mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting
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.
Details:
Molecular Therapy - Methods & Clinical Development, Volume 32, Issue 4, 2024-12-12
Article Link: Click here
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.