Production and Biomedical Application of Flavivirus-like Particles

Abstract

Many viruses belonging to the Flaviviridae family are transmitted by invertebrate vectors. Among those transmitted by mosquitos, there are many human pathogens of great medical importance, such as Japanese encephalitis virus, West Nile virus, dengue virus, Zika virus, or yellow fever virus. Millions of people contract mosquito-borne diseases each year, leading to thousands of deaths. Co-circulation of genetically similar flaviviruses in the same areas result in the generation of crossreactive antibodies, which is of serious concern for the development of effective vaccines and diagnostic tests. This review provides comprehensive insight into the potential use of virus-like particles as safe and effective antigens in both diagnostics tests, as well as in the development of vaccines against several mosquito-borne flaviviruses. State of the Art Vaccine Development against Mosquito-borne FlavivirusesMosquito-borne viruses belonging to the Flavivirus genus comprise a large group of species that are spread worldwide. Due to climate changes, mosquitoes have gradually colonized new territories, resulting in the spread of associated flaviviruses. Depending on their vector, flaviviruses are classified as those transmitted by mosquitoes of Culex spp. [e.g., Japanese encephalitis virus (JEV) and West Nile virus (WNV)] or Aedes spp. [e.g., dengue virus (DENV), Zika virus (ZIKV), or yellow fever virus (YFV)]. The co-circulation of flaviviruses in different parts of the world can pose a problem for diagnosis on account of their high genetic and structural similarity; it can also result in antibody-dependent enhancement of infection (ADE), as initially observed for heterotypic infection with DENV. ADE (described in detail in Boxes 1 and 2) is the augmentation of secondary flaviviral infection due to pre-existing, nonneutralizing antibodies. Consequently, the development of efficient vaccines and diagnostic tests remain top priorities.Vaccines approved for human use against YFV, JEV, and DENV are based on live-attenuated or inactivated viruses. Both types of vaccines have some limitations. For live-attenuated vaccines there is some risk of virus reversion to pathogenic state, while the latter may not be completely inactivated. Thus, it is not surprising that other vaccine platforms are currently under investigation; these include viral vectors encoding Flavivirus genes, synthetic peptides, protein nanoparticles, mRNA vaccines, subunit antigens, and virus-like particles (VLPs). VLPs, due to their past successes in vaccination, probably have the greatest potential. They are composed of recombinant viral proteins, organized almost identically to the native virions. Moreover, VLPs do not contain viral genetic material, which makes them noninfectious, therefore potentially they can be used as optimum antigens in vaccine development. VLPs are often spontaneously produced during Flavivirus infection [1], and they can be generated using different expression systems. VLP-based vaccines against different human viruses, including hepatitis ...

Mosquito Cell-Derived Japanese Encephalitis Virus-Like Particles Induce Specific Humoral and Cellular Immune Responses in Mice

“…JEV GIII immunization programs have proven effective in controlling JEV [10]; however, subsequent JEV genotype I (GI) displacement and poor protective efficacy against JEV genotype V (GV) suggest that an improved vaccine is needed [2,11,12]. New classes of JEV vaccines, such as protein subunit vaccines, DNA vaccines, viral vectors, and vaccines based on virus-like particles (VLPs) have yet to undergo extensive pre-clinical testing [13]; however, research on VLP-based vaccines is gaining traction [14,15]. When precursor membrane protein (prM) and envelope (E) flavivirus proteins are expressed together within a cell, they self-assemble into VLPs, which are released into the extracellular environment [16][17][18].…”

Production of dengue virus-like particles serotype-3 in silkworm larvae and their ability to elicit a humoral immune response in mice

“…The expression of prM-E or co-expression with the CprME structural proteins was an effective approach for the development of recombinant avivirus virus-like particles (VLPs). The C protein can stabilize the assembly of the VLPs, although it is not necessary for particle formation (Krol et al 2019). VLPs are self-assembled particles, which consist of viral structural proteins.…”

Virus-Like Particle Systems for Vaccine Development against Viruses in the Flaviviridae Family

“…While most vaccines approved for human use against Flaviviridae viruses, and many vaccine candidates in ongoing development and trials, are based on purified inactivated and live inactivated vaccines, which can elicit good immunogenicity, these vaccines are generally limited by safety concerns over incomplete inactivation and the risk of infectious attenuated virus reversion to a pathogenic state, respectively [7]. In comparison, non-infectious subunit vaccines possess superior safety.…”

“…Of which, the VLP vaccine platform possess additional unique advantageous qualities over purified inactivated and live-attenuated vaccines, and other subunit vaccine types, making it highly potential for development of successful Flaviviridae vaccines. The VLP vaccine platform is based on the simple expression of self-assembling viral structural proteins (prME or CprME for most members of the Flaviviridae family, and C, E1 and E2 for HCV) [7,8] to produce non-replicative VLPs lacking a viral genome but retaining the morphology and antigenicity of live infectious virions, thus rendering VLP vaccines highly safe but immunogenic [9]. Their unique feature of presenting viral antigens in highly native surface geometry organization and conformation allow VLP vaccines to efficiently elicit strong B-cell activation for high titre neutralizing antibody production, as well as activation of cellular immune response, thus inducing more potent protective immune responses as compared to subunit vaccines based on single proteins [9,10].…”

“…VLP vaccines also present significant advantages with respect to their low cost and ease of production, mainly requiring relatively inexpensive stable mammalian, insect, plant, yeast, or bacteria producer cell lines as the VLP expression system [9]. Finally, VLP vaccines have achieved successful protection against hepatitis B virus (HBV), human papilloma virus, hepatitis E virus, and influenza virus, and are licensed for use in humans [7], supporting its suitability as an effective vaccination strategy. Here in this review, we focus on the potential of the VLP vaccine platform in the current vaccine development against the different species of Flaviviridae viruses named above.…”