TY - GEN
T1 - mRNA vaccines encoding membrane-anchored receptor-binding domains of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting
AU - Al-Wassiti, Harry
AU - Fabb, Stewart A.
AU - Grimley, Samantha L.
AU - Panakkal Kochappan, Ruby
AU - Ho, Joan
AU - Wong, Chinn Yi
AU - Tan, Chee Wah
AU - Payne, Thomas J.
AU - Takanashi, Aska
AU - Sicilia, Horatio
AU - Teo, Serena
AU - McAuley, Julie L.
AU - Ellenberg, Paula
AU - Cooney, James P.
AU - Davidson, Kathryn
AU - Bowen, Richard A.
AU - Pellegrini, Marc
AU - Rockman, Steven
AU - Godfrey, Dale Ian
AU - Nolan, Terry M.
AU - Wang, Lin-fa
AU - Deliyannis, Georgia
AU - Purcell, Damian F.J.
AU - Pouton, Colin W.
PY - 2023/10/4
Y1 - 2023/10/4
N2 - 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 28spike equivalent. This advantage will enable tetravalent mRNA vaccines to be developed at well-tolerated doses of formulated mRNA.One Sentence Summary mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants are effective vaccines that can overcome immune imprinting in miceCompeting Interest StatementTwo provisional patents (PCT/AU2022/050912 and PCT/AU2022/050913) covering the RBD-TM mRNA vaccine design and the LNP formulation used in this study, and underlying technology, have been submitted through Monash University, with CWP, HAW and SAF as co-inventors of 050912 and CWP, HAW and JKH as co-inventors of 050913. CWT and L-FW are co-inventors of a patent on the surrogate virus neutralization test (sVNT) platform. T.N. receives research contracts to conduct clinical trials, with funding to institutions from Moderna, SanofiPasteur, GSK, Iliad Biotechnologies, Dynavax, Seqirus, Janssen, MSD. T.N. receives consulting fees from GSK, Seqirus, MSD, SanofiPasteur, AstraZeneca, Moderna, BioNet, Pfizer. T.N. serves on DSMBs for Seqirus, Clover, Moderna, Emergent, Serum Institute of India, SK Bioscience Korea, Emergent Biosolutions, Novavax. S.R. is an employee of CSL Seqirus that is a maker of influenza vaccines. C.Y.W. is a shareholder of Ena Respiratory. DIG has received research funding from CSL for an unrelated project. All other authors declare no conflict of interests.
AB - 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 28spike equivalent. This advantage will enable tetravalent mRNA vaccines to be developed at well-tolerated doses of formulated mRNA.One Sentence Summary mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants are effective vaccines that can overcome immune imprinting in miceCompeting Interest StatementTwo provisional patents (PCT/AU2022/050912 and PCT/AU2022/050913) covering the RBD-TM mRNA vaccine design and the LNP formulation used in this study, and underlying technology, have been submitted through Monash University, with CWP, HAW and SAF as co-inventors of 050912 and CWP, HAW and JKH as co-inventors of 050913. CWT and L-FW are co-inventors of a patent on the surrogate virus neutralization test (sVNT) platform. T.N. receives research contracts to conduct clinical trials, with funding to institutions from Moderna, SanofiPasteur, GSK, Iliad Biotechnologies, Dynavax, Seqirus, Janssen, MSD. T.N. receives consulting fees from GSK, Seqirus, MSD, SanofiPasteur, AstraZeneca, Moderna, BioNet, Pfizer. T.N. serves on DSMBs for Seqirus, Clover, Moderna, Emergent, Serum Institute of India, SK Bioscience Korea, Emergent Biosolutions, Novavax. S.R. is an employee of CSL Seqirus that is a maker of influenza vaccines. C.Y.W. is a shareholder of Ena Respiratory. DIG has received research funding from CSL for an unrelated project. All other authors declare no conflict of interests.
U2 - 10.1101/2023.10.04.560777
DO - 10.1101/2023.10.04.560777
M3 - Other contribution
PB - bioRxiv
ER -
