mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting

• Published in: Molecular therapy. Methods & clinical development 2024-12, Vol.32 (4), p.101380, Article 101380
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: anchored RBD vaccine; COVID vaccine; immune imprinting; lipid nanoparticle; mRNA vaccine; Original; virus neutralization
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2024.101380

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. [Display omitted] Next-generation COVID vaccines are needed to protect against infection by a broad spectrum of emerging SARS-CoV-2 variants. This study demonstrates that mRNA vaccines focused on the receptor-binding RBDs of variant spike proteins have the potential to achieve this goal by overcoming the problem of immune imprinting.