A Tetravalent Formulation Based on Recombinant Nucleocapsid-like Particles from Dengue Viruses Induces a Functional Immune Response in Mice and Monkeys

Abstract

Despite the considerable effort that has been invested in elucidating the mechanisms of protection and immunopathogenesis associated with dengue virus infections, a reliable correlate of protection against the disease remains to be found. Neutralizing Abs, long considered the prime component of a protective response, can exacerbate disease severity when present at subprotective levels, and a growing body of data is challenging the notion that their titers are positively correlated with disease protection. Consequently, the protective role of cell-mediated immunity in the control of dengue infections has begun to be studied. Although earlier research implicated cellular immunity in dengue immunopathogenesis, a wealth of newer data demonstrated that multifunctional CD8 T cell responses are instrumental for avoiding the more severe manifestations of dengue disease. In this article, we describe a new tetravalent vaccine candidate based on recombinant dengue virus capsid proteins, efficiently produced in Escherichia coli and purified using a single ion-exchange chromatography step. After aggregation to form nucleocapsid-like particles upon incubation with an oligodeoxynucleotide containing immunostimulatory CpG motifs, these Ags induce, in mice and monkeys, an IFN-γ-secreting cell response that significantly reduces viral load after challenge without the contribution of antiviral Abs. Therefore, this new vaccine candidate may not carry the risk for disease enhancement associated with Ab-based formulations.

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…In a Thai cohort study, higher frequencies of DENV-specific TNF-α-, IFN-γ-, and IL-2-producing T cells were associated with reduced disease severity during a secondary infection (75). Importantly, in the context of vaccine development, the ability of a DENV vaccine to induce multifunctional T cells has become an important criterion to evaluate vaccine efficacy (23)(24)(25)(26). Consistently, we observed a high frequency of bifunctional (CD107a…”

“…Recent evidence from mouse and human studies suggests indeed that T cells, particularly the CD8 + subset, may be important mediators of protection (17)(18)(19)(20)(21)(22). Greater appreciation of the importance of T cells is also evident from recent vaccine developments that focus on the assessment of T cell activity in vaccinated individuals and animals (23)(24)(25)(26).…”

The tetravalent formulation of domain III‐capsid proteins recalls memory B‐ and T‐cell responses induced in monkeys by an experimental dengue virus infection

“…In fact, studies with human sera have revealed that upon natural infection, antibodies do not recognize the capsid protein 33 . Moreover, sera from mice and monkeys immunized with recombinant capsid proteins do not recognize the viruses neither neutralize the in vitro viral infections 34 . On the other hand, control monkeys (that is, naive) that were immunized with only one dose of Tetra DIIIC did not develop antiviral and neutralizing antibodies, as it has been previously observed 14 …”

Screening for immune response against Dengue virus in Vietnamese non‐human primates: implications for vaccine developers

“…Moreover, our group has developed CMI‐based vaccine candidates using the recombinant capsid protein from DENV 3 , 12 . Recently, these authors reported that the tetravalent formulation based on recombinant nucleocapsid‐like particles from dengue viruses induces in both mice and monkeys an IFNγ‐secreting cell response that significantly reduces viral load after challenge without the contribution of neutralizing antibodies 16 …”

“…3,12 Recently, these authors reported that the tetravalent formulation based on recombinant nucleocapsid-like particles from dengue viruses induces in both mice and monkeys an IFNγ-secreting cell response that significantly reduces viral load after challenge without the contribution of neutralizing antibodies. 16 In our study, animals were not screened for another flavivirus such as Japanese encephalitis or Zika. However, if the detected IFNγ response was due to a DENV cross-reactive response induced by any flavivirus, the implication of our findings on DENV vaccine evaluation remains.…”