Optimization of an LNP-mRNA vaccine candidate targeting SARS-CoV-2 receptor-binding domain

Kobiyama, K.; Imai, M.; Jounai, N.; Nakayama, M.; Hioki, K.; Iwatsuki-Horimoto, K.; Yamayoshi, S.; Tsuchida, J.; Niwa, T.; Suzuki, T.; Ito, M.; Yamada, S.; Watanabe, T.; Kiso, M.; Negishi, H.; Temizoz, B.; Ishigaki, H.; Kitagawa, Y.; Nguyen, C. T.; Itoh, Y.; Takeshita, F.; Kawaoka, Y.; Ishii, K. J.

doi:10.1101/2021.03.04.433852

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bioRxiv · 10.1101/2021.03.04.433852

Optimization of an LNP-mRNA vaccine candidate targeting SARS-CoV-2 receptor-binding domain

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Abstract

In 2020, two mRNA-based vaccines, encoding the full length of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, have been introduced for control of the coronavirus disease (COVID-19) pandemic1,2. However, reactogenicity, such as fever, caused by innate immune responses to the vaccine formulation remains to be improved. Here, we optimized a lipid nanoparticle (LNP)-based mRNA vaccine candidate, encoding the SARS-CoV-2 spike protein receptor-binding domain (LNP-mRNA-RBD), which showed improved immunogenicity by removing reactogenic materials from the vaccine formulation and protective potential against SARS-CoV-2 infection in cynomolgus macaques. LNP-mRNA-RBD induced robust antigen-specific B cells and follicular helper T cells in the BALB/c strain but not in the C57BL/6 strain; the two strains have contrasting abilities to induce type I interferon production by dendritic cells. Removal of reactogenic materials from original synthesized mRNA by HPLC reduced type I interferon (IFN) production by dendritic cells, which improved immunogenicity. Immunization of cynomolgus macaques with an LNP encapsulating HPLC-purified mRNA induced robust anti-RBD IgG in the plasma and in various mucosal areas, including airways, thereby conferring protection against SARS-CoV-2 infection. Therefore, fine-tuning the balance between the immunogenic and reactogenic activity of mRNA-based vaccine formulations may offer safer and more efficacious outcomes.

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Kobiyama, K., Imai, M., Jounai, N., Nakayama, M., Hioki, K., Iwatsuki-Horimoto, K., Yamayoshi, S., Tsuchida, J., Niwa, T., Suzuki, T., Ito, M., Yamada, S., Watanabe, T., Kiso, M., Negishi, H., Temizoz, B., Ishigaki, H., Kitagawa, Y., Nguyen, C. T., Itoh, Y., Takeshita, F., Kawaoka, Y., Ishii, K. J.. 2021-03-04. Optimization of an LNP-mRNA vaccine candidate targeting SARS-CoV-2 receptor-binding domain. https://doi.org/10.1101/2021.03.04.433852

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