Abstract
The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.
Highlights
Dengue viruses 1–4 (DENV-1-4) are mosquito-borne flaviviruses annually responsible for 50– 100 million dengue cases in humans, that have been classified as dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), and further re-classified as dengue and severe dengue [1,2]
Using a multiparameter approach, including characterization of viral replication and biomarkers relevant to dengue/severe dengue in humans, we were able to detect vaccine-associated safety signals in this model. While these results enabled us to discontinue at an early stage the dengue purified and inactivated vaccine (DPIV) development, this improved dengue macaque model may be instrumental for early assessment of efficacy/safety of future dengue vaccines
As the measured dengue virus (DENV)-nAb titers did mostly not differ between months 5 and 8 post-second immunization (S1 Table), we assumed the DENV-nAb response detected eight months following vaccination was representative of long-term immunity
Summary
Dengue viruses 1–4 (DENV-1-4) are mosquito-borne flaviviruses annually responsible for 50– 100 million dengue cases in humans, that have been classified as dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), and further re-classified as dengue (with or without warning signs) and severe dengue [1,2]. Pre-existing sub-optimal immunity to DENV is thought to be the strongest risk factor for DHF/DSS, for which antibodydependent enhancement (ADE) of DENV infection is proposed to be the early underlying mechanism. The reported association between specific pre-existing DENV-antibody titers and the risk of DHF/DSS further confirmed the role of ADE in severe dengue [7]. The pre-existing immunity risk factor for DHF/DSS has complicated dengue vaccine development. It is believed that a dengue vaccine needs to elicit protective immune responses against all 4 DENV types while not inducing DENV-enhancing antibodies that could increase the risk of severe disease in vaccinated individuals [8,9]. The only licensed dengue vaccine, Dengvaxia, was shown to increase the risk of hospitalization for severe dengue in children naïve to DENV before vaccination, further emphasizing the need to assess dengue vaccine safety at the earliest development stages prior to human vaccination [10]
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