Dengue-2 Vaccine: Viremia and Immune Responses in Rhesus Monkeys

Abstract

Studies were undertaken in Indian rhesus monkeys ( Macaca mulatta ) to determine the safety, potency, immunogenicity, and mosquito infectivity of a small-plaque, temperature-sensitive variant of dengue type 2 (DEN-2) virus, a vaccine candidate. Fifteen monkeys were inoculated subcutaneously with the vaccine virus, ten receiving 10 3.1 plaque-forming units (PFU) and five receiving 10 4.5 PFU. After primary immunization, viremia was detected in only one monkey, a recipient of the higher dose of vaccine. The recovered virus had the same growth characteristics as the vaccine strain. Aedes aegypti mosquitoes did not become infected when they were allowed to feed on monkeys that received the lower dose of vaccine. As expected, the immunization produced no evidence of illness in any of the animals. A dose response to vaccine was detected; all five of the high-dose recipients developed neutralizing antibodies, whereas only five of ten low-dose recipients did so. In both groups, neutralizing antibody was often transient. Its presence at 30 days did not always correlate with protection from viremia in those animals challenged 4 to 6 months after vaccination with wild-type DEN-2 virus. However, immunized animals developed anamnestic antibody responses after challenge, and none demonstrated adverse effects to infection. Reimmunization of monkeys 4 months after primary immunization led to the production of low-titered but persistent neutralizing antibody which protected the animals from a wild-type virus challenge.

Induction of Neutralizing Antibodies and Partial Protection From Viral Challenge in Macaca Fascicularis Immunized With Recombinant Dengue 4 Virus Envelope Glycoprotein Expressed in Pichia Pastoris

“…27 It has been demonstrated that neutralizing antibody is important for protection against infection with dengue virus. Similar to previous reports, 10,28 the presence of neutralizing antibody in our animals did not correlate with protection from viremia. All vaccinated monkeys had the same neutralizing antibody titer (1:30) at the time of challenge.…”

Viremia and antibody response in green monkeys (Chlorocebus aethiops sabaeus) infected with dengue virus type 2: A potential model for vaccine testing

“…Green monkeys inoculated with 10 4 PFU of DEN2 virus developed viremias with an average duration of over five days. These results are comparable with those reported for the species most commonly used for the study of DEN infection and the evaluation of candidates for vaccines in nonhuman primates, such as rhesus (9,36,39) and cynomolgus macaques (39)(40)(41).…”

In vitro virulence marker: growth of dengue-2 virus in human leukocyte suspension cultures

“…Included in these studies were the large-plaque, temperature-resistant PR-159 parent DEN-2 strain and two derivative small-plaque, temperature-sensitive strains, one grown in primary African green monkey kidney (S-1 PGMK) cells and the other in fetal rhesus lung cells (S-1 vaccine strain). Each of the small plaque variants demonstrated reduced virulence for monkeys as compared with the parent strain (10,14), but only the S-1 PGMK small-plaque variant showed reduced growth in monolayer cultures of human monocytes as compared with parental strain. It was concluded that replication in adherent monocytes in vitro did not correlate with virulence for monkeys in vivo.…”

“…An important constraint in the selection and evaluation of DEN virus strains as candidate vaccines is the absence of a simple marker of human virulence. The property of DEN viruses to produce viremic infection and to elicit an antibody response in subhuman primates is currently considered to be the strongest correlate of virulence for man (14). However, the use of subhuman primates to characterize the biological properties of DEN viruses is costly.…”