IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines

Tähtinen, Siri; Tong, Ann-Jay; Himmels, Patricia; Oh, Jaehak; Paler-Martı́nez, Andrés; Kim, Leesun; Wichner, S; Oei, Yoko; McCarron, Mark J.; Freund, Emily C.; Amir, Zhainib Adel; Cruz, Cecile C. de la; Haley, Benjamin; Blanchette, Craig D.; Schartner, Jill; Ye, Weilan; Yadav, Mahesh; Şahin, Uğur; Delamarre, Lélia; Mellman, Ira

doi:10.1038/s41590-022-01160-y

Cited by 267 publications

(224 citation statements)

References 51 publications

Supporting

Mentioning

172

Contrasting

Order By: Relevance

“…Of note, LNPs can provide danger signals and stimulate innate immunity through pattern recognition receptors. mRNA-1273 LNPs seem to induce a higher pro-inflammatory response than those used in the BNT162b2 vaccine 167 . mRNA modifications also affect protein production, therefore modulating immunogenicity 58 .…”

Section: Strategies To Improve Vaccination Responsesmentioning

confidence: 92%

Vaccination in patients with kidney failure: lessons from COVID-19

2022

View full text Add to dashboard Cite

Infection is the second leading cause of death in patients with chronic kidney disease (CKD). Adequate humoral (antibody) and cellular (T cell-driven) immunity are required to minimize pathogen entry and promote pathogen clearance to enable infection control. Vaccination can generate cellular and humoral immunity against specific pathogens and is used to prevent many life-threatening infectious diseases. However, vaccination efficacy is diminished in patients with CKD. Premature ageing of the immune system and chronic systemic low-grade inflammation are the main causes of immune alteration in these patients. In the case of SARS-CoV-2 infection, COVID-19 can have considerable detrimental effects in patients with CKD, especially in those with kidney failure. COVID-19 prevention through successful vaccination is therefore paramount in this vulnerable population. Although patients receiving dialysis have seroconversion rates comparable to those of patients with normal kidney function, most kidney transplant recipients could not generate humoral immunity after two doses of the COVID-19 vaccine. Importantly, some patients who were not able to produce antibodies still had a detectable vaccine-specific T cell response, which might be sufficient to prevent severe COVID-19. Correlates of protection against SARS-CoV-2 have not been established for patients with kidney failure, but they are urgently needed to enable personalized vaccination regimens.

show abstract

Section: Strategies To Improve Vaccination Responsesmentioning

confidence: 92%

Vaccination in patients with kidney failure: lessons from COVID-19

2022

View full text Add to dashboard Cite

show abstract

“…As a result, the effective dose of iLNP vaccines was able to be reduced. Meanwhile, comb-structured mRNA improved the vaccine effects of less immunostimulating anionic lipoplex (18) ( Figure 6 ) and even almost non-inflammatory PM (26, 41) ( Figure 7B ). Thus, our strategy of integrating adjuvancy into comb-structured mRNA provides more freedom in choosing formulation materials for mRNA vaccines with focusing on essential properties other than immunostimulation, including the reduction of side reactions and the improvement in targetability of antigen-presenting cells.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the comb-structured mRNA successfully potentiated three types of existing mRNA vaccine formulations possessing completely different immunogenic properties. iLNPs intrinsically have intense adjuvant functionalities (16)(17)(18), synergizing with comb-structured mRNA adjuvant to further improve vaccination effects (Figure 7A). As a result, the effective dose of iLNP vaccines was able to be reduced.…”

Section: Discussionmentioning

confidence: 99%

“…An alternative approach that has emerged recently is to directly integrate adjuvancy into the packaging materials used for formulating mRNA (13-15). Ionizable lipids used for formulating lipid nanoparticles (LNPs) are typical examples of such materials with intrinsic immunostimulatory properties (16-18). Adjuvancy integration into packaging materials instead of using separate adjuvant molecules is beneficial for formulating clinically-translatable vaccines because of the simplicity in the production process (19).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comb-structured mRNA vaccine tethered with short double-stranded RNA adjuvants maximizes cellular immunity for cancer treatment

Tockary

Abbasi

Masai

et al. 2022

Preprint

View full text Add to dashboard Cite

Immunostimulatory adjuvants play pivotal roles in mRNA cancer vaccines. Herein, mRNA architectonics-based approach was employed to enhance immunostimulatory properties of mRNA, by tethering immunostimulatory short 24-base-pair double-stranded RNA (dsRNA) to mRNA via hybridization, for specific stimulation of retinoic acid-inducible gene-I (RIG-I), an innate immune receptor triggering effective cellular immunity. This approach ensures the co-delivery of mRNA and adjuvants to obtain antigen expression and immune activation in the same antigen presenting cells for effective vaccination, and allows the tuning of immunostimulatory effects by controlling dsRNA number to avoid safety concerns associated with excessive immunostimulation. Thorough in vitro screening provided optimal mRNA structure that induces the secretion of a broad spectrum of proinflammatory molecules and effectively activated mouse and human dendritic cells, with minimal effect on antigen translation efficiency of mRNA. The optimal mRNA formulation improved the potency of mRNA vaccine to induce cytotoxic immune responses after encapsulation into mRNA lipoplex, and exhibited high therapeutic efficiency in lung metastatic model of melanoma using mRNA encoding tumor associated antigen. Furthermore, this system is versatile to potentiate vaccination effect with the use of mRNA polyplex micelle.

show abstract

“…As for the second signal, LNPs designed in a similar fashion as for the COVID-19 mRNA vaccines—but without mRNA—induced a strong pro-inflammatory cytokine profile (including IL-1β and IL-6) in mice upon injection into the skin [ 51 ]. Indeed, mRNA–liposome NPs induced IL-1β secretion in human peripheral blood mononuclear cells, induced by activation of the NLRP3 inflammasome [ 52 ]. However, the inclusion of N1mψ-modified mRNA abrogated this induction.…”

Section: Discussionmentioning

confidence: 99%

Efficient Induction of Antigen-Specific CD8+ T-Cell Responses by Cationic Peptide-Based mRNA Nanoparticles

et al. 2022

View full text Add to dashboard Cite

A major determinant for the success of mRNA-based vaccines is the composition of the nanoparticles (NPs) used for formulation and delivery. Cationic peptides represent interesting candidate carriers for mRNA, since they have been shown to efficiently deliver nucleic acids to eukaryotic cells. mRNA NPs based on arginine-rich peptides have previously been demonstrated to induce potent antigen-specific CD8+ T-cell responses. We therefore compared the histidine-rich amphipathic peptide LAH4-L1 (KKALLAHALHLLALLALHLAHALKKA) to the fully substituted arginine variant (LAH4-L1R) for their capacity to formulate mRNA and transfect dendritic cells (DCs). Although both peptides encapsulated mRNA to the same extent, and showed excellent uptake in DCs, the gene expression level was significantly higher for LAH4-L1. The LAH4-L1–mRNA NPs also resulted in enhanced antigen presentation in the context of MHC I compared to LAH4-L1R in primary murine CD103+ DCs. Both peptides induced DC maturation and inflammasome activation. Subsequent ex vivo stimulation of OT-I splenocytes with transfected CD103+ DCs resulted in a high proportion of polyfunctional CD8+ T cells for both peptides. In addition, in vivo immunization with LAH4-L1 or LAH4-L1R–mRNA NPs resulted in proliferation of antigen-specific T cells. In conclusion, although LAH4-L1 outperformed LAH4-L1R in terms of transfection efficiency, the immune stimulation ex vivo and in vivo was equally efficient.

show abstract

IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines

Cited by 267 publications

References 51 publications

Vaccination in patients with kidney failure: lessons from COVID-19

Vaccination in patients with kidney failure: lessons from COVID-19

Comb-structured mRNA vaccine tethered with short double-stranded RNA adjuvants maximizes cellular immunity for cancer treatment

Efficient Induction of Antigen-Specific CD8+ T-Cell Responses by Cationic Peptide-Based mRNA Nanoparticles

Contact Info

Product

Resources

About