Immunogenicity and Protection Efficacy of a Naked Self-Replicating mRNA-Based Zika Virus Vaccine

Abstract

To combat emerging infectious diseases like Zika virus (ZIKV), synthetic messenger RNAs (mRNAs) encoding viral antigens are very attractive as they allow a rapid, generic, and flexible production of vaccines. In this work, we engineered a self-replicating mRNA (sr-mRNA) vaccine encoding the pre-membrane and envelope (prM-E) glycoproteins of ZIKV. Intradermal electroporation of as few as 1 µg of this mRNA-based ZIKV vaccine induced potent humoral and cellular immune responses in BALB/c and especially IFNAR1-/- C57BL/6 mice, resulting in a complete protection of the latter mice against ZIKV infection. In wild-type C57BL/6 mice, the vaccine resulted in very low seroconversion rates and antibody titers. The potency of the vaccine was inversely related to the dose of mRNA used in wild-type BALB/c or C57BL/6 mice, as robust type I interferon (IFN) response was determined in a reporter mice model (IFN-β+/Δβ-luc). We further investigated the inability of the sr-prM-E-mRNA ZIKV vaccine to raise antibodies in wild-type C57BL/6 mice and found indications that type I IFNs elicited by this naked sr-mRNA vaccine might directly impede the induction of a robust humoral response. Therefore, we assume that the efficacy of sr-mRNA vaccines after intradermal electroporation might be increased by strategies that temper their inherent innate immunogenicity.

Corticosteroids and cellulose purification improve respectively the in vivo translation and vaccination efficacy of self-amplifying mRNAs

“…Evidently, a strong type I IFN mediated inflammatory response should also be avoided when synthetic mRNAs are considered for protein-replacement therapy, gene editing or stem cell reprogramming [25,26]. In line with previous reports [8,11,15], we found that intradermal electroporation of our formerly developed ZIKVac-sa-mRNA vaccine results in a very rapid upregulation of type I IFNs, with a maximal induction within 5 hours after sa-mRNA administration (Fig. 2).…”

“…However, our data do not support this idea, as the peak in IFN-β production occurs directly after the delivery of the sa-mRNA and thus not at the moment of sa-mRNA replication. Moreover, we recently reported a similar IFN-β induction for replication-deficient and replication-competent sa-mRNAs in mice [15].…”

“…However, in vivo administration of sa-mRNAs may induce a strong type I IFN response [5,11,23]. While this can be considered advantageous when the sa-mRNA is used for vaccination purposes [11,24], several studies have demonstrated that triggering type I IFN production can negatively impact the intended adaptive immune response of intramuscularly and intradermally administered mRNA vaccines [9,11,15]. Evidently, a strong type I IFN mediated inflammatory response should also be avoided when synthetic mRNAs are considered for protein-replacement therapy, gene editing or stem cell reprogramming [25,26].…”

“…It is generally accepted that a strong innate immune response after mRNA delivery has a negative impact on its translation efficacy [9][10][11]15]. Therefore, we evaluated in BALB/c mice the effect of clobetasol, BAY11 and ODN2088 on the translation efficacy of sa-mRNA encoding luciferase (LUC-sa-mRNA).…”

“…We recently demonstrated that the innate immune response triggered by the selfamplifying mRNA platform [4,5,11] reduced the cellular and humoral responses of an sa-mRNA vaccine against Zika virus [15]. Therefore, strategies that can reduce the innate immunity of sa-mRNAs may improve the efficacy of sa-mRNA vaccines and the acceptance of sa-mRNA therapeutics in general.…”