Utility, Limitations, and Future of Non-Human Primates for Dengue Research and Vaccine Development

Abstract

Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.

Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus

“…Previously, we reported a strong negative correlation between pre-challenged Neut50 DENV titres and duration of viremia in macaques challenged with DENV after being exposed to different DENV vaccine formulations. Although some macaques with Neut50 titres >20 showed breakthrough viremia (23, 24.4, 5.5 and 28% after DENV-1, 2, 3 and 4 challenge, respectively) the viremia was shorter11. Furthermore, it has been shown in rhesus macaques that the serum IgG profiles and neutralization titres demonstrate that non-neutralizing, pan-reactive, and serotype-specific NAbs persist for over a year in DENV-infected macaques42.…”

“…This mechanism suggests that antibodies (Abs), generated in response to the primary infection with DENV, are not of sufficient concentration or avidity to neutralize a secondary infection with DENV of a different serotype, and may even facilitate its replication. ADE has been confirmed and demonstrated to occur in vitro , and has also been shown to drive higher loads of DENV in animal models101112. Another mechanism proposed for the development of DHF/DSS is the production of cross-reactive T-cell clones during the primary infection1314.…”

Characterization of a 2016 Clinical Isolate of Zika Virus in Non-human Primates

“…Since these mouse models are deficient in innate immune response, an immune competent animal model is needed. Non-human primates have been well documented as a more relevant animal model for flavivirus infections (Sariol and White, 2014, Zompi and Harris, 2012), and have been widely used for DENV and WNV pathogenesis studies and vaccine efficacy tests (Sariol and White, 2014). ZIKV was first isolated from a febrile rhesus macaques (Dick et al, 1952).…”

Evaluation of protection induced by a dengue virus serotype 2 envelope domain III protein scaffold/DNA vaccine in non-human primates

“…6). While these FRNT 50 titers associated with sterilizing immunity are considerably higher than what have been observed as a sterilizing protective neutralization threshold for humans vaccinated with LAV DENV vaccines [40], following natural infection [41] they are only two-fold greater than what has been observed for other vaccinated NHPs [42]. These findings suggest that recombinant protein vaccine-induced neutralizing antibodies may differ from antibodies raised by natural infection or LAV vaccination and that higher neutralizing antibody titers may have to be achieved by recombinant protein vaccines in macaques to establish sterilizing protection.…”