Evaluation of chimeric DNA vaccines consisting of premembrane and envelope genes of Japanese encephalitis and dengue viruses as a strategy for reducing induction of dengue virus infection‐enhancing antibody response

Abstract

Neutralizing antibodies induced by dengue virus (DENV) infection show viral infection-enhancing activities at sub-neutralizing doses. On the other hand, preimmunity against Japanese encephalitis virus (JEV), a congener of DENV, does not increase the severity of DENV infection. Several studies have demonstrated that neutralizing epitopes in the genus Flavivirus are mainly located in domain III (DIII) of the envelope (E) protein. In this study, chimeric premembrane and envelope (prM-E) genebased expression plasmids of JEV and DENV1 with DIII substitution of each virus were constructed for use as DNA vaccines and their immunogenicity evaluated. Sera from C3H/He and ICR mice immunized with a chimeric gene containing DENV1 DIII on a JEV prM-E gene backbone showed high neutralizing antibody titers with less DENV infection-enhancing activity. Our results confirm the applicability of this approach as a new dengue vaccine development strategy.Key words Antibody-dependent enhancement, chimera, dengue, vaccine.Dengue virus, a member of the genus Flavivirus, is the causative agent of dengue fever and dengue hemorrhagic fever, an estimated 50 million infections occurring annually (1). Although DENV infection is a global public health concern, no approved vaccines or antiviral substances are currently available (2). Several research groups are currently trying to establish an effective DENV vaccine by using various strategies to induce anti-DENV neutralizing antibodies, which mediate the most effective anti-DENV immune response (3-6).The pathogenic mechanism of DENV infection has not been fully elucidated. Difference in disease severity upon secondary exposure to homotypic (protection) and heterotypic (deterioration) infection is the primary characteristic distinguishing dengue fever from dengue hemorrhagic fever (7). Antibody dependent enhancement (ADE) is the proposed mechanism for deterioration induced by secondary DENV infection; this is suggested by the observation that pre-existing neutralizing antibodies that have been induced by primary infection crossprotectively neutralize viruses during some post-infection periods only. In addition, the Fc portion of the antibody molecule may facilitate viral uptake to Fc receptorbearing cells, eventually enhancing viral propagation (8). Intriguingly, ADE activity has been detected in both polyclonal and monoclonal antibody states (9). List of Abbreviations: ADE, antibody-dependent enhancement; DENV, dengue virus; DENV-1, DENV type-1; DI, domain I; DII, domain II; DIII, domain III; E, envelope; JEV, Japanese encephalitis virus; pcD1ME, pcDNA3-based expression plasmid DENV1 Mochizuki; pcJEME, pcDNA3-based expression plasmid for prM and E proteins of JEV Nakayama; prM, premembrane.

A Therapeutic Oral Vaccine Candidate against Propionibacterium acnes: Preparation and Immunological Evaluation of Nanoparticles Encapsulated Sialidase-CAMP Fusion Protein

“…Accordingly, the present study sought to introduce a chimeric protein antigen encapsulated in chitosan nanoparticle being able to induce local as well as systemic immune responses against P. acnes. Chimeric vaccines, with utmost attention in infectious disease prevention, have some benefits such as increased safety, cost-benefit, and less antigenic competition, making them appropriate vaccine candidates in may studies (18,19). Therefore, in our recent bio-computational study, we introduced a Sialidase-CAMP chimeric vaccine candidate, based on two separated Nakatsuji studies (6, 7), and postulated that it could be able to induce immune responses (8).…”

Replacement of pr gene with Japanese encephalitis virus pr using reverse genetics reduces antibody-dependent enhancement of dengue virus 2 infection

“…Most current DENV vaccine candidates, including naturally attenuated, recombinantly attenuated, chemically inactivated viruses, and DENV-yellow fever chimeras, contain native dengue prM sequences (Murphy and Whitehead 2011 ; Sjatha et al 2014 ). It may be worthwhile to consider alternative vaccine approaches that minimize or eliminate anti-prM responses during vaccine design.…”

Adaptive Immunity to Dengue Virus: Slippery Slope or Solid Ground for Rational Vaccine Design?

“…Alternatively, one could exploit the minimal cross-reactivity of prM protein–specific antibodies between DENV and members of the JEV serocomplex for the production of improved chimeric vaccines [ 70 , 177 ]. In fact, replacement of the DENV pr peptide with its JEV counterpart or expression of DENV protein subunits in a JEV backbone proved to be an effective measure to reduce the enhancing activity of vaccine-induced antibodies while retaining full neutralising capacity [ 178 , 179 , 180 ].…”