Animal models for dengue vaccine development and testing

Na, Woonsung; Yeom, Minjoo; Choi, Il-Kyu; Yook, Heejun; Song, Daesub

Until now, the use of NHP models has been limited to patho- genesis studies, testing the efficacy of vaccines that reduce viremia after challenge, and studies on the extent and specificity of the immune response. NHP dengue infection models include rhesus macaque and chimpanzees. Both NHP models showed detectable viremia when they were inoculated through subcutaneous or intradermal injections. Especially, rhesus macaque presented anti-DENV immune responses including T-cell responses and showed lymphadenopathy, splenomegaly, hepatomegaly, mild dehydration and mild rash. However, chimpanzee models do not show symptoms of DENV (Table 1) . Studies on the number of DENV required to infect NHPs have estimated that 10 4 -10 6 PFU of DENV are delivered by a mosquito bite, and subcutaneous inoculation of this titer could lead to sustainable viral replication [25] . However, NHPs have a limitation in that they do not present clinical symptoms [26, 27] . However, when DENV was administered at high concentration via the intravenous route, hemorrhage appeared 3 days after infection [28] . As DENV serotypes evoke cross-reactive antibody responses in humans, secondary DE NV infection of NHPs also induces increased viremia due to antibody-dependent enhancement (ADE) [27] , which was experimentally proven by the fact that injection of an anti DE NV monoclonal antibody leads to a 3-to 100-fold increase in viremia in NHPs [29] . Although NHPs exhibit immunologically similar responses, such as viremia and ADE, they do not develop vascular leaks, DHF, or DSS, which limits the use of NHP models for the study of pathogenesis/immunopathogenesis.