Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

Abstract

RNA-based vaccines have recently emerged as a promising alternative to the use of DNA-based and viral vector vaccines, in part because of the potential to simplify how vaccines are made and facilitate a rapid response to newly emerging infections. SAM vaccines are based on engineered self-amplifying mRNA (SAM) replicons encoding an Ag, and formulated with a synthetic delivery system, and they induce broad-based immune responses in preclinical animal models. In our study, in vivo imaging shows that after the immunization, SAM Ag expression has an initial gradual increase. Gene expression profiling in injection-site tissues from mice immunized with SAM-based vaccine revealed an early and robust induction of type I IFN and IFN-stimulated responses at the site of injection, concurrent with the preliminary reduced SAM Ag expression. This SAM vaccine-induced type I IFN response has the potential to provide an adjuvant effect on vaccine potency, or, conversely, it might establish a temporary state that limits the initial SAM-encoded Ag expression. To determine the role of the early type I IFN response, SAM vaccines were evaluated in IFN receptor knockout mice. Our data indicate that minimizing the early type I IFN responses may be a useful strategy to increase primary SAM expression and the resulting vaccine potency. RNA sequence modification, delivery optimization, or concurrent use of appropriate compounds might be some of the strategies to finalize this aim.

mRNA vaccines — a new era in vaccinology

“…Potential safety concerns that are likely to be evaluated in future preclinical and clinical studies include local and systemic inflammation, the biodistribution and persistence of expressed immunogen, stimulation of auto-reactive antibodies and potential toxic effects of any non-native nucleotides and delivery system components. A possible concern could be that some mRNA-based vaccine platforms 54,166 induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity 167,168 . Thus, identification of individuals at an increased risk of autoimmune reactions before mRNA vaccination may allow reasonable precautions to be taken.…”

Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice

“…We have previously shown that expression from a SAM vaccine carrying RSV F antigen peaked at day 7, followed by a > 100-fold decay at day 14, and became undetectable at day 21. 16 While we have not performed the expression study with VEEV antigens in the present work, we believe that SAM expression and antibody response could follow a similar pattern. Moreover, if there were a failure for the initial immune response to contract in the presented study, we would also expect a stronger boost effect at lower doses, where antigen levels were lower and immune responses were more likely to have started to contract, instead of the high dose of 10 mg.…”

“…7,15 Vaccine platforms derived from a replicating RNA viral genome are particularly attractive because replicating RNA itself potently stimulates the innate immune system by engaging pattern recognition receptors. [16][17][18][19] RNA amplification gives rise to many copies of transcripts that are used as templates to drive robust antigen expression. Furthermore, antigen expression from RNA vaccines peaks in hours and is followed by a rapid decay, resembling acute viral infection, which is effective for induction of robust antigen-specific immune responses.…”

Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice

“…However, it needs to be examined whether the induced innate immune response after administration of the sa-RNA-LNPs is balanced enough to potentiate adaptive immune responses. Indeed, it has been shown that a too high innate immune response can also be detrimental for the adaptive immune response [54,55].…”