The Univeristy of Melbourne The Royal Melbourne Hopspital

A joint venture between The University of Melbourne and The Royal Melbourne Hospital


Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine


  • Deliyannis, Georgia
  • Gherardin, Nicholas A.
  • Wong, Chinn Yi
  • Grimley, Samantha L.
  • Cooney, James P.
  • Redmond, Samuel J.
  • Ellenberg, Paula
  • Davidson, Kathryn C.
  • Mordant, Francesca L.
  • Smith, Tim
  • Gillard, Marianne
  • Lopez, Ester
  • McAuley, Julie
  • Tan, Chee Wah
  • Wang, Jing J.
  • Zeng, Weiguang
  • Littlejohn, Mason
  • Zhou, Runhong
  • Fuk-Woo Chan, Jasper
  • Chen, Zhi-wei
  • Hartwig, Airn E.
  • Bowen, Richard
  • Mackenzie, Jason M.
  • Vincan, Elizabeth
  • Torresi, Joseph
  • Kedzierska, Katherine
  • Pouton, Colin W.
  • Gordon, Tom P.
  • Wang, Lin-fa
  • Kent, Stephen J.
  • Wheatley, Adam K.
  • Lewin, Sharon R.
  • Subbarao, Kanta
  • Chung, Amy W.
  • Pellegrini, Marc
  • Munro, Trent
  • Nolan, Terry
  • Rockman, Steven
  • Jackson, David C.
  • Purcell, Damian F.J.
  • Godfrey, Dale I.


eBioMedicine, Volume 92, 2023-06-30

Article Link: Click here

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 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 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 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 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.