Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy.
Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy.
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DOI：
10.1073/pnas.2102775118
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发表时间：
2021-07-20
影响因子：
11.1
通讯作者：
Mueller S
中科院分区：
文献类型：
--
作者：
Wang Y;Yang C;Song Y;Coleman JR;Stawowczyk M;Tafrova J;Tasker S;Boltz D;Baker R;Garcia L;Seale O;Kushnir A;Wimmer E;Mueller S
这项工作证明了合理设计和合成候选疫苗的可行性，以应对真实的世界条件下出现的疾病。此外，使用活的减毒密码子对去优化的病毒方法确保宿主免疫系统的所有组分都将参与，并且避免了来自杂合活病毒的载体序列的潜在影响。来自其他密码子去优化病毒的证据表明，COVI-VAC将对由于抗原漂移引起的逆转和效力丧失具有抗性。在允许的条件下易于大规模病毒生长，加上单剂量鼻内给药的潜力，使COVI-VAC成为可能用于大规模免疫计划的临床测试的有吸引力的候选者。成功抗击COVID-19大流行取决于大规模接种合适的疫苗以实现群体免疫。在这里，我们描述了COVI-VAC，这是目前临床开发中唯一的严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）减毒活疫苗。COVI-VAC是通过用同义次优密码子对（密码子对去优化）重新编码病毒刺突蛋白的一段，从而引入283个沉默（点）突变而开发的。此外，从病毒基因组中删除刺突蛋白内的弗林蛋白酶切割位点，以增加疫苗株的安全性。除了弗林蛋白酶切割位点缺失外，COVI-VAC和亲本SARS-CoV-2的氨基酸序列是相同的，确保所有病毒蛋白质都可以与疫苗接受者的宿主免疫系统接合。COVI-VAC在体外对温度敏感，但在允许温度下生长稳健（>107空斑形成单位/mL）。与接种野生型（WT）病毒的叙利亚金黄仓鼠相比，鼻内接种COVI-VAC的叙利亚金黄仓鼠（Mesocricetus auratus）的组织病毒载量始终较低，肺部病理学较轻，体重减轻减轻。COVI-VAC接种产生的加标IgG抗体水平和空斑减少中和滴度与接种WT病毒的仓鼠相似。在用WT病毒攻击后，COVI-VAC疫苗接种降低了肺攻击病毒滴度，导致大脑中检测不到病毒，并保护仓鼠免受几乎所有SARS-CoV-2相关的体重减轻。高度减毒的COVI-VAC在相关体内模型中以单次鼻内剂量具有保护作用。这一点，加上其大规模生产的潜力，支持其在大规模疫苗接种计划中的潜在用途。
This work demonstrates the feasibility of rationally designing and synthesizing vaccine candidates for testing in response to an emerging disease in real world conditions. Furthermore, using a live attenuated codon-pair–deoptimized virus approach ensures that all components of the host immune system will be engaged, and potential effects from the vector sequences from hybrid live viruses are avoided. Evidence from other codon-deoptimized viruses suggests that COVI-VAC will be resistant to reversion and loss of potency due to antigenic drift. The ease of large-scale virus growth under permissive conditions coupled with the potential for single-dose intranasal administration make COVI-VAC an appealing candidate for clinical testing for possible use in mass immunization programs. Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>107 plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters (Mesocricetus auratus) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2–associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
影响因子：
--
作者：
Durmaz B;Abdulmajed O;Durmaz R
通讯作者：
Durmaz R
影响因子：
2.9
作者：
Maitra, Arindam;Sarkar, Mamta Chawla;Das, Saumitra
通讯作者：
Das, Saumitra
DOI：
10.1073/pnas.1619242114
发表时间：
2017-01-17
影响因子：
11.1
作者：
Le Nouen, Cyril;McCarty, Thomas;Buchholz, Ursula J.
通讯作者：
Buchholz, Ursula J.
DOI：
10.1073/pnas.86.10.3699
发表时间：
1989-05-01
影响因子：
11.1
作者：
GUTMAN, GA;HATFIELD, GW
通讯作者：
HATFIELD, GW