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Parenteral Vaccination with an Adjuvanted mRNA Vaccine Induces Protective Mucosal Immunity Against Rotavirus in neonatal mice

ABSTRACT: Gastrointestinal viruses such as rotavirus remain a major cause of childhood gastroenteritis and mortality worldwide. Although current live-attenuated rotavirus vaccines are effective, they face challenges including production, reduced efficacy in low- and middle-income countries, and rare adverse events, highlighting the need for vaccines that can induce strong gut mucosal immunity. Herein, we introduce a lipid nanoparticle (LNP) platform that co-delivers messenger RNA (mRNA) and the retinoic acid receptor agonist Am80 (Am80-LNP), enabling antigen-specific mucosal immune responses in the gut via parenteral intramuscular vaccination. Am80 incorporation preserved the vaccine’s ability to imprint expression of the gut-homing receptors CCR9 and α4β7 on T and B cells, improved mRNA delivery, enhanced lymph node accumulation, and mitigated injection-site inflammation driven by the LNP. In mice and Bama miniature pigs, Am80-LNP induced antigen-specific serum antibody titers, cellular immune responses, and intestinal IgA production. Importantly, neonatal mice vaccinated with Am80-LNP exhibited reduced incidence and duration of diarrhea following live rotavirus challenge, whereas LNPs without Am80 conferred negligible protection. These findings highlight the importance of gut mucosal immunity in mediating protection against rotavirus and suggest that Am80-LNP may offer a versatile mRNA vaccine platform against gastrointestinal viruses.

ORGANISM(S): Mus musculus

PROVIDER: GSE314070 | GEO | 2026/02/11

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE314070_FPKM_and_TPM_allsamples.xlsx	Xlsx
	GSE314070_gene_raw_read_count_allsamples.xlsx	Xlsx

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Project description:Intestinal epithelial cells (IECs) serve as both a physical barrier and a source of robust antiviral interferon (IFN) response. As such, they constitute the primary barrier that enteric viruses, such as rotavirus, need to overcome to initiate infection. The gut is characterized by very low oxygen levels (hypoxia) within the lumen, resulting in a unique hypoxic physiological environment in which rotavirus infection occurs. Depending on the tissues or viruses, conflicting results have been described for the role of hypoxia in regulating viral infections, where hypoxia could have either a proviral or antiviral function. Since intestinal epithelial cells naturally exist in a hypoxic environment, it is essential to investigate how these conditions affect rotavirus infection. We found that hypoxia promotes rotavirus infection, resulting in increased virus replication and production of infectious virus particles. We showed that this increased production of rotavirus particles under hypoxia is due to a decreased induction of both type I and III IFNs leading to a decreased expression of IFN stimulated genes (ISGs) and antiviral protection. RNA sequencing showed a robust decrease in ISG production in hypoxia for both rotavirus infection and poly I:C transfection, suggesting a conserved inhibition of IFN responses in hypoxia for IECs. Functional analyses revealed that hypoxia impairs signal transduction leading to IFN expression by negatively regulating the activation of the master signaling molecule TBK1. Mechanistically, we determined that hypoxia induces the expression of the protein phosphatase PP2A which is responsible for the hypoxia-induced impairment of TBK1 activation. Importantly, we observed that this hypoxia-mediated dampening of immune response was not restricted to rotavirus infection but dampened the IFN induction of a broad range of viruses and immune stimuli. Together, we propose that hypoxia creates an immune-suppressive environment through downregulation of IFN, representing a novel proviral mechanism for hypoxia in the human gastro-intestinal tract.

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Parenteral Vaccination with an Adjuvanted mRNA Vaccine Induces Protective Mucosal Immunity Against Rotavirus in neonatal mice

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