Al-Wassiti Hareth A, Fabb Stewart A, Grimley Samantha L, Kochappan Ruby, Ho Joan K, Wong Chinn Yi, Tan Chee Wah, Payne Thomas J, Takanashi Asuka, Lee Chee Leng, Mugan Rekha Shandre, Sicilia Horatio, Teo Serena L Y, McAuley Julie, Ellenberg Paula, Cooney James P, Davidson Kathryn C, Bowen Richard, Pellegrini Marc, Rockman Steven, Godfrey Dale I, Nolan Terry M, Wang Lin-Fa, Deliyannis Georgia, Purcell Damian F J, Pouton Colin W
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Peter Doherty Institute for Infection and Immunity, and Department of Infectious Diseases, University of Melbourne, Melbourne, VIC 3000, Australia.
Mol Ther Methods Clin Dev. 2024 Nov 15;32(4):101380. doi: 10.1016/j.omtm.2024.101380. eCollection 2024 Dec 12.
We investigated mRNA vaccines encoding a membrane-anchored receptor-binding domain (RBD), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail fragments of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In naive mice, RBD-TM mRNA vaccines against SARS-CoV-2 variants induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays revealed broad neutralizing activity against a range of variant RBDs. In the setting of a heterologous boost, against the background of exposure to ancestral whole-spike vaccines, sVNT studies suggested that BA.1 and BA.5 RBD-TM vaccines had the potential to overcome the detrimental effects of immune imprinting. A subsequent heterologous boost study using XBB.1.5 booster vaccines was evaluated using both sVNT and authentic virus neutralization. Geometric mean XBB.1.5 neutralization values after third-dose RBD-TM or whole-spike XBB.1.5 booster vaccines were compared with those after a third dose of ancestral spike booster vaccine. Fold-improvement over ancestral vaccine was just 1.3 for the whole-spike XBB.1.5 vaccine, similar to data published using human serum samples. In contrast, the fold-improvement achieved by the RBD-TM XBB.1.5 vaccine was 16.3, indicating that the RBD-TM vaccine induced the production of antibodies that neutralize the XBB.1.5 variant despite previous exposure to ancestral spike protein.
我们研究了编码膜锚定受体结合域（RBD）的mRNA疫苗，每个疫苗都是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的变异RBD、跨膜（TM）和胞质尾片段的融合体。在未接触过疫苗的小鼠中，针对SARS-CoV-2变异株的RBD-TM mRNA疫苗诱导了针对目标RBD的强烈体液免疫反应。多重替代病毒中和（sVNT）试验显示对一系列变异RBD具有广泛的中和活性。在异源加强接种的情况下，在接触过原始全刺突疫苗的背景下，sVNT研究表明，BA.1和BA.5 RBD-TM疫苗有可能克服免疫印记的有害影响。随后使用XBB.1.5加强疫苗进行的异源加强接种研究通过sVNT和真实病毒中和试验进行了评估。将第三剂RBD-TM或全刺突XBB.1.5加强疫苗后的几何平均XBB.1.5中和值与第三剂原始刺突加强疫苗后的中和值进行了比较。全刺突XBB.1.5疫苗相对于原始疫苗的改善倍数仅为1.3，与使用人类血清样本发表的数据相似。相比之下，RBD-TM XBB.1.5疫苗实现的改善倍数为16.3，这表明尽管之前接触过原始刺突蛋白，但RBD-TM疫苗仍能诱导产生中和XBB.1.5变异株的抗体。
