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A glycan-based adjuvant expands the breadth and duration of protection of mRNA-based vaccines.

ABSTRACT: Inflammation initiated in response to a microbial encounter, or deliberately induced upon vaccination, is central for the activation of adaptive lymphocytes. The stimulation of pattern recognition receptors (PRRs) orchestrates the inflammatory programs that regulate adaptive immunity. Here, we took advantage of an mRNA-based vaccine generated against the ancestral spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to test whether tuning inflammation via PRR stimulation enhances the efficacy of mRNA vaccines. We combined mRNA-based vaccine with mannadjuvant, a formulation of fungal mannan and aluminum hydroxide that targets Dectin-2, a C-type lectin PRR. In mice and non-human primates, mannadjuvant increased the magnitude and durability of the response elicited by the mRNA-based vaccine, and it also led to the induction of neutralizing antibodies directed against variants of concern with a high escape capacity, overcoming antigenic imprinting. Mechanistically, we demonstrated that prolonged type I interferon production and potentiated interleukin-1 signaling are necessary and sufficient to exert the activities of mannadjuvant in mice and in human myeloid cells. Overall, our data demonstrate that an anti-fungal PRR can be harnessed to create more potent and durable mRNA-based vaccines.

ORGANISM(S): Mus musculus

PROVIDER: GSE315320 | GEO | 2025/12/30

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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A glycan-based adjuvant expands the breadth and duration of protection of mRNA-based vaccines.

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