<scp>CD</scp>8 T‐cell priming upon <scp>mRNA</scp> vaccination is restricted to bone‐marrow‐derived antigen‐presenting cells and may involve antigen transfer from myocytes

Lazzaro, Sandra; Giovani, Cinzia; Mangiavacchi, Simona; Magini, Diletta; Maione, Domenico; Baudner, Barbara C.; Geall, Andrew J.; Gregorio, Ennio De; D’Oro, Ugo; Buonsanti, Cecilia

doi:10.1111/imm.12505

Cited by 64 publications

(55 citation statements)

References 57 publications

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“…RNAs were formulated with LNPs as previously described [ 34 ] and diluted to the desired RNA concentration (1 ng/μl) with PBS. For the SAM(NP)+SAM(M1) formulation, an equal amount of SAM(NP) and SAM(M1) RNAs was mixed prior to complexion with LNP.…”

Section: Methodsmentioning

confidence: 99%

Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge

et al. 2016

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Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines.

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Section: Methodsmentioning

confidence: 99%

Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge

et al. 2016

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“…Importantly, the immunostimulation was limited to the injection site and lymphoid organs as no proinflammatory cytokines were detected in the serum of the immunized mice. Lazzaro et al demonstrated that CD8 + T-cell priming is restricted to bone-marrow-derived APCs and may involve antigen transfer from myocytes suggesting cross-priming as the prevalent mechanism upon IM injection of self-amplifying mRNA vaccines in mice ( 166 ). In a recent publication, Lutz et al provided first mechanistic insights into the mode of action of LNP-formulated non-replicating sequence optimized mRNA vaccines, demonstrating a strong activation of the innate immune response at the injection site and in the dLNs in mice.…”

Section: Vaccine Technologiesmentioning

confidence: 99%

New Vaccine Technologies to Combat Outbreak Situations

et al. 2018

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Ever since the development of the first vaccine more than 200 years ago, vaccinations have greatly decreased the burden of infectious diseases worldwide, famously leading to the eradication of small pox and allowing the restriction of diseases such as polio, tetanus, diphtheria, and measles. A multitude of research efforts focuses on the improvement of established and the discovery of new vaccines such as the HPV (human papilloma virus) vaccine in 2006. However, radical changes in the density, age distribution and traveling habits of the population worldwide as well as the changing climate favor the emergence of old and new pathogens that bear the risk of becoming pandemic threats. In recent years, the rapid spread of severe infections such as HIV, SARS, Ebola, and Zika have highlighted the dire need for global preparedness for pandemics, which necessitates the extremely rapid development and comprehensive distribution of vaccines against potentially previously unknown pathogens. What is more, the emergence of antibiotic resistant bacteria calls for new approaches to prevent infections. Given these changes, established methods for the identification of new vaccine candidates are no longer sufficient to ensure global protection. Hence, new vaccine technologies able to achieve rapid development as well as large scale production are of pivotal importance. This review will discuss viral vector and nucleic acid-based vaccines (DNA and mRNA vaccines) as new approaches that might be able to tackle these challenges to global health.

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“…After intramuscular application, transfected myocytes may undergo apoptosis. Apoptotic bodies are engulfed by APC and the exogenous antigen is cross-presented on MHCI resulting in a CD8 + T cell response [ 17 ]. Early studies on DNA vaccination demonstrated that priming of CD8 + cytotoxic T lymphocytes (CTL) is mostly dependent on bone marrow-derived DC rather than induced by tissue specific cells [ 18 ], and was strictly dependent on CD4 + T cell help [ 19 ].…”

Section: Course Of Action Of Dna Vaccinesmentioning

confidence: 99%

DNA Vaccines—How Far From Clinical Use?

Hobernik

Bros

2018

IJMS

371

332

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Two decades ago successful transfection of antigen presenting cells (APC) in vivo was demonstrated which resulted in the induction of primary adaptive immune responses. Due to the good biocompatibility of plasmid DNA, their cost-efficient production and long shelf life, many researchers aimed to develop DNA vaccine-based immunotherapeutic strategies for treatment of infections and cancer, but also autoimmune diseases and allergies. This review aims to summarize our current knowledge on the course of action of DNA vaccines, and which factors are responsible for the poor immunogenicity in human so far. Important optimization steps that improve DNA transfection efficiency comprise the introduction of DNA-complexing nano-carriers aimed to prevent extracellular DNA degradation, enabling APC targeting, and enhanced endo/lysosomal escape of DNA. Attachment of virus-derived nuclear localization sequences facilitates nuclear entry of DNA. Improvements in DNA vaccine design include the use of APC-specific promotors for transcriptional targeting, the arrangement of multiple antigen sequences, the co-delivery of molecular adjuvants to prevent tolerance induction, and strategies to circumvent potential inhibitory effects of the vector backbone. Successful clinical use of DNA vaccines may require combined employment of all of these parameters, and combination treatment with additional drugs.

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CD8 T‐cell priming upon mRNA vaccination is restricted to bone‐marrow‐derived antigen‐presenting cells and may involve antigen transfer from myocytes

Cited by 64 publications

References 57 publications

Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge

Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge

New Vaccine Technologies to Combat Outbreak Situations

DNA Vaccines—How Far From Clinical Use?

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