A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T cell mediated immunity

Sean McCafferty, Akm Ashiqul Haque, Aster Vandierendonck, Brian Weidensee, Magalie Plovyt, Magdalena Stuchlíková, Nathalie François, Sophie Valembois, Leo Heyndrickx, Johan Michiels, Kevin K Ariën, Linos Vandekerckhove, Rana Abdelnabi, Caroline S Foo, Johan Neyts, Itishri Sahu, Niek N Sanders

Research output: Contribution to journalA1: Web of Science-articlepeer-review

Abstract

Self-amplifying RNA vaccines may induce equivalent or more potent immune responses at lower doses compared to non-replicating mRNA vaccines via amplified antigen expression. In this paper, we demonstrate that 1 μg of an LNP-formulated dual-antigen self-amplifying RNA vaccine (ZIP1642), encoding both the S-RBD and N antigen, elicits considerably higher neutralizing antibody titers against Wuhan-like Beta B.1.351 and Delta B.1.617.2 SARS-CoV-2 variants compared to those of convalescent patients. In addition, ZIP1642 vaccination in mice expanded both S- and N-specific CD3 +CD4 + and CD3 +CD8 + T cells and caused a Th1 shifted cytokine response. We demonstrate that the induction of such dual antigen-targeted cell-mediated immune response may provide better protection against variants displaying highly mutated Spike proteins, as infectious viral loads of both Wuhan-like and Beta variants were decreased after challenge of ZIP1642 vaccinated hamsters. Supported by these results, we encourage redirecting focus toward the induction of multiple antigen-targeted cell-mediated immunity in addition to neutralizing antibody responses to bypass waning antibody responses and attenuate infectious breakthrough and disease severity of future SARS-CoV-2 variants.

Original languageEnglish
JournalMolecular Therapy
Volume30
Issue number9
Pages (from-to)2968-2983
Number of pages16
ISSN1525-0016
DOIs
Publication statusPublished - 2022

Keywords

  • Animals
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • CD8-Positive T-Lymphocytes
  • COVID-19 Vaccines
  • COVID-19/prevention & control
  • Cricetinae
  • Humans
  • Immunity, Cellular
  • Immunity, Humoral
  • Mice
  • Mice, Inbred BALB C
  • RNA
  • SARS-CoV-2/genetics
  • Vaccination
  • Vaccines, Synthetic
  • Viral Vaccines
  • mRNA Vaccines

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