Engineering Modified mRNA-Based Vaccine against Dengue Virus Using Computational and Reverse Vaccinology Approaches

Abstract

Dengue virus belonging to the family Flaviviridae and its four serotypes are responsible for dengue infections, which extend over 60 countries in tropical and subtropical areas of the world including Pakistan. During the ongoing dengue outbreak in Pakistan (2022), over 30,000 cases have been reported, and over 70 lives have been lost. The only commercialized vaccine against DENV, Dengvaxia, cannot be administered as a prophylactic measure to cure this infection due to various complications. Using machine learning and reverse vaccinology approaches, this study was designed to develop a tetravalent modified nucleotide mRNA vaccine using NS1, prM, and EIII sequences of dengue virus from Pakistani isolates. Based on high antigenicity, non-allergenicity, and toxicity profiling, B-cell epitope, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) putative vaccine targets were predicted. Molecular docking confirmed favorable interactions between T-cell epitopes and their respective HLA alleles, while normal mode analysis validated high-affinity interactions of vaccine proteins with immune receptors. In silico immune simulations confirmed adequate immune responses to eliminate the antigen and generate memory. Codon optimization, physicochemical features, nucleotide modifications, and suitable vector availability further ensured better antigen expression and adaptive immune responses. We predict that this vaccine construct may prove to be a good vaccinal candidate against dengue virus in vitro as well.

Approaches of dengue control: vaccine strategies and future aspects

“…Computational advances, including advances in immunoinformatics ( 149 ), can enable improved dengue vaccine design strategies. Such approaches may include improvements in the identification of antigenic sites, structural modeling of the viral proteins, molecular docking experiments, and the examination of molecular biomimicry ( 150 – 152 ). By examining different serotypes and predicting how likely different parts of the dengue genome are to evolve over time, vaccines of improved efficacy, tailored for more dengue viral serotypes, can be achieved ( 153 , 154 ).…”

Vaccine Strategies for Dengue Fever

“…mRNA vaccines possess advantageous characteristics such as low cost and simple production procedures, and hold the potential for swift adaptation to newly evolving viral strains. At present, a number of mRNA-based vaccines intended to counteract dengue fever are undergoing preclinical development (Mukhtar et al 2022).…”

Exploring the inhibitory potential of Nigella sativa against dengue virus NS2B/NS3 protease and NS5 polymerase using computational approaches

“…The only approved vaccination at the moment is CYD-TDV (Dengvaxia®), however WHO advises using it for those between the ages of 9 and 45. 8 Moreover, a re-infection with the same DENV serotype can occur aer immunization due to genetic and antigenic variations 9,10 DENV is a positive sense single-stranded RNA (+ssRNA) virus with an overall genome size of approximately 10.7 kb (i.e., 3391 amino acids) encoding a precursor polyprotein. 11 The precursor polyprotein (5 ′ -C-prME-NS1-NS2A-NS2B-NS3-NS4A-NS4BNS5-3 ′ ) is further cleaved to produce three structural proteins (capsid protein C, membrane protein prM and envelope protein E) and seven non-structural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5).…”

“…The only approved vaccination at the moment is CYD-TDV (Dengvaxia®), however WHO advises using it for those between the ages of 9 and 45. 8 Moreover, a re-infection with the same DENV serotype can occur after immunization due to genetic and antigenic variations 9,10…”