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

Al-Wassiti, H. A.; Fabb, S. A.; Grimley, S. L.; Kochappan, R.; Ho, J. K.; Wong, C. Y.; Tan, C. W.; Payne, T. J.; Takanashi, A.; Sicilia, H.; Teo, S. L. Y.; McAuley, J. L.; Ellenberg, P.; Cooney, J. P.; Davidson, K. C.; Bowen, R.; Pellegrini, M.; Rockman, S.; Godfrey, D. I.; Nolan, T. M.; Wang, L.-F.; Deliyannis, G.; Purcell, D. F. J.; Pouton, C. W.

doi:10.1101/2023.10.04.560777

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bioRxiv · 10.1101/2023.10.04.560777

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

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Abstract

To address the limitations of whole-spike COVID vaccines, we explored mRNA vaccines encoding membrane-anchored receptor-binding domain (RBD-TMs), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail (CT) fragments of the SARS-CoV-2 spike protein. In naive mice, RBD-TM mRNA vaccines against ancestral SARS-CoV-2, Beta, Delta, Delta-plus, Kappa, Omicron BA.1 or BA.5, all induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays indicated 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 RBD-TM vaccines were able to overcome the detrimental effects of immune imprinting. Omicron BA.1 and BA.5 RBD-TM booster vaccines induced serum antibodies with 12 and 22-fold higher neutralizing activity against the target RBD than their equivalent whole spike variants. Boosting with BA.1 or BA.5 RBD-TM provided good protection against more recent variants including XBB and XBB.1.5. Each RBD-TM mRNA is 28% of the length of its whole-spike equivalent. This advantage will enable tetravalent mRNA vaccines to be developed at well-tolerated doses of formulated mRNA. One Sentence SummarymRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants are effective vaccines that can overcome immune imprinting in mice

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Al-Wassiti, H. A., Fabb, S. A., Grimley, S. L., Kochappan, R., Ho, J. K., Wong, C. Y., Tan, C. W., Payne, T. J., Takanashi, A., Sicilia, H., Teo, S. L. Y., McAuley, J. L., Ellenberg, P., Cooney, J. P., Davidson, K. C., Bowen, R., Pellegrini, M., Rockman, S., Godfrey, D. I., Nolan, T. M., Wang, L.-F., Deliyannis, G., Purcell, D. F. J., Pouton, C. W.. 2023-10-04. mRNA vaccines encoding membrane-anchored receptor-binding domains of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting. https://doi.org/10.1101/2023.10.04.560777

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