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NPJ Vaccines
. 2025 Nov 28.
doi: 10.1038/s41541-025-01323-6. Online ahead of print. A novel chimeric coronavirus spike vaccine combining SARS-CoV-2 RBD and scaffold domains from HKU-1 elicits potent neutralising antibody responses
Veronica P Zoest 1 , Wen Shi Lee 1 , Lydia Murdiyarso 1 , Lauren Burmas 1 , Phillip Pymm 2 , Robyn Esterbauer 1 , Andrew Kelly 1 , Hannah G Kelly 1 3 , Isaac Barber-Axthelm 1 4 , James P Cooney 2 5 , Kathryn C Davidson 2 5 , Merle Dayton 2 , Courtney E McAleese 6 , Marianne Gillard 6 , Karen Hughes 6 , Martina L Jones 6 , Marc Pellegrini 2 5 7 , Wai-Hong Tham 2 5 8 , Ben Hughes 6 9 , Stephen J Kent 1 10 , Adam K Wheatley 11 , Jennifer A Juno 12 , Hyon-Xhi Tan 13
Affiliations
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+/BA.2+ 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.
. 2025 Nov 28.
doi: 10.1038/s41541-025-01323-6. Online ahead of print. A novel chimeric coronavirus spike vaccine combining SARS-CoV-2 RBD and scaffold domains from HKU-1 elicits potent neutralising antibody responses
Veronica P Zoest 1 , Wen Shi Lee 1 , Lydia Murdiyarso 1 , Lauren Burmas 1 , Phillip Pymm 2 , Robyn Esterbauer 1 , Andrew Kelly 1 , Hannah G Kelly 1 3 , Isaac Barber-Axthelm 1 4 , James P Cooney 2 5 , Kathryn C Davidson 2 5 , Merle Dayton 2 , Courtney E McAleese 6 , Marianne Gillard 6 , Karen Hughes 6 , Martina L Jones 6 , Marc Pellegrini 2 5 7 , Wai-Hong Tham 2 5 8 , Ben Hughes 6 9 , Stephen J Kent 1 10 , Adam K Wheatley 11 , Jennifer A Juno 12 , Hyon-Xhi Tan 13
Affiliations
- PMID: 41315254
- DOI: 10.1038/s41541-025-01323-6
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+/BA.2+ 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.