[Accessed 27 Apr 2019]
Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines
Maria Beatriz Borges, Renato Sergio Marchevsky, Renata Carvalho Pereira, Ygara da Silva Mendes, Luiz Gustavo Almeida Mendes, Leonardo Diniz-Mendes, Michael A. Cruz, Ouafaâ Tahmaoui, Sébastien Baudart, Marcos Freire, Akira Homma, Kirsten Schneider-Ohrum, David W. Vaughn, Yannick Vanloubbeeck, Clarisse Lorin, Marie-Pierre Malice, Elena Caride, Lucile Warter
| published 22 Apr 2019 PLOS Pathogens
The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting 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.
Dengue virus (DENV) is responsible for the most widespread arboviral disease affecting humans. A pre-existing suboptimal immunity to DENV is accepted as being the major risk factor for severe dengue. Thus, if vaccination does not elicit optimal DENV-specific immunity, a vaccine might, instead, increase the risk of severe dengue in vaccinated individuals, as seen with the only licensed vaccine (Dengvaxia) in children naïve to DENV at vaccination. It is thus crucial to assess dengue vaccine safety at the earliest development stages, ideally in the preclinical stage. The dengue macaque model has been used to assess preclinical efficacy of dengue vaccines, with post-challenge DENV replication as the sole efficacy endpoint. However, this model had not predicted the Dengvaxia-associated safety signals. Here we characterized, in macaques, a dengue purified and inactivated vaccine (DPIV) candidate for its immunogenicity and efficacy/safety. 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 DPIV development, this improved dengue macaque model may also be instrumental for early assessment of efficacy/safety of future dengue vaccines.