Self-Adjuvanting Lipoprotein Conjugate αGalCer-RBD Induces Potent Immunity against SARS-CoV‑2 and its Variants of Concern

Safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are the best approach to successfully combat the COVID-19 pandemic. The receptor-binding domain (RBD) of the viral spike protein is a major target to develop candidate vaccines. α-Galactosylceramide (αGalCer), a potent invariant natural killer T cell (iNKT) agonist, was site-specifically conjugated to the N-terminus of the RBD to form an adjuvant–protein conjugate, which was anchored on the liposome surface. This is the first time that an iNKT cell agonist was conjugated to the protein antigen. Compared to the unconjugated RBD/αGalCer mixture, the αGalCer-RBD conjugate induced significantly stronger humoral and cellular responses. The conjugate vaccine also showed effective cross-neutralization to all variants of concern (B.1.1.7/alpha, B.1.351/beta, P.1/gamma, B.1.617.2/delta, and B.1.1.529/omicron). These results suggest that the self-adjuvanting αGalCer-RBD has great potential to be an effective COVID-19 vaccine candidate, and this strategy might be useful for designing various subunit vaccines.针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）及其变异株的安全有效疫苗，是成功对抗新型冠状病毒肺炎（COVID-19）大流行的最优策略。病毒刺突蛋白的受体结合域（RBD）是候选疫苗开发的主要靶点。α-半乳糖基神经酰胺（αGalCer）作为一种强效的恒定自然杀伤T细胞（iNKT）激动剂，被定点偶联至RBD的N端以形成佐剂-蛋白偶联物，并锚定在脂质体表面。本研究首次将iNKT细胞激动剂与蛋白抗原进行偶联。与未偶联的RBD/αGalCer混合物相比，αGalCer-RBD偶联物可诱导显著更强的体液免疫与细胞免疫应答。该偶联疫苗还对所有关切变异株（B.1.1.7/Alpha、B.1.351/Beta、P.1/Gamma、B.1.617.2/Delta及B.1.1.529/Omicron）展现出有效的交叉中和活性。上述结果表明，自佐剂型αGalCer-RBD具备成为高效COVID-19候选疫苗的巨大潜力，该策略也可为各类亚单位疫苗的设计提供参考。