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

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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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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 SARSCoV-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.
Original languageEnglish
Article number104574
Number of pages25
Publication statusPublished - Jun 2023


  • SARS-CoV-2
  • COVID-19
  • Vaccine
  • Receptor-binding domain
  • RBD


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