SARS-CoV-2 prefusion spike protein stabilized by six rather than two prolines is more potent for inducing antibodies that neutralize viral variants of concern.
SARS-CoV-2 prefusion spike protein stabilized by six rather than two prolines is more potent for inducing antibodies that neutralize viral variants of concern.
复制标题
DOI：
10.1073/pnas.2110105119
复制
发表时间：
2022-08-30
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
突发严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）变体使阻止2019冠状病毒病（COVID-19）大流行的战斗复杂化。目前批准的疫苗通常表达原生全长S或presp - 2p。在这里，我们发现HexaPro作为SARS-CoV-2疫苗的免疫原优于2P或天然全长S蛋白。HexaPro表达效率更高，可诱导更强的SARS-CoV-2特异性抗体和th1偏倚T细胞免疫反应。HexaPro诱导的抗体中和SARS-CoV-2变体的效率是presp - 2p诱导的抗体的两到四倍。通过比较不同免疫剂量，我们发现HexaPro比2P具有更强的免疫原性和保护性。这项工作强调了在开发下一代COVID-19疫苗中使用HexaPro的重要性，因为它对SARS-CoV-2变体具有广泛的保护作用。严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的刺突蛋白是中和抗体（nab）的主要靶点。S蛋白三聚体以预融合（preS）但亚稳态的形式锚定在病毒粒子膜上。通过引入两个或六个脯氨酸取代来稳定preS蛋白，生成稳定的，可溶的2P或HexaPro (6P) preS蛋白。目前，尚不清楚哪种形式最具免疫原性。在这里，我们产生了表达press - 2p、press - hexapro和天然全长S的重组水疱性口炎病毒（rVSV），并比较了它们在小鼠和仓鼠中的免疫原性。与rvsv - press - 2p相比，rvsv - press - hexapro产生和分泌的preS蛋白显著增加。重要的是，在小鼠和仓鼠中，rvsv - press - hexapro均比rvsv - press - 2p触发更多的press特异性血清IgG抗体。press - hexapro诱导的抗体中和B.1.1.7、B.1.351、P.1、B.1.427和B.1.617.2变体的效果是press - 2p诱导的抗体的2 - 4倍。此外，与presp - 2p相比，presp - hexapro诱导的th1偏倚细胞免疫反应更强。rvsv - press - hexapro和rvsv - press - 2p单剂量（104 pfu）免疫对小鼠适应型SARS-CoV-2和B.1.617.2变体的攻击提供完全保护，而rVSV-S仅提供部分保护。当免疫剂量降低至103 pfu时，rvsv - press - hexapro在仓鼠体内诱导的抗体应答比rvsv - press - 2p高2 - 6倍。此外，rvsv - press - hexapro对肺部感染具有70%的保护作用，而rvsv - press - 2p仅具有30%的保护作用。总的来说，我们的数据表明，press - 2p和press - hexapro都是高效的，但press - hexapro更具免疫原性和保护性，突出了在下一代SARS-CoV-2疫苗中使用press - hexapro的优势。
The emergent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants complicate the battle to halt the coronavirus disease 2019 (COVID-19) pandemic. The currently approved vaccines typically express native full-length S or preS-2P. Here, we show that HexaPro is superior to 2P or the native full-length S protein as a SARS-CoV-2 vaccine immunogen. HexaPro is expressed more efficiently and induces more robust SARS-CoV-2 specific antibody and Th1-biased T cell immune responses. Antibodies induced by HexaPro also neutralize SARS-CoV-2 variants two- to fourfold more efficiently than those induced by preS-2P. By comparing different immunization doses, we found that HexaPro is more immunogenic and protective than 2P. This work highlights the importance of using HexaPro in the development of next generation COVID-19 vaccines because of its broad protection against SARS-CoV-2 variants. The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main target for neutralizing antibodies (NAbs). The S protein trimer is anchored in the virion membrane in its prefusion (preS) but metastable form. The preS protein has been stabilized by introducing two or six proline substitutions, to generate stabilized, soluble 2P or HexaPro (6P) preS proteins. Currently, it is not known which form is the most immunogenic. Here, we generated recombinant vesicular stomatitis virus (rVSV) expressing preS-2P, preS-HexaPro, and native full-length S, and compared their immunogenicity in mice and hamsters. The rVSV-preS-HexaPro produced and secreted significantly more preS protein compared to rVSV-preS-2P. Importantly, rVSV-preS-HexaPro triggered significantly more preS-specific serum IgG antibody than rVSV-preS-2P in both mice and hamsters. Antibodies induced by preS-HexaPro neutralized the B.1.1.7, B.1.351, P.1, B.1.427, and B.1.617.2 variants approximately two to four times better than those induced by preS-2P. Furthermore, preS-HexaPro induced a more robust Th1-biased cellular immune response than preS-2P. A single dose (104 pfu) immunization with rVSV-preS-HexaPro and rVSV-preS-2P provided complete protection against challenge with mouse-adapted SARS-CoV-2 and B.1.617.2 variant, whereas rVSV-S only conferred partial protection. When the immunization dose was lowered to 103 pfu, rVSV-preS-HexaPro induced two- to sixfold higher antibody responses than rVSV-preS-2P in hamsters. In addition, rVSV-preS-HexaPro conferred 70% protection against lung infection whereas only 30% protection was observed in the rVSV-preS-2P. Collectively, our data demonstrate that both preS-2P and preS-HexaPro are highly efficacious but preS-HexaPro is more immunogenic and protective, highlighting the advantages of using preS-HexaPro in the next generation of SARS-CoV-2 vaccines.
登录
查看更多内容
影响因子：
16.6
作者：
Li A;Yu J;Lu M;Ma Y;Attia Z;Shan C;Xue M;Liang X;Craig K;Makadiya N;He JJ;Jennings R;Shi PY;Peeples ME;Liu SL;Boyaka PN;Li J
通讯作者：
Li J
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
通讯作者：
Chen, Bing
影响因子：
158.5
作者：
Keech, Cheryl;Albert, Gary;Glenn, Gregory M.
通讯作者：
Glenn, Gregory M.
DOI：
10.1056/nejmoa2115463
发表时间：
2022-01-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dickerman BA;Gerlovin H;Madenci AL;Kurgansky KE;Ferolito BR;Figueroa Muñiz MJ;Gagnon DR;Gaziano JM;Cho K;Casas JP;Hernán MA
通讯作者：
Hernán MA