The type-specific neutralizing antibody response elicited by a dengue vaccine candidate is focused on two amino acids of the envelope protein

• Published in: PLoS pathogens Vol. 9; no. 12; p. e1003761
• Main Authors: VanBlargan, Laura A, Mukherjee, Swati, Dowd, Kimberly A, Durbin, Anna P, Whitehead, Stephen S, Pierson, Theodore C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2013; Public Library of Science (PLoS)
• Subjects: Amino Acids - chemistry; Amino Acids - genetics; Amino Acids - immunology; Antibodies; Antibodies, Neutralizing - biosynthesis; Antibodies, Viral; Antibody Formation - genetics; Antibody Specificity; Clinical Trials, Phase I as Topic; Dengue; Dengue fever; Dengue Vaccines - immunology; Dengue Virus - genetics; Dengue Virus - immunology; Disease; Dosage and administration; Epitope Mapping; Epitopes - chemistry; Epitopes - immunology; Experiments; Genomes; Health aspects; HEK293 Cells; Humans; Infections; Medical research; Medicine, Experimental; Models, Molecular; Mutagenesis, Site-Directed; Mutation; Physiological aspects; Prevention; Proteins; Vaccines; Viral antibodies; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology; United States; Antibodies, Neutralizing; Antibody Specificity; Epitope Mapping; Mutagenesis, Site-Directed; Dengue Vaccines; Humans; Viral Envelope Proteins; Models, Molecular; Epitopes; Antibodies, Viral; Amino Acids; Dengue Virus; HEK293 Cells; Antibody Formation; Clinical Trials, Phase I as Topic
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003761

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.