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.