Modified mRNA-LNP Vaccines Confer Protection against Experimental DENV-2 Infection in Mice

Abstract

Dengue virus (DENV) infection is a major global public health concern, and there is no effective vaccine for it. In this study, we describe the design and characterization of three nucleotide-modified mRNA vaccines (prME-mRNA, E80-mRNA, and NS1-mRNA) for DENV-2. Our results showed that vaccination with E80-mRNA alone or a combination of E80-mRNA and NS1-mRNA can induce high levels of neutralizing antibodies and antigen-specific T cell responses; furthermore, these vaccines confer complete protection against DENV-2 challenge in immunocompetent mice. These data provide foundations for further development of a tetravalent DENV vaccine based on nucleotide-modified mRNA.

A mRNA-LNP vaccine against Dengue Virus elicits robust, serotype-specific immunity

“…Here, we developed a vaccine against DENV1 with a modified mRNA encoding for the prM and ENV viral proteins encapsulated in a lipid nanoparticle (LNP). The mRNA-LNP vaccine platform has now been developed for several viruses including rabies virus (26), influenza virus (26), and HIV (43) (23,24,48). In our study, the tPA signal peptide led to far greater ENV expression and VLP secretion in C2C12 cells compared to other signal peptides, including the JEV signal peptide.…”

“…These flavivirus vaccines encode for the viral structural proteins which are expressed and lead to the development of neutralizing antibodies against the viral structural proteins. Recently another group published the results of a mRNA vaccine against DENV2(48). Zhang et al developed mRNA vaccines encoding for full length prM-ENV, the soluble portion of ENV, and NS1.…”

“…Vaccination with the mRNA encoding for the soluble portion of DENV2 ENV (E80) elicited humoral and cell mediated immune responses that protected against a lethal challenge with a homologous serotype of DENV2, similar to our findings with a DENV1 serotype mRNA vaccine. However, the DENV2 E80 mRNA vaccine induced serotype cross-reactive immune responses and high levels of heterologous ADE(48). On the contrary, our mRNA vaccine elicits serotype specific immune responses with low levels of heterotypic ADE.…”

“…The signal peptide plays a critical role in directing the translated protein into the appropriate locations for processing and secretion. Previous flaviviral mRNA vaccines have included a N-terminal JEV or IgE signal peptide(23, 24, 48). In our study, the tPA signal peptide led to far greater ENV expression and VLP secretion in C2C12 cells compared to other signal peptides, including the JEV signal peptide.…”

Self-assembled mRNA vaccines

“…6 C and 7 ) [ [177] , [178] , [179] , [180] ]. MC3 was consequently shown to be effective in delivering mRNA as well [ 166 , [181] , [182] , [183] , [184] , [185] , [186] , [187] , [188] ]. MC3 has a long plasma half-life of 72 hours, which limits its chronic administration [ 126 , 189 ].…”