Enhanced dengue vaccine virus replication and neutralizing antibody responses in immune primed rhesus macaques

Michael K Mccracken,Rafael De La Barrera,Jeffrey R Currier,Heather Friberg,Kaitlin A Victor,Chandrika B Kannadka,Hayden C Siegfried,Gregory D Gromowski,David A Barvir,Caitlin H Kuklis,Kristin L Hatch,Shannon D Walls,Mark A Sanborn,Richard G Jarman,Wiriya Rutvisuttinunt,Adam T Waickman

doi:10.1038/s41541-021-00339-y

Michael K Mccracken, Rafael De La Barrera + Show 14 more

Open Access

https://doi.org/10.1038/s41541-021-00339-y

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Journal: npj Vaccines	Publication Date: May 21, 2021
Citations: 12	License type: open-access

Affiliation: Walter Reed Army Institute of Research

Abstract

Antibody-dependent enhancement (ADE) is suspected to influence dengue virus (DENV) infection, but the role ADE plays in vaccination strategies incorporating live attenuated virus components is less clear. Using a heterologous prime-boost strategy in rhesus macaques, we examine the effect of priming with DENV purified inactivated vaccines (PIVs) on a tetravalent live attenuated vaccine (LAV). Sera exhibited low-level neutralizing antibodies (NAb) post PIV priming, yet moderate to high in vitro ADE activity. Following LAV administration, the PIV primed groups exhibited DENV-2 LAV peak viremias up to 1,176-fold higher than the mock primed group, and peak viremia correlated with in vitro ADE. Furthermore, PIV primed groups had more balanced and higher DENV-1–4 NAb seroconversion and titers than the mock primed group following LAV administration. These results have implications for the development of effective DENV vaccine prime-boost strategies and for our understanding of the role played by ADE in modulating DENV replication.

Highlights

Dengue virus (DENV) is a positive-sense RNA virus transmitted by mosquito vectors, primarily of the genus Aedes, consisting of four types in the genus Flavivirus
We used a rhesus macaque model to examine the effect of monovalent, bivalent, and tetravalent purified inactivated vaccines (PIVs) priming on the replication of and immune responses to a DENV-1–4 tetravalent live attenuated vaccine (LAV)
Animals primed with bivalent or either of the monovalent formulations of PIV produced a level of DENV-2 LAV viremia peak, as well as neutralizing antibodies (NAb) titers, that were comparable to that of the DENV-2 challenge virus in unvaccinated control animals

Summary

INTRODUCTION

Dengue virus (DENV) is a positive-sense RNA virus transmitted by mosquito vectors, primarily of the genus Aedes, consisting of four types in the genus Flavivirus. Against DENV-2, the NAb GMT for the tetravalent the quality of the immune responses post LAV boost, and, primed group was significantly higher than that of the monoultimately, determine the feasibility of reducing the number of PIV valent (D3) and monovalent (D1) primed groups and was virus components required for this vaccination approach. Lower levels of in vitro ADE were observed geometric means of peak viremias were greater for the for DENV-4, with the tetravalent (4.4 mean fold-ADE) and bivalent monovalent (D1) (92-fold) and tetravalent (5.8-fold) primed groups (5.4 mean fold-ADE) groups being the highest

DISCUSSION

Ethics Statement

Findings

DATA AVAILABILITY STATEMENT