Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine.
COVID-19
RBD
Receptor-binding domain
SARS-CoV-2
Vaccine
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
15
09
2022
revised:
02
03
2023
accepted:
01
04
2023
medline:
19
6
2023
pubmed:
6
5
2023
entrez:
6
5
2023
Statut:
ppublish
Résumé
The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The 'beta variant' RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial. This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.
Sections du résumé
BACKGROUND
BACKGROUND
The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines.
METHODS
METHODS
We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine.
FINDINGS
RESULTS
Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The 'beta variant' RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5.
INTERPRETATION
CONCLUSIONS
These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial.
FUNDING
BACKGROUND
This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.
Identifiants
pubmed: 37148585
pii: S2352-3964(23)00139-1
doi: 10.1016/j.ebiom.2023.104574
pmc: PMC10159263
pii:
doi:
Substances chimiques
Carrier Proteins
0
COVID-19 Vaccines
0
MF59 oil emulsion
0
spike protein, SARS-CoV-2
0
Protein Subunits
0
Adjuvants, Immunologic
0
Antibodies, Neutralizing
0
Antibodies, Viral
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104574Informations de copyright
Copyright © 2023. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of interests Two provisional patents (PCT/AU2021/051553 and PCT/AU2023/050093) covering the RBD-Fc vaccines described in this study, and underlying technology, have been submitted through The University of Melbourne, with D.I.G., G.D., N.A.G., D.C.J. and D.F.J.P. as co-inventors. C.W.T. and L.-f.W. are co-inventors of a patent on the surrogate virus neutralization test (sVNT) platform. S.R.L. receives consulting fees from ViiV, Vaxxinity, Esfam, Abbvie, and Gilead. S.R.L. has received honoraria from Merck, Sharpe and Dohme, and from Gilead. K.S. is on a DSMB for a vaccine study in Thailand, and is Chair of the WHO Technical Advisory Group on COVID-19 vaccines (TAG-CO-VAC). T.N. receives research contracts to conduct clinical trials, with funding to institution 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. D.C.J. is a founder and shareholder of Ena Respiratory. C.Y.W. and W.Z. are shareholders of Ena Respiratory. D.I.G. has received research funding from CSL for an unrelated project. All other authors declare no conflict of interests.