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Synergistic Effect of Nucleoside Modification and Ionizable Lipid Composition on Translation and Immune Responses to mRNA Vaccines

ABSTRACT: Lipid nanoparticle (LNP) structural components can impact the safety and immunogenicity of mRNA vaccines. Here we examine the mechanisms contributing to the performance of mRNA-LNP vaccines by exploring the impact of nucleoside modifications and LNP components on translational efficiency, innate immune activation, and immunogenicity, by employing in vitro (cell culture) and in vivo (mice and cynomolgus macaques) models. Our data reveal several molecular and immunological parameters affected by nucleoside modification. These include: i) a sequence-dependent increase in antigen expression; ii) decreased induction of genes associated with antiviral activity and RNA degradation in modified mRNA compared with unmodified mRNA; iii) reduced innate immune recognition of nucleoside-modified mRNA, accompanied by lower levels of inflammatory cytokines and chemokines in non-human primates; and iv) a synergistic effect of the mRNA and ionizable lipid composition on the immune activation triggered by the mRNA-LNP formulation. Our data show that changes in the LNP composition, independent from whether the mRNA is modified or unmodified, caused differential expression of genes associated with innate and antiviral immunity. For instance, modification of mRNA was able to silence the innate immune signatures more efficiently for certain LNPs but not others. We believe these findings offer valuable insights into mRNA vaccine function and offer strategies for enhancing vaccine efficacy and reducing the reactogenicity of next generation mRNA vaccines.

ORGANISM(S): Macaca fascicularis Homo sapiens

PROVIDER: GSE303153 | GEO | 2025/09/11

REPOSITORIES: GEO

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Project description:Introduction: Vaccine platforms such as viral vectors and mRNA can accelerate vaccine development in response to newly emerging pathogens, as demonstrated during the COVID-19 pandemic. However, the differential effects of platform and antigen insert on vaccine immunogenicity remain incompletely understood. Innate immune responses induced by viral vector vaccines are suggested to have an adjuvant effect for subsequent adaptive immunity. Integrating data on both innate and adaptive immunity, systems vaccinology approaches can improve the understanding of vaccine-induced immune mechanisms. Methods: Two vaccine candidates against SARS-CoV-2, both based on the viral vector Modified Vaccinia virus Ankara (MVA) and encoding the native (MVA SARS-2-S) or prefusion-stabilized spike protein (MVA-SARS-2-ST), were evaluated in phase 1 clinical trials (ClinicalTrials.gov: NCT04569383, NCT04895449). Longitudinal dynamics of innate and early adaptive immune responses induced by vaccination in SARS-CoV-2-naïve individuals were analyzed based on transcriptome and flow cytometry data, in comparison to the licensed ChAd and mRNA vaccines. Results: Compared to MVA-SARS-2-S, MVA-SARS-2-ST (encoding the prefusion-stabilized spike protein) induced a stronger transcriptional activation early after vaccination, as well as higher virus neutralizing antibodies. Positive correlations were observed between innate and adaptive immune responses induced by a second MVA-SARS-2-ST vaccination. MVA-, ChAd- and mRNA-based vaccines induced distinct immune signatures, with the overall strongest transcriptional activation as well as monocyte and T follicular helper cell responses induced by ChAd. Discussion: Our findings suggest a potential impact of the spike protein conformation not only on adaptive but also on innate immune responses. As indicated by positive correlations between several immune parameters induced by MVA-SARS-2-ST, the distinct transcriptional activation early after vaccination may be linked to the induction of classical monocytes and activation of cTFH1 cells, which may in turn result in the superior adaptive immunogenicity of MVA-SARS-2-ST, compared to MVA-SARS-2-S. Overall, our data demonstrate that both the vaccine platform and antigen insert can affect innate immune responses and subsequent vaccine immunogenicity in humans.

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Synergistic Effect of Nucleoside Modification and Ionizable Lipid Composition on Translation and Immune Responses to mRNA Vaccines

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