Mosaic receptor-binding domain nanoparticles induce protective immunity against SARS-CoV-2 challenges

Lee, D. B.; Kim, H.; Jeong, J. H.; Jang, E. s.; Chang, Y. Y.; Roh, S.; Jeon, H.; Kim, E. J.; Han, S. Y.; Maeng, J. Y.; Magez, S.; Radwanska, M.; Mun, J. Y.; Jun, H. S.; Lee, G.; Song, M.-S.; Lee, H.-R.; Chung, M. S.; Baek, Y. H.; Kim, K. H.

doi:10.1101/2022.02.18.480994

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bioRxiv · 10.1101/2022.02.18.480994

Mosaic receptor-binding domain nanoparticles induce protective immunity against SARS-CoV-2 challenges

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Abstract

Recurrent spillovers of - and {beta}-coronaviruses (CoV) such as acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-2, and possibly human CoV (NL63, 229E, OC43, and HKU1) have caused serious morbidity and mortality worldwide. Six receptor binding domains (RBDs) derived from - and {beta}-CoV that are considered to have originated from animals and cross-infected humans were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric subunits, PCNA1, PCNA2, and PCNA3. These were used to form a scaffold-based mosaic multivalent antigen, 6RBD-np. Electron microscopic and atomic force microscopic images show a ring-shaped disk with six protruding RBDs, like jewels in a crown, with a size of 40 nm. Prime-boost immunizations with 6RBD-np in BALB/c mice elicited strong, dose-dependent antibody responses. In human angiotensin converting enzyme 2-transgenic mice, the same immunization induced full-protection against SARS-CoV-2 wild type and Delta challenges, resulting in a 100% survival rate. The mosaic 6RBD-np provides a potential platform for developing a pan-CoV vaccine against newly emerging SARS-CoV-2 variants and future CoV spillovers. SignificanceDespite the arsenal of COVID-19 vaccines, hospitalization and mortality associated with SARS-CoV-2 (acute respiratory syndrome coronavirus 2) variants remain high. There is an urgent need to develop next-generation COVID vaccines that provide broad protection against diseases by current and newly emerging SARS-CoV-2 variants. In this study, six receptor binding domains (RBDs) derived from - and {beta}-CoV were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric scaffolds. They assemble to create a stable mosaic multivalent nanoparticle, 6RBD-np, displaying a ring-shaped disk with six protruding antigens. The prime-boost immunization in BALB/c and human angiotensin converting enzyme 2-transgenic mice with the 6RBD-np elicited strong, dose-dependent antibody responses and induced full-protection against both the SARS-CoV-2 wild type (WT) and Delta challenges. This study provides proof-of-concept that the mosaic 6RBD-np induces 100% protection against SARS-CoV-2 WT and Delta. It provides the potential of co-displaying heterologous antigens for novel vaccine designs, which can be deployed countering future pandemics.

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Lee, D. B., Kim, H., Jeong, J. H., Jang, E. s., Chang, Y. Y., Roh, S., Jeon, H., Kim, E. J., Han, S. Y., Maeng, J. Y., Magez, S., Radwanska, M., Mun, J. Y., Jun, H. S., Lee, G., Song, M.-S., Lee, H.-R., Chung, M. S., Baek, Y. H., Kim, K. H.. 2022-02-18. Mosaic receptor-binding domain nanoparticles induce protective immunity against SARS-CoV-2 challenges. https://doi.org/10.1101/2022.02.18.480994

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