Implications of Dengue Virus Maturation on Vaccine Induced Humoral Immunity in Mice.

Connor A P Scott,Natalee D Newton,David A Muller,Alberto A Amarilla,Jody Hobson-Peters,Daniel Watterson,Naphak Modhiran,Roy A Hall,Keith J Chappell,Paul R Young,Summa Bibby

doi:10.3390/v13091843

Abstract

The use of dengue virus (DENV) vaccines has been hindered by the complexities of antibody dependent enhancement (ADE). Current late-stage vaccine candidates utilize attenuated and chimeric DENVs that produce particles of varying maturities. Antibodies that are elicited by preferentially exposed epitopes on immature virions have been linked to increased ADE. We aimed to further understand the humoral immunity promoted by DENV particles of varying maturities in an AG129 mouse model using a chimeric insect specific vaccine candidate, bDENV-2. We immunized mice with mature, partially mature, and immature bDENV-2 and found that immunization with partially mature bDENV-2 produced more robust and cross-neutralizing immune responses than immunization with immature or mature bDENV-2. Upon challenge with mouse adapted DENV-2 (D220), we observed 80% protection for mature bDENV-2 vaccinated mice and 100% for immature and partially mature vaccinated mice, suggesting that protection to homotypic challenge is not dependent on maturation. Finally, we found reduced in vitro ADE at subneutralising serum concentrations for mice immunized with mature bDENV-2. These results suggest that both immature and mature DENV particles play a role in homotypic protection; however, the increased risk of in vitro ADE from immature particles indicates potential safety benefits from mature DENV-based vaccines.

Highlights

dengue virus (DENV), a member of the Flaviviridae, has four distinct serotypes (1–4) and is transmitted to vertebrate hosts by Aedes mosquitos
We showed that immunization with mature, immature, or partially mature bDENV-2 resulted in robust IgG responses to DENV-2 and protection from DENV-2 D220 challenge in an AG129 model
We observed that immunization with partially mature bDENV-2 adjuvanted with QA resulted in higher neutralization titres for all four serotypes despite having similar total IgG titres

Summary

Introduction

DENV, a member of the Flaviviridae, has four distinct serotypes (1–4) and is transmitted to vertebrate hosts by Aedes mosquitos. While often causing a self-limiting febrile illness, known as dengue fever, it can result in severe dengue disease, which is characterized by dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) [2,3]. Following infection with one serotype, humans develop both lifelong type-specific and transient cross serotype immunity [3,4]. Severe dengue disease is associated with secondary anamnestic dengue infection, which is likely explained in part by antibody dependent enhancement (ADE) [5]. ADE occurs when the antibodies developed from primary infection increase uptake of a secondary heterosubtypic virus on the Fc receptor bearing cells such as macrophages (extrinsic ADE) and modulate innate and adaptive immune responses (intrinsic ADE) to enhance infection [6]. Reducing the risk of ADE requires a vaccine/therapeutic strategy that provides broad and potent protection from all four serotypes

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