title: The type-specific neutralizing antibody response elicited by a dengue vaccine candidate is focused on two amino acids of the envelope protein.
abstract: Dengue viruses are mosquito-borne flaviviruses that circulate in nature as four distinct serotypes (DENV1-4). These emerging pathogens are responsible for more than 100 million human infections annually. Severe clinical manifestations of disease are predominantly associated with a secondary infection by a heterotypic DENV serotype. The increased risk of severe disease in DENV-sensitized populations significantly complicates vaccine development, as a vaccine must simultaneously confer protection against all four DENV serotypes. Eliciting a protective tetravalent neutralizing antibody response is a major goal of ongoing vaccine development efforts. However, a recent large clinical trial of a candidate live-attenuated DENV vaccine revealed low protective efficacy despite eliciting a neutralizing antibody response, highlighting the need for a better understanding of the humoral immune response against dengue infection. In this study, we sought to identify epitopes recognized by serotype-specific neutralizing antibodies elicited by monovalent DENV1 vaccination. We constructed a panel of over 50 DENV1 structural gene variants containing substitutions at surface-accessible residues of the envelope (E) protein to match the corresponding DENV2 sequence. Amino acids that contribute to recognition by serotype-specific neutralizing antibodies were identified as DENV mutants with reduced sensitivity to neutralization by DENV1 immune sera, but not cross-reactive neutralizing antibodies elicited by DENV2 vaccination. We identified two mutations (E126K and E157K) that contribute significantly to type-specific recognition by polyclonal DENV1 immune sera. Longitudinal and cross-sectional analysis of sera from 24 participants of a phase I clinical study revealed a markedly reduced capacity to neutralize a E126K/E157K DENV1 variant. Sera from 77% of subjects recognized the E126K/E157K DENV1 variant and DENV2 equivalently (<3-fold difference). These data indicate the type-specific component of the DENV1 neutralizing antibody response to vaccination is strikingly focused on just two amino acids of the E protein. This study provides an important step towards deconvoluting the functional complexity of DENV serology following vaccination.
authors.affiliation: Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Laura A
authors.initials: LA
authors.lastname: VanBlargan
authors.affiliation: Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Swati
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Dowd
authors.affiliation: Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Durbin
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Whitehead
authors.affiliation: Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Pierson
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000096:biosynthesis*; D000914:Antibodies, Viral; D000917:Antibody Formation / Q000235:genetics; D000918:Antibody Specificity; D017321:Clinical Trials, Phase I as Topic; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
chemical_list: D000596:Amino Acids; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D000939:Epitopes; D014759:Viral Envelope Proteins