Construction and evaluation of a self-replicative RNA vaccine against SARS-CoV-2 using yellow fever virus replicon

PLoS One. 2022 Oct 20;17(10):e0274829. doi: 10.1371/journal.pone.0274829. eCollection 2022.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global threat. To forestall the pandemic, developing safe and effective vaccines is necessary. Because of the rapid production and little effect on the host genome, mRNA vaccines are attractive, but they have a relatively low immune response after a single dose. Replicon RNA (repRNA) is a promising vaccine platform for safety and efficacy. RepRNA vaccine encodes not only antigen genes but also the genes necessary for RNA replication. Thus, repRNA is self-replicative and can play the role of an adjuvant by itself, which elicits robust immunity. This study constructed and evaluated a repRNA vaccine in which the gene encoding the spike (S) protein of SARS-CoV-2 was inserted into a replicon of yellow fever virus 17D strain. Upon electroporation of this repRNA into baby hamster kidney cells, the S protein and yellow fever virus protein were co-expressed. Additionally, the self-replication ability of repRNA vaccine was confirmed using qRT-PCR, demonstrating its potency as a vaccine. Immunization of C57BL/6 mice with 1 μg of the repRNA vaccine induced specific T-cell responses but not antibody responses. Notably, the T-cell response induced by the repRNA vaccine was significantly higher than that induced by the nonreplicative RNA vaccine in our experimental model. In the future, it is of the essence to optimize vaccine administration methods and improve S protein expression, like protection of repRNA by nanoparticles and evasion of innate immunity of the host to enhance the immune-inducing ability of the repRNA vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines
  • COVID-19* / prevention & control
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • RNA / genetics
  • Replicon
  • SARS-CoV-2* / genetics
  • Spike Glycoprotein, Coronavirus
  • Vaccines, Synthetic / genetics
  • Yellow fever virus
  • mRNA Vaccines

Substances

  • COVID-19 Vaccines
  • Vaccines, Synthetic
  • RNA
  • Spike Glycoprotein, Coronavirus
  • Antibodies, Viral
  • Antibodies, Neutralizing
  • spike protein, SARS-CoV-2

Grants and funding

This study was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP20he082206; KAKENHI Grant-in-Aid for Young Scientists (20K20200); a subsidy for postcorona society realization, Hyogo prefecture. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.