Polytopic vaccination with a live-attenuated dengue vaccine enhances B-cell and T-cell activation, but not neutralizing antibodies

Abstract

Dengue, caused by dengue viruses (DENVs), is the most common arboviral disease of humans. Several dengue vaccine candidates are at different stages of clinical development and one has been licensed. Inoculation with live-attenuated DENV constructs is an approach that has been used by vaccine developers. Unfortunately, the simultaneous injection of all four attenuated DENV serotypes (DENV1-4) into a single injection site (monotopic vaccination) has been postulated to result in interference in the replication of some serotypes in favor of others, an important obstacle in obtaining a balanced immune response against all serotypes. Here, we demonstrate the virus replicative and immunostimulatory effects of polytopic monovalent dengue vaccination (PV) in which, each of the four components of the tetravalent vaccine is simultaneously delivered to four different sites versus the more traditional monotopic tetravalent vaccination (MV) in a non-human primate (NHP) model. With the exception of DENV-2, there was no significant difference in detectable viral RNA levels between PV and MV inoculation. Interestingly, longer periods of detection and higher viral RNA levels were seen in the lymph nodes of NHPs inoculated PV compared to MV. Induction of lymph node dendritic cell maturation and of blood T- and B-cell activation showed different kinetics in PV inoculated NHPs compared to MV. The MV inoculated group showed earlier maturation of dendritic cells and activation of B and T cells compared to PV inoculated NHPs. A similar kinetic difference was also observed in the cytokine response: MV induced earlier cytokine responses compared to PV. However, similar levels of DENV neutralizing antibodies were observed in PV and MV NHPs. These findings indicate that cellular immune response after vaccination may be affected by the location of inoculation. Design of vaccine delivery may need to take into account the effects of locations of vaccine delivery of multiples serotype live viral vaccine on the induction of immune response.

Designing a polytope for use in a broad-spectrum dengue virus vaccine

“…Subunit vaccines are potential substitutes for the current live attenuated dengue virus vaccine approved by the World Health Organization 9 . A recently published study found that this live attenuated vaccine stimulated B and T cells but did not increase production of neutralizing antibodies 13 . We combined these four epitopes into a polytope to create a candidate vaccine.…”

“…These live attenuated vaccines have associated risks because pathogens are used as the vaccinating agent. One recent study found that injection of polytopic live attenuated dengue virus enhanced B- and T-cell activation, but failed to lead to neutralizing antibody production 13 . Subunit viral proteins also have potential for use in vaccines.…”

Polytopic fractional delivery of an HIV vaccine alters cellular responses and results in increased epitope breadth in a phase 1 randomized trial

“… 27 , 28 , 29 Comparison of polytopic and monotopic Dengue vaccination in NHP showed that while single-site vaccination resulted in more rapid cytokine production, durability was higher in NHP vaccinated via polytopic, separated antigen delivery. 30 Murine studies have also demonstrated the ability to overcome immunodominance by separating vaccine antigens across several anatomic sites. 31 , 32 , 33 , 34 It was recently shown that co-administration of DNA and protein HIV vaccines as fractional polytopic delivery in NHP elicited higher immune responses and offered greater protection from SIV than separating the DNA and protein to contralateral sites.…”