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

Abstract

Tetra DIIIC is a vaccine candidate against dengue virus (DENV) composed by four chimeric proteins that fuse the domain III of the envelope protein of each virus to the corresponding capsid protein. Containing B- and T-cell epitopes, these proteins form aggregates after the incubation with an immunostimulatory oligodeoxynucleotide, and their tetravalent formulation induces neutralizing antibodies and cellular immune response in mice and monkeys. Also, Tetra DIIIC protects mice after challenge with each DENV, and the monovalent formulation obtained from DENV-2 protects monkeys upon homologous viral challenge. However, in the last years, new evidences have arisen regarding domain III of DENV envelope protein as irrelevant target for neutralizing antibodies in humans. Nevertheless, vaccination with domain III induces a neutralizing antibody response that confers protection against re-infection. In addition, it has been demonstrated that the induction of a cellular immune response is essential to protect during the infection. This response can also avoid severe manifestations of dengue disease, associated to the antibody-dependent enhancement of the infection. In this study, we observed that Tetra DIIIC was able to boost the antiviral and neutralizing antibody responses previously generated in monkeys during an experimental DENV infection, demonstrating that domain III is targeted by B cells during the viral infection. Additionally, Tetra DIIIC successfully boosted the cellular immune response generated by the viruses, probably against T-cells epitopes in the capsid proteins. These results highlight the functionality of Tetra DIIIC as a vaccine candidate against DENV.

Recent Developments in Recombinant Protein–Based Dengue Vaccines

“…This protein boosted neutralizing antibody responses previously generated in monkeys. These results suggested the potential use of a Tetra DIIIC as a dengue vaccine candidate ( 108 ).…”

A dose-response study in mice of a tetravalent recombinant dengue envelope domain III protein secreted from insect cells

“…Accumulating studies have proved that EDIII-based vaccine candidates can elicit specific neutralizing antibodies [38][39][40] Choosing only domain III rather than whole envelope protein could reduce the risk of ADE due to the lack of other non-neutralizing or cross-reactive epitopes. Hence, most of recent efforts have focused on utilization of EDIII to produce a subunit dengue vaccine [41][42][43]. We have constructed a tetravalent domain III in tandem using the Gly4SerGly4 linker, and testified its potential utility in the diagnosis of DENV infections with a high degree of sensitivity and specificity [41].…”

“…Hence, most of recent efforts have focused on utilization of EDIII to produce a subunit dengue vaccine [41][42][43]. We have constructed a tetravalent domain III in tandem using the Gly4SerGly4 linker, and testified its potential utility in the diagnosis of DENV infections with a high degree of sensitivity and specificity [41]. In this study, we attempted to develop this tetravalent protein (rEIII) as vaccine candidates against DENV and evaluated the immune responses in mice.…”

Antibody-Dependent Enhancement of Viral Infections

“…Monoclonal antibody-based studies have helped identify neutralizing and enhancing viral epitopes, making design of such tailored vaccines possible. DENV EDIII induces predominantly neutralizing antibodies, thus making recombinant EDIII an attractive subunit vaccine candidate (Gil et al 2017;Frei et al 2018). DENV NS1 has also been considered as a vaccine candidate as it avoids ADE (Hertz et al 2017).…”