RBD-down stabilization of SARS-CoV-2 spike enhances cross-neutralizing antibody responses by redirecting immunodominance toward conserved epitopes

The continuous emergence of SARS-CoV-2 variants has enabled partial escape from neutralizing antibodies, necessitating frequent updates of vaccine antigens. These observations motivate vaccine strategies that can redirect antibody responses toward conserved regions of the spike (S) protein. Here, we engineered a SARS-CoV-2 S protein that exclusively maintains its trimeric conformation while concealing the receptor-binding motif (RBM), designated S-cred. In mice, S-cred elicited antibody responses targeting the conserved regions, particularly the subdomain 1 (SD1) and S2 subunits. Neutralizing antibody titers against closely related variants were modestly increased, whereas neutralizing antibody titers against antigenically distant strains remained limited. Additionally, antibodies targeting the receptor-binding domain showed increased recognition of conserved non-RBM regions. Immunization with BA.2-based S-cred improved survival following lethal challenge with a mouse-adapted ancestral SARS-CoV-2 strain. These findings demonstrate that conformational control of the S protein can reproducibly bias immunodominance toward conserved epitopes, providing a framework for next-generation coronavirus vaccine design.

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Publication Details

Journal
npj Vaccines
Published
2026-10-07
DOI
https://doi.org/10.1038/s41541-026-01598-3
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.00

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article

RBD-down stabilization of SARS-CoV-2 spike enhances cross-neutralizing antibody responses by redirecting immunodominance toward conserved epitopes

Akira Ainai, Yoshimasa Takahashi, Tomo Nomai, Satoru Nagatoishi et al.
npj Vaccines
SARS-CoV-2 and COVID-19 Research
article

RBD-down stabilization of SARS-CoV-2 spike enhances cross-neutralizing antibody responses by redirecting immunodominance toward conserved epitopes

Akira Ainai, Yoshimasa Takahashi, Tomo Nomai, Satoru Nagatoishi, Tadaki Suzuki, Katsumi Maenaka, Saya Moriyama, Shiori Ueno, Nanami Hirose, Takao Hashiguchi, Takuya Hemmi, Hisano Yajima, Kouhei Tsumoto, Rin Shirota, Sho Miyamoto, Takeshi Noda, Shunsuke Kita, Kei Asayama, Yukihiko Sugita
article en

Abstract

The continuous emergence of SARS-CoV-2 variants has enabled partial escape from neutralizing antibodies, necessitating frequent updates of vaccine antigens. These observations motivate vaccine strategies that can redirect antibody responses toward conserved regions of the spike (S) protein. Here, we engineered a SARS-CoV-2 S protein that exclusively maintains its trimeric conformation while concealing the receptor-binding motif (RBM), designated S-cred. In mice, S-cred elicited antibody responses targeting the conserved regions, particularly the subdomain 1 (SD1) and S2 subunits. Neutralizing antibody titers against closely related variants were modestly increased, whereas neutralizing antibody titers against antigenically distant strains remained limited. Additionally, antibodies targeting the receptor-binding domain showed increased recognition of conserved non-RBM regions. Immunization with BA.2-based S-cred improved survival following lethal challenge with a mouse-adapted ancestral SARS-CoV-2 strain. These findings demonstrate that conformational control of the S protein can reproducibly bias immunodominance toward conserved epitopes, providing a framework for next-generation coronavirus vaccine design.

npj Vaccines
Hokkaido University of Science (JP), Kyushu University (JP), Chiba University (JP), Tokyo University of Science (JP), Hokkaido University (JP), Kyoto University (JP), National Institute of Infectious Diseases (JP), Institute for Life and Medical Sciences, Kyoto University (JP), The University of Tokyo (JP)
Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Hokkaido University, Chiba University, Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology
Good health and well-being
Openalex Percentile: Top 12%
SARS-CoV-2 and COVID-19 Research
DOIOpen Access PDFOpenAlex
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