A novel chimeric coronavirus spike vaccine combining SARS-CoV-2 RBD and scaffold domains from HKU-1 elicits potent neutralising antibody responses
The SARS-CoV-2 spike receptor binding domain (RBD) is the major target for neutralising antibodies. However, subdomains like RBD may constrain the availability of CD4 T follicular helper (TFH) cells and impact immunogenicity. We engineered a chimeric trimeric RBD (CTR) glycoprotein, replacing the RBD of HKU-1 spike with SARS-CoV-2 RBD (ancestral WT/Omicron BA.2). This maintains trimerised RBD, while providing CD4 help via the HKU-1 scaffold. In C57BL/6 mice, CTR-BA.2 elicited high anti-BA.2-RBD IgG and neutralising titres, matching native spike responses. Germinal centre B cells were predominantly WT<sup>+</sup>/BA.2<sup>+</sup> cross-reactive, and TFH predominantly recognised HKU-1 epitopes, demonstrating scaffold-directed help. In macaques, CTR-WT elicited comparable anti-RBD IgG, anti-spike IgG and neutralising responses to native spike, with elevated RBD-specific GC B cells in draining lymph nodes. Macaque TFH responses targeted RBD, NTD/S2 or HKU-1 peptides. This chimeric design overcomes poor RBD immunogenicity by engaging CD4 TFH, maintaining neutralising responses that is non-inferior to native spike.
Authors
- Adam K. Wheatley (ORCID: https://orcid.org/0000-0002-5593-9387)
- Courtney E. McAleese (ORCID: https://orcid.org/0000-0002-9976-8663)
- Robyn Esterbauer (ORCID: https://orcid.org/0000-0002-7091-0048)
- Karen Hughes (ORCID: https://orcid.org/0000-0001-8097-3395)
- Marianne Gillard (ORCID: https://orcid.org/0000-0002-2233-9975)
- Merle Dayton
- Hannah G. Kelly (ORCID: https://orcid.org/0000-0002-4652-5609)
- Isaac Barber-Axthelm (ORCID: https://orcid.org/0000-0002-7892-6802)
- Wai‐Hong Tham (ORCID: https://orcid.org/0000-0001-7950-8699)
- Martina L. Jones (ORCID: https://orcid.org/0000-0002-5154-6017)
- Jennifer A. Juno (ORCID: https://orcid.org/0000-0002-9072-1017)
- Lydia Murdiyarso
- Stephen John Kent (ORCID: https://orcid.org/0000-0002-8539-4891)
- Marc Pellegrini (ORCID: https://orcid.org/0000-0003-3627-3126)
- Benjamin Hughes (ORCID: https://orcid.org/0009-0000-3289-2195)
- Hyon‐Xhi Tan (ORCID: https://orcid.org/0000-0003-1064-3934)
- Wen Shi Lee (ORCID: https://orcid.org/0000-0001-7285-4054)
- Phillip Pymm (ORCID: https://orcid.org/0000-0003-2722-4621)
- James P. Cooney (ORCID: https://orcid.org/0000-0003-3680-4644)
- Kathryn C. Davidson
- Andrew P. Kelly (ORCID: https://orcid.org/0000-0003-2719-6544)
- Lauren Burmas
- Veronica Zoest
Institutions
- Australian National University (AU)
- The University of Sydney (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Washington (US)
- Centenary Institute (AU)
- Australian National Fabrication Facility (AU)
- Melbourne Sexual Health Centre (AU)
- Peter Doherty Institute (AU)
- Monash University (AU)
Publication Details
- Journal
- npj Vaccines
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41541-025-01323-6
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Burnet Institute
- Australian Government
- Monash University
- University of Queensland
- Therapeutic Innovation Australia
- Medical Research Council
- National Health and Medical Research Council