PDF(Pubmed)
Abstract：
Vaccination with the primary two-dose series of SARS-CoV-2 mRNA protects against infection with the ancestral strain, and limits the presentation of severe disease after re-infection by multiple variants of concern (VOC), including Omicron, despite the lack of a strong neutralizing response to these variants. We compared antibody responses in serum samples collected from mRNA-1273 (Moderna) vaccinated subjects to identify mechanisms of immune escape and cross-protection. Using pseudovirus constructs containing domain-specific amino acid changes representative of Omicron BA.1, combined with domain competition and RBD-antibody depletion, we showed that RBD antibodies were primarily responsible for virus neutralization and variant escape. Antibodies to NTD played a less significant role in antibody neutralization but acted along with RBD to enhance neutralization. S2 of Omicron BA.1 had no impact on neutralization escape, suggesting it is a less critical domain for antibody neutralization; however, it was as capable as S1 at eliciting IgG3 responses and NK-cell mediated, antibody-dependent cell cytotoxicity (ADCC). Antibody neutralization and ADCC activities to RBD, NTD, and S1 were all prone to BA.1 escape. In contrast, ADCC activities to S2 resisted BA.1 escape. In conclusion, S2 antibodies showed potent ADCC function and resisted Omicron BA.1 escape, suggesting that S2 contributes to cross-protection against Omicron BA.1. In line with its conserved nature, S2 may hold promise as a vaccine target against future variants of SARS-CoV-2.
摘要：
使用SARS-CoV-2mRNA的主要两剂量系列疫苗接种可防止祖先菌株的感染，并限制了多种关注变种（VOC）再次感染后严重疾病的表现，包括Omicron,尽管对这些变体缺乏强烈的中和反应。我们比较了从mRNA-1273（Moderna）接种疫苗的受试者收集的血清样品中的抗体反应，以确定免疫逃逸和交叉保护的机制。使用含有代表OmicronBA.1的结构域特异性氨基酸变化的假病毒构建体，结合结构域竞争和RBD抗体消耗，我们表明RBD抗体主要负责病毒中和和变异逃逸。NTD抗体在抗体中和作用不那么显著,但与RBD一起作用以增强中和。OmicronBA.1的S2对中和逃逸没有影响，这表明它是抗体中和的一个不太关键的结构域；然而，它在引发IgG3反应和NK细胞介导方面与S1一样有能力，抗体依赖性细胞毒性（ADCC）。对RBD的抗体中和和ADCC活性，NTD,S1均容易发生BA.1逃逸。相比之下,ADCC对S2的活动阻止了BA.1的逃脱。总之,S2抗体显示出有效的ADCC功能并抵抗OmicronBA.1逃逸，表明S2有助于对OmicronBA.1的交叉保护。根据其保守的性质，S2可能有望作为针对SARS-CoV-2未来变体的疫苗靶标。
