Senior Scientist Pfizer, Inc. Bloomfield, New Jersey, United States
Disclosure(s):
Christopher Lopez, PhD: No relevant disclosure to display
Introduction/Rationale: Double-stranded RNA (dsRNA) is a natural activator of innate immune responses in mammalian cells and can form as a limited byproduct during in vitro transcription of mRNA vaccines
Methods: We sought to further characterize humoral and cell-mediated immune responses to varying levels of dsRNA using a prototype nucleoside-modified mRNA (modRNA) based respiratory syncytial virus (RSV) vaccine. The modRNA lipid nanoparticle formulations contained defined quantities of a full-length dsRNA generated from complementary sense and antisense strands of RSV modRNA.
Results: In vivo analysis in BALB/c mice revealed that increasing levels of dsRNA impurities in a modRNA LNP vaccine delivered intramuscularly led to a modest induction of inflammatory cytokines, including Type I interferons, but had no effect on neutralizing antibody titers or the functionality of CD4+ and CD8+ T cells. In parallel, in vitro analysis of human PBMCs exposed to the same formulations showed no significant changes in inflammatory cytokine production or cell-mediated immunity; Increasing levels of dsRNA impurities did not alter population composition, antigen-presenting cell (APC) activation, or CD4+ and CD8+ T cell exhaustion, indicating limited immunostimulatory potential of N1-Methylpseudouridine (m1Ψ) modified dsRNA in immune cells.
Conclusion: Together, these results improve our understanding of potential dsRNA impurities and immune responses in mRNA vaccines.
