象，而是跟杆状的融合后（post-F）构象更相似。但硬说他们蛋白是prefusogenic的。其实是在赌：说不定能成呢。第一个RSV疫苗的诱惑实在太大了。

一条路走到底，结果如上所说，再一次跌得很惨。

那样的境况下，大概只有上帝能拯救他们了。

然而上帝出手了，新冠疫情爆发。

这对困境中的Novavax来说，是一个绝地反击的机会。

然而相比于Moderna这类根正苗红的资本宠儿，他们境况依然不佳。多年积累下的，只有RSV疫苗研发失败的经验。之前的SARS，MERS，埃博拉他们似乎都尝试过，没有一个进入临床。

从头再来吧。刚刚经历毁灭性的失败，重压下居然没有垮，这已是奇迹。然而如何持续凝聚人心则是一个问题。

在整个研发中，可以想象他们经历的困难。他们用的是全长S蛋白，是带有跨膜区的。纯化的时候要用去垢剂，更关键的问题是蛋白不带有任何外源纯化标签，纯化难度奇大。专业做结构的我肃然起敬，深表叹服。他们用的是杆状病毒-昆虫细胞表达系统，没有用哺乳动物细胞构建稳定表达细胞株。这其实是一个弱点，但这样的好处是突变株出来的时候相对容易更新：真是命运眷顾，要啥来啥。

其实先前RSV疫苗的失败不全是坏事。比如说这次他们就认识到了蛋白构象的重要性。他们在新疫苗中用上了S-2P。配合他们的Matrix-M佐剂，动物实验中一鸣惊人。

动物实验的论文最近也发表到Nature Communications，同步发表了审稿意见。两名审稿人都问到了为什么用PP 版本（下图）。回复也很明确：他们试过，野生型的不稳定，PP版本能经受住热稳定性测试和大规模纯化，要好很多。这应该是之前两次失败买来的教训吧。

他们这次拿到了更多钱，一开始就拿到CEPI的400万，之后又追加3.84亿，后来又从政府拿钱。Operation Warp Speed总共给六个疫苗资助了40亿，其中给了他们16亿。没办法，牛逼的技术在转化成产品前还只是虚无，混了三十多年还归于startup，并且濒临破产，穷得叮当响只剩一腔热血。他们之前似乎还发展了副业，比如卖孕期维生素。混成这样也是不容易。多给点钱也是理所应当。

新冠疫苗进展顺利的同时，他们的流感疫苗NanoFlu也进展顺利，正等待FDA最终审批。

之前说过，Moderna是美国政府的亲儿子，NIH出钱出人，梦幻专家团队鼎力相助，资本市场也是风生水起，并且有MERS疫苗研发的经验。而Novavax自始至终没有巨头加持，不知道是本身有骨气还是巨头看不上。只能默默的自己往下走。然后，我想起那句激励我无数次的话：一个一心向着目标前进的人，整个世界都会为他让路。

最终，他们坚持着，在mRNA疫苗和病毒载体疫苗林立的当下，不信邪，并杀出一条血路。守住了自己，也是重组蛋白疫苗的最后防线，背水一战，然后绝境重生，力挽狂澜。

他们高扬的股价背后，是唐吉柯德式的屡败屡战，是长久的沉淀和厚积薄发，似乎也是舍生忘死、敢为天下先的理想主义。他们几十年来的股价起伏比过山车要刺激的多（图4）。这在整体不景气的疫苗行业真可谓一朵奇葩。

疫苗开发本不容易。当我们仔细去体会这一个个疫苗公司，一个个研发人员，中国的，外国的，穿透岁月历经的的那些跌宕起伏，辛酸苦楚，请用理解、信赖、支持向他们的付出致敬吧。

公司新闻稿

Novavax, Inc. (Nasdaq: NVAX), today announced that NVX-CoV2373, its recombinant nanoparticle protein-based COVID-19 vaccine, demonstrated 100% protection against moderate and severe disease, 90.4% efficacy overall, and met the primary endpoint in its PREVENT-19 pivotal Phase 3 trial. 

The study enrolled 29,960 participants across 119 sites in the U.S. and Mexico to evaluate efficacy, safety and immunogenicity, with an emphasis on recruiting a representative population of communities and demographic groups most impacted by the disease.

“Today, Novavax is one step closer to addressing the critical and persistent global public health need for additional COVID-19 vaccines. These clinical results reinforce that NVX-CoV2373 is extremely effective and offers complete protection against both moderate and severe COVID-19 infection,” said Stanley C. Erck, President and Chief Executive Officer, Novavax. “Novavax continues to work with a sense of urgency to complete our regulatory submissions and deliver this vaccine, built on a well understood and proven platform, to a world that is still in great need of vaccines.”

The company intends to file for regulatory authorizations in the third quarter, upon completion of the final phases of process qualification and assay validation needed to meet chemistry, manufacturing and controls (CMC) requirements. Upon regulatory approvals, Novavax remains on track to reach manufacturing capacity of 100 million doses per month by the end of the third quarter and 150 million doses per month by the end of the fourth quarter of 2021.

“PREVENT-19 confirms that NVX-CoV2373 offers a reassuring tolerability and safety profile,” said Gregory M. Glenn, M.D., President of Research and Development, Novavax. “These data show consistent, high levels of efficacy and reaffirm the ability of the vaccine to prevent COVID-19 amid ongoing genetic evolution of the virus. Our vaccine will be a critical part of the solution to COVID-19 and we are grateful to the study participants and trial staff who made this study possible, as well as our supporters, including the U.S. Government.”

Results: Consistent, high efficacy among circulating variants

In the placebo-controlled, observer-blinded study randomized 2:1, NVX-CoV2373 demonstrated overall efficacy of 90.4% (95% CI: 82.9, 94.6), achieving its primary endpoint. Seventy-seven cases were observed: 63 in the placebo group and 14 in the vaccine group. All cases observed in the vaccine group were mild as defined by the trial protocol. Ten moderate cases and four severe cases were observed, all in the placebo group, yielding a vaccine efficacy of 100% (95% CI: 87, 100) against moderate or severe disease.

Efficacy endpoints were accrued from January 25 through April 30, 2021 — a time when the Alpha (B.1.1.7) variant, first identified in the U.K., became the predominant strain in the U.S. Other strains, including Variants of Interest (VoI) and Variants of Concern (VoC), were also on the rise during the PREVENT-19 endpoint accrual window. Click here for CDC definitions of variants.

Sequence data are available for 54 of the 77 cases. PREVENT-19 met its key secondary endpoint, demonstrating 100% efficacy (95% CI: 80.8, 100) against variants not considered VoC/VoI. Of the sequenced cases, 35 (65%) were VoC, 9 (17%) were VoI, and 10 (19%) were other variants. Against VoC/VoI, which represented 82% of the cases, vaccine efficacy was 93.2% (95% CI: 83.9, 97.1), achieving a key exploratory endpoint of the study. Thirty-eight of the VoC/VoI cases were in the placebo group and 6 were in the vaccine group.

NVX-CoV2373 also showed success among “high-risk” populations (defined as over age 65, under age 65 with certain comorbidities or having life circumstances with frequent COVID-19 exposure): vaccine efficacy was 91.0% (95% CI: 83.6, 95.0), with 62 COVID-19 cases in the placebo group and 13 COVID-19 cases in the vaccine group.

Results: Reasserting a favorable safety profile

Preliminary safety data from PREVENT-19 showed the vaccine to be generally well-tolerated. Serious and severe adverse events were low in number and balanced between vaccine and placebo groups. No single adverse event term was reported by more than 1% of participants. In assessing reactogenicity 7 days after Dose 1 and Dose 2, injection site pain and tenderness, generally mild to moderate in severity, were the most common local symptoms, lasting less than 3 days. Fatigue, headache and muscle pain were the most common systemic symptoms, lasting less than 2 days.

Study Endpoints

The primary endpoint for PREVENT-19 was the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second dose in serologically negative (to SARS-CoV-2) adult participants at baseline. The statistical success criterion included a lower bound of 95% CI >30%.

Novavax expects to share further details of the PREVENT-19 trial results as additional data become available. Further analyses of the trial are ongoing and will be shared via preprint servers as well as submitted to peer-review journals for publication.

The placebo-controlled portion of PREVENT-19 continues in adolescents from 12 to less than 18 years of age, which recently completed enrollment with 2,248 participants.

Variant Virus Strains

The CDC has defined Variant of Interest (VoI) as a variant with genetic markers that have been associated with changes to receptor binding, reduced neutralization by antibodies generated against previous infection or vaccination, or predicted increase in transmissibility or disease severity. A Variant of Concern (VoC) is defined as a variant for which there is evidence of an increase in transmissibility, more severe disease, significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.

转自公众号 伊洛：原文链接