Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/Chinese Academy of Medical Science), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Biosafety Level 3 Laboratory, Fudan University, Shanghai 200032, China.
Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 200032, China.
Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2221713120. doi: 10.1073/pnas.2221713120. Epub 2023 Mar 10.
The recently emerged Omicron subvariants XBB and BQ.1.1 have presented striking immune evasion against most monoclonal neutralizing antibodies and convalescent plasma. Therefore, it is essential to develop broad-spectrum COVID-19 vaccines to combat current and future emerging variants. Here, we found that the human IgG Fc-conjugated RBD of the original SARS-CoV-2 strain (WA1) plus a novel STING agonist-based adjuvant CF501 (CF501/RBD-Fc) could induce highly potent and durable broad-neutralizing antibody (bnAb) responses against Omicron subvariants, including BQ.1.1 and XBB in rhesus macaques with NT50s ranging from 2,118 to 61,742 after three doses. A decline of 0.9- to 4.7-fold was observed in the neutralization activity of sera in the CF501/RBD-Fc group against BA.2.2, BA.2.9, BA.5, BA.2.75, and BF.7 relative to D614G after three doses, while a significant decline of NT50 against BQ.1.1 (26.9-fold) and XBB (22.5-fold) relative to D614G. However, the bnAbs were still effective in neutralizing BQ.1.1 and XBB infection. These results suggest that the conservative but nondominant epitopes in RBD could be stimulated by CF501 to generate bnAbs, providing a proof-of-concept for using "nonchangeable against changeables" strategy to develop pan-sarbecovirus vaccines against sarbecoviruses, including SARS-CoV-2 and its variants.
最近出现的奥密克戎亚变种 XBB 和 BQ.1.1 对大多数单克隆中和抗体和恢复期血浆表现出明显的免疫逃逸。因此，开发广谱 COVID-19 疫苗来对抗当前和未来出现的变种至关重要。在这里，我们发现，原始 SARS-CoV-2 株（WA1）的人 IgG Fc 缀合 RBD 加上新型 STING 激动剂为基础的佐剂 CF501（CF501/RBD-Fc）可以诱导针对奥密克戎亚变种的高度有效和持久的广谱中和抗体（bnAb）反应，包括 BQ.1.1 和 XBB 在恒河猴中，三剂后 NT50 范围为 2,118 至 61,742。在 CF501/RBD-Fc 组中，与 D614G 相比，三剂后血清对 BA.2.2、BA.2.9、BA.5、BA.2.75 和 BF.7 的中和活性下降了 0.9-4.7 倍，而对 BQ.1.1（26.9 倍）和 XBB（22.5 倍）的 NT50 显著下降。然而，bnAbs 仍然有效中和 BQ.1.1 和 XBB 感染。这些结果表明，RBD 中的保守但非优势表位可以被 CF501 刺激产生 bnAbs，为使用“不变性对抗可变性”策略开发针对包括 SARS-CoV-2 及其变种在内的 sarbecovirus 的泛 sarbecovirus 疫苗提供了概念验证。
