Attenuation and immunogenicity of recombinant yellow fever 17D-dengue type 2 virus for rhesus monkeys

Abstract

A chimeric yellow fever (YF)-dengue serotype 2 (dengue 2) virus was constructed by replacing the premembrane and envelope genes of the YF 17D virus with those from dengue 2 virus strains of Southeast Asian genotype. The virus grew to high titers in Vero cells and, after passage 2, was used for immunogenicity and attenuation studies in rhesus monkeys. Subcutaneous immunization of naive rhesus monkeys with the 17D-D2 chimeric virus induced a neutralizing antibody response associated with the protection of 6 of 7 monkeys against viremia by wild-type dengue 2 virus. Neutralizing antibody titers to dengue 2 were significantly lower in YF-immune animals than in YFnaive monkeys and protection against challenge with wild-type dengue 2 virus was observed in only 2 of 11 YF-immune monkeys. An anamnestic response to dengue 2, indicated by a sharp increase of neutralizing antibody titers, was observed in the majority of the monkeys after challenge with wild-type virus. Virus attenuation was demonstrated using the standard monkey neurovirulence test. The 17D-D2 chimera caused significantly fewer histological lesions than the YF 17DD virus. The attenuated phenotype could also be inferred from the limited viremias compared to the YF 17DD vaccine. Overall, these results provide further support for the use of chimeric viruses for the development of a new live tetravalent dengue vaccine.

Innate Immune Responses in Human Dendritic Cells Upon Infection by Chimeric Yellow-Fever Dengue Vaccine Serotypes 1–4

“…In conclusion, the activation/maturation of DCs associated with a strong induction of type I interferons, a restricted expression of TNF-␣, and no production of IL-10 suggests that the exposure of DCs to the ChimeriVax™-Dengue 1-4 chimera results in a tightly controlled inflammatory response and a potential adaptive immunity. Although these results are insufficient to predict the safety of the CYD1-4 vaccine candidates in humans, they are encouraging and, taken together with other in vitro and in vivo preclinical studies in mosquitoes and monkeys, 41,42 they support their safety and immunogenicity, which is consistent with clinical observations with other ChimeriVax™ vaccines. 4…”

Risk Factors for Dengue Virus Infection in Rural Amazonia: Population-based Cross-sectional Surveys

“…Three DENV seroconverters (Subjects 17, 172, and 229) also had > 3-fold increases in the PRNT titers of antibodies to YFV ( Table 3), suggesting that they might have been recently exposed to either wild-type YFV or yellow fever vaccine. However, given the very little (if any) cross-reactivity observed between the antibodies to DENV and YFV in PRNT, 28 we consider the large increases in DENV-specific PRNT antibody titers in these three subjects to be clearly diagnostic of recent exposure to the virus. The PRNT-confirmed seroconversion rate was therefore estimated as 3.67 episodes/100 person-years at risk (95% CI, 2.24-5.67 episodes/100 personyears).…”

The Synergistic Effect of Combined Immunization with a DNA Vaccine and Chimeric Yellow Fever/Dengue Virus Leads to Strong Protection against Dengue

“…Expression of the recombinant E protein was previously demonstrated in vitro , in BHK cells transfected with the pE1D2 plasmid, and results revealed that the t-PA signal sequence was able to mediate secretion of the ectodomain with expected molecular weight [20], which is an important characteristic for efficient humoral immune response activation by DNA vaccines [26]–[28]. The YF17D-D2, in its turn, is a live attenuated chimeric virus derived from the yellow fever 17D vaccine virus in which the pre-M and E genes were replaced by the corresponding sequences from DENV-2 [21], [29].…”