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A Dengue Virus Serotype 1 mRNA-LNP Vaccine Elicits Protective Immune Responses.

ABSTRACT: Dengue virus (DENV) is the most common vector-borne viral disease, with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding the membrane and envelope structural proteins from DENV serotype 1 encapsulated in lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection, with high levels of neutralizing antibody titers and antiviral CD4⁺ and CD8⁺ T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine or a vaccine with mutations in the immunodominant fusion loop epitope elicited equivalent humoral and cell-mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype-specific immunity with minimal serum cross-reactivity and reduced ADE in comparison to a live DENV1 viral infection.IMPORTANCE With 400 million worldwide infections each year, dengue is the most common vector-borne viral disease. Forty percent of the world's population is at risk, with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing suboptimally, the need for an effective dengue vaccine is urgent. Here, we develop and characterize a novel mRNA vaccine encoding the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement (ADE). Importantly our vaccine induced only serotype-specific immune responses and did not induce ADE.

SUBMITTER: Wollner CJ

PROVIDER: S-EPMC8315947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The hemagglutinin (HA) surface protein is the primary immune target for most influenza vaccines. The neuraminidase (NA) surface protein is often a secondary target for vaccine designs. In this study, computationally optimized broadly reactive antigen (COBRA) methodology was used to generate the N1-I NA vaccine antigen that was designed to cross-react with avian, swine, and human influenza viruses of the N1 NA subtype. The elicited antibodies bound to NA proteins derived from A/California/07/2009 (H1N1)pdm09, A/Brisbane/59/2007 (H1N1), A/Swine/North Carolina/154074/2015 (H1N1), and A/Viet Nam/1203/2004 (H5N1) influenza viruses, with NA-neutralizing activity against a broad panel of HXN1 influenza strains. Mice vaccinated with the N1-I COBRA NA vaccine were protected from mortality and viral lung titers were lower when challenged with four different viral challenges (A/California/07/2009, A/Brisbane/59/2007, A/Swine/North Carolina/154074/2015, and A/Viet Nam/1203/2004). Vaccinated mice had little to no weight loss against both homologous, but also cross-NA, genetic clade challenges. Lung viral titers were lower than the mock-vaccinated mice and, at times, equivalent to the homologous control. Thus, the N1-I COBRA NA antigen has the potential to be a complementary component in a multiantigen universal influenza virus vaccine formulation that also contains HA antigens. IMPORTANCE The development and distribution of a universal influenza vaccine would alleviate global economic and public health stress from annual influenza virus outbreaks. The influenza virus NA vaccine antigen allows for protection from multiple HA subtypes and virus host origins, but it has not been the focus of vaccine development. The N1-I NA antigen described here protected mice from direct challenge of four distinct influenza viruses and inhibited the enzymatic activity of an N1 influenza virus panel. The use of the NA antigen in combination with the HA antigen widens the breadth of protection against various virus strains. Therefore, this research opens the door to the development of a longer-lasting vaccine with increased protective breadth.

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A Dengue Virus Serotype 1 mRNA-LNP Vaccine Elicits Protective Immune Responses.

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