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MRNA Encoding a Bispecific Single Domain Antibody Construct Protects against Influenza A Virus Infection in Mice.

ABSTRACT: To date, mRNA-based biologics have mainly been developed for prophylactic and therapeutic vaccination to combat infectious diseases or cancer. In the past years, optimization of the characteristics of in vitro transcribed mRNA has led to significant reduction of the inflammatory responses. Thanks to this, mRNA therapeutics have entered the field of passive immunization. Here, we established an mRNA treatment that is based on mRNA that codes for a bispecific single-domain antibody construct that can selectively recruit innate immune cells to cells infected with influenza A virus. The constructs consist of a single-domain antibody that binds to the ectodomain of the conserved influenza A matrix protein 2, while the other single-domain antibody binds to the activating mouse Fc? receptor IV. Formulating the mRNA into DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)/cholesterol nanoparticles and delivering these intratracheally to mice allowed the production of the bispecific single-domain antibody in the lungs, and administration of these mRNA-particles prior to influenza A virus infection was associated with a significant reduction in viral titers and a reduced morbidity in mice. Overall, our data provide evidence that the local delivery of mRNA encoding a bispecific single-domain antibody format in the lungs could be a promising pulmonary antiviral prophylactic treatment.

SUBMITTER: Van Hoecke L

PROVIDER: S-EPMC7240188 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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mRNA Encoding a Bispecific Single Domain Antibody Construct Protects against Influenza A Virus Infection in Mice.

Van Hoecke Lien L Verbeke Rein R De Vlieger Dorien D Dewitte Heleen H Roose Kenny K Van Nevel Sharon S Krysko Olga O Bachert Claus C Schepens Bert B Lentacker Ine I Saelens Xavier X

Molecular therapy. Nucleic acids 20200501

To date, mRNA-based biologics have mainly been developed for prophylactic and therapeutic vaccination to combat infectious diseases or cancer. In the past years, optimization of the characteristics of in vitro transcribed mRNA has led to significant reduction of the inflammatory responses. Thanks to this, mRNA therapeutics have entered the field of passive immunization. Here, we established an mRNA treatment that is based on mRNA that codes for a bispecific single-domain antibody construct that ...[more]

PMID: 32438313

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Project description:BackgroundCurrent human influenza vaccines lack the adaptability to match the mutational rate of the virus and therefore require annual revisions. Because of extensive manufacturing times and the possibility that antigenic alterations occur during viral vaccine strain production, an inherent risk exists for antigenic mismatch between the new influenza vaccine and circulating viruses. Targeting more conserved antigens such as nucleoprotein (NP) could provide a more sustainable vaccination strategy by inducing long term and heterosubtypic protection against influenza. We previously demonstrated that intranodal mRNA injection can induce potent antigen-specific T-cell responses. In this study, we investigated whether intranodal administration of mRNA encoding NP can induce T-cell responses capable of protecting against a heterologous influenza virus challenge.MethodsBALB/c mice were immunized in the inguinal lymph nodes with different vaccination regimens of mRNA encoding NP. Immune responses were compared with NP DNA vaccination via IFN-? ELISPOT and in vivo cytotoxicity. For survival experiments, mice were prime-boost vaccinated with 17 µg NP mRNA and infected with 1LD50 of H1N1 influenza virus 8 weeks after boost. Weight was monitored and viral titers, cytokines and immune cell populations in the bronchoalveolar lavage, and IFN-? responses in the spleen were analyzed.ResultsOur results demonstrate that NP mRNA induces superior systemic T-cell responses against NP compared to classical DNA vaccination. These responses were sustained for several weeks even at low vaccine doses. Upon challenge infection, vaccination with NP mRNA resulted in reduced lung viral titers and improved recovery from infection. Finally, we show that vaccination with NP mRNA affects the immune response in infected lungs by lowering immune cell infiltration while increasing the fraction of T cells, monocytes and MHC II+ alveolar macrophages within immune infiltrates. This change was associated with altered levels of both pro- and anti-inflammatory cytokines.ConclusionsThese findings suggest that intranodal vaccination with NP mRNA induces cross-strain immunity against influenza, but also highlight a paradox of influenza immunity, whereby robust immune responses can provide protection, but can also transiently exacerbate symptoms during infection.

Dataset Information

MRNA Encoding a Bispecific Single Domain Antibody Construct Protects against Influenza A Virus Infection in Mice.

Publications

mRNA Encoding a Bispecific Single Domain Antibody Construct Protects against Influenza A Virus Infection in Mice.

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