Impact of Dengue Virus Serotype 2 Strain Diversity on Serological Immune Responses to Dengue

Sarah L. Keasey; Jessica L. Smith; Stefan Fernandez; Anna P. Durbin; Bryan M. Zhao; Robert G. Ulrich

doi:10.1021/acsinfecdis.8b00185

Impact of Dengue Virus Serotype 2 Strain Diversity on Serological Immune Responses to Dengue

Sarah L. Keasey, Jessica L. Smith, Stefan Fernandez, Anna P. Durbin, Bryan M. Zhao, Robert G. Ulrich

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Dengue is a mosquito-borne disease caused by four dengue virus serotypes (DENV1-4) that are loosely categorized by sequence commonalities and antibody recognition profiles. The highly variable envelope protein (E) that is prominently displayed on the surface of DENV is an essential component of vaccines currently under development, yet the impact of using single strains to represent each serotype in tetravalent vaccines has not been adequately studied. We synthesized chimeric E by replacing highly variable residues from a dengue virus serotype 2 vaccine strain (PUO-218) with those from 16 DENV2 lineages spanning 60 years of antigen evolution. Examining sera from human and rhesus macaques challenged with single strains of DENV2, antibody-E interactions were markedly inhibited or enhanced by residues mainly focused within a 480 Å ² footprint displayed on the E backbone. The striking impact of E diversity on polyclonal immune responses suggests that frequent antigen updates may be necessary for vaccines to counter shifts in circulating strains.

Original language	English (US)
Pages (from-to)	1705-1717
Number of pages	13
Journal	ACS Infectious Diseases
Volume	4
Issue number	12
DOIs	https://doi.org/10.1021/acsinfecdis.8b00185
State	Published - Oct 22 2018

Keywords

antibody response
dengue strain variability
dengue vaccine
dengue virus
dengue virus envelope
protein microarray

ASJC Scopus subject areas

Infectious Diseases

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10.1021/acsinfecdis.8b00185

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title = "Impact of Dengue Virus Serotype 2 Strain Diversity on Serological Immune Responses to Dengue",

abstract = " Dengue is a mosquito-borne disease caused by four dengue virus serotypes (DENV1-4) that are loosely categorized by sequence commonalities and antibody recognition profiles. The highly variable envelope protein (E) that is prominently displayed on the surface of DENV is an essential component of vaccines currently under development, yet the impact of using single strains to represent each serotype in tetravalent vaccines has not been adequately studied. We synthesized chimeric E by replacing highly variable residues from a dengue virus serotype 2 vaccine strain (PUO-218) with those from 16 DENV2 lineages spanning 60 years of antigen evolution. Examining sera from human and rhesus macaques challenged with single strains of DENV2, antibody-E interactions were markedly inhibited or enhanced by residues mainly focused within a 480 {\AA} 2 footprint displayed on the E backbone. The striking impact of E diversity on polyclonal immune responses suggests that frequent antigen updates may be necessary for vaccines to counter shifts in circulating strains. ",

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author = "Keasey, {Sarah L.} and Smith, {Jessica L.} and Stefan Fernandez and Durbin, {Anna P.} and Zhao, {Bryan M.} and Ulrich, {Robert G.}",

note = "Funding Information: Funding was provided to R.G.U. and S.F. by the Military Infectious Disease Research Program, project S0453_14_AF. This research was supported in part by the National Academies of Sciences, Engineering, and Medicine through a National Research Council (NRC) research associateship awarded to J.L.S. and by an appointment of S.L.K. and B.M.Z. to the Postgraduate Research Participation Program administered by Oak Ridge Institute for Science and Education through an interagency agreement with the U.S. Department of Energy. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

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AU - Zhao, Bryan M.

AU - Ulrich, Robert G.

N1 - Funding Information: Funding was provided to R.G.U. and S.F. by the Military Infectious Disease Research Program, project S0453_14_AF. This research was supported in part by the National Academies of Sciences, Engineering, and Medicine through a National Research Council (NRC) research associateship awarded to J.L.S. and by an appointment of S.L.K. and B.M.Z. to the Postgraduate Research Participation Program administered by Oak Ridge Institute for Science and Education through an interagency agreement with the U.S. Department of Energy. Publisher Copyright: © 2018 American Chemical Society.

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N2 - Dengue is a mosquito-borne disease caused by four dengue virus serotypes (DENV1-4) that are loosely categorized by sequence commonalities and antibody recognition profiles. The highly variable envelope protein (E) that is prominently displayed on the surface of DENV is an essential component of vaccines currently under development, yet the impact of using single strains to represent each serotype in tetravalent vaccines has not been adequately studied. We synthesized chimeric E by replacing highly variable residues from a dengue virus serotype 2 vaccine strain (PUO-218) with those from 16 DENV2 lineages spanning 60 years of antigen evolution. Examining sera from human and rhesus macaques challenged with single strains of DENV2, antibody-E interactions were markedly inhibited or enhanced by residues mainly focused within a 480 Å 2 footprint displayed on the E backbone. The striking impact of E diversity on polyclonal immune responses suggests that frequent antigen updates may be necessary for vaccines to counter shifts in circulating strains.

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Impact of Dengue Virus Serotype 2 Strain Diversity on Serological Immune Responses to Dengue

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