tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Wen Shi Lee[SUP] 1 [/SUP], Lydia Murdiyarso[SUP] 1 [/SUP], Lauren Burmas[SUP] 1 [/SUP], Phillip Pymm[SUP] 2 [/SUP], Robyn Esterbauer[SUP] 1 [/SUP], Andrew Kelly[SUP] 1 [/SUP], Hannah G Kelly[SUP] 1 3 [/SUP], Isaac Barber-Axthelm[SUP] 1 4 [/SUP], James P Cooney[SUP] 2 5 [/SUP], Kathryn C Davidson[SUP] 2 5 [/SUP], Merle Dayton[SUP] 2 [/SUP], Courtney E McAleese[SUP] 6 [/SUP], Marianne Gillard[SUP] 6 [/SUP], Karen Hughes[SUP] 6 [/SUP], Martina L Jones[SUP] 6 [/SUP], Marc Pellegrini[SUP] 2 5 7 [/SUP], Wai-Hong Tham[SUP] 2 5 8 [/SUP], Ben Hughes[SUP] 6 9 [/SUP], Stephen J Kent[SUP] 1 10 [/SUP], Adam K Wheatley[SUP] 11 [/SUP], Jennifer A Juno[SUP] 12 [/SUP], Hyon-Xhi Tan[SUP] 13 [/SUP]
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[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.
. 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[SUP] 1 [/SUP], Wen Shi Lee[SUP] 1 [/SUP], Lydia Murdiyarso[SUP] 1 [/SUP], Lauren Burmas[SUP] 1 [/SUP], Phillip Pymm[SUP] 2 [/SUP], Robyn Esterbauer[SUP] 1 [/SUP], Andrew Kelly[SUP] 1 [/SUP], Hannah G Kelly[SUP] 1 3 [/SUP], Isaac Barber-Axthelm[SUP] 1 4 [/SUP], James P Cooney[SUP] 2 5 [/SUP], Kathryn C Davidson[SUP] 2 5 [/SUP], Merle Dayton[SUP] 2 [/SUP], Courtney E McAleese[SUP] 6 [/SUP], Marianne Gillard[SUP] 6 [/SUP], Karen Hughes[SUP] 6 [/SUP], Martina L Jones[SUP] 6 [/SUP], Marc Pellegrini[SUP] 2 5 7 [/SUP], Wai-Hong Tham[SUP] 2 5 8 [/SUP], Ben Hughes[SUP] 6 9 [/SUP], Stephen J Kent[SUP] 1 10 [/SUP], Adam K Wheatley[SUP] 11 [/SUP], Jennifer A Juno[SUP] 12 [/SUP], Hyon-Xhi Tan[SUP] 13 [/SUP]
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[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.