Live Attenuated Tetravalent Dengue Virus Host Range Vaccine Is Immunogenic in African Green Monkeys following a Single Vaccination

Abstract

The causative agent of dengue fever, dengue virus (DENV), is transmitted by mosquitoes, and as distribution of these insects has expanded, so has dengue-related disease. DENV is a member of the Flaviviridae family and has 4 distinct serotypes (DENV-1, -2, -3, and -4). No lasting cross protection is afforded to heterologous serotypes following infection by any one of the individual serotypes. The presence of nonneutralizing antibodies to one serotype can facilitate the occurrence of more-severe dengue hemorrhagic fever through immune enhancement upon infection with a second serotype. For this reason, the development of a safe, tetravalent vaccine to produce a balanced immune response to all four serotypes is critical. We have developed a novel approach to produce safe and effective live-attenuated vaccines for DENV and other insect-borne viruses. Host range (HR) mutants of each DENV serotype were created by truncating transmembrane domain 1 of the E protein and selecting for strains of DENV that replicated well in insect cells but not mammalian cells. These vaccine strains were tested for immunogenicity in African green monkeys (AGMs). No vaccine-related adverse events occurred. The vaccine strains were confirmed to be attenuated in vivo by infectious center assay (ICA). Analysis by 50% plaque reduction neutralization test (PRNT 50 ) established that by day 62 postvaccination, 100% of animals seroconverted to DENV-1, -2, -3, and -4. Additionally, the DENV HR tetravalent vaccine (HR-Tet) showed a tetravalent anamnestic immune response in 100% (16/16) of AGMs after challenge with wild-type (WT) DENV strains. IMPORTANCEWe have generated a live attenuated viral (LAV) vaccine capable of eliciting a strong immune response in African green monkeys (AGMs) in a single dose. This vaccine is delivered by injecting one of four attenuated serotypes into each limb of the animal. 100% of animals given the vaccine generated antibodies against all 4 serotypes, and this response was found to be balanced in nature. This is also one of the first studies of dengue in AGMs, and our study suggests that viremia and antibody response in AGMs may be similar to those seen in DENV infection in humans.

Ancient hybridization and strong adaptation to viruses across African vervet monkey populations

“…Vervet monkeys (genus Chlorocebus , also known as African green monkeys), are highly abundant in savannahs and riverine forests throughout sub-Saharan Africa, as well as on several Caribbean islands where they were introduced during the colonial era. There is a long history of research on vervet monkeys, ranging from studies of their social behavior 1 , 2 to their use as an important model for a variety of human diseases 3 and in vaccine research 4 – 6 . Vervet research colonies have been established, one of which is currently being genetically characterized 7 , 8 .…”

Dengue: Status of current and under‐development vaccines

“…Tetravalent vaccine for dengue that comprises four viral strains carrying host-range (HR) mutations, generated by truncating a transmembrane segment of the envelope protein. 66…”

Epigenetic clock and methylation studies in vervet monkeys

“…Beyond applications in aging studies, animals from VRC are used in a wide range of research in areas such as the efficacy and enhancement of vaccines for infectious diseases, e.g., influenza and dengue [54][55][56]; investigations of diabetes, metabolic disease, and obesity [57][58][59]; and the development of novel non-invasive biomedical imaging methodologies [60,61].…”