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.
Highlights
Dengue virus (DENV) is a mosquito-transmitted flavivirus responsible for 390 million human infections each year [1]
We identified amino acids on DENV1 recognized by type-specific neutralizing antibodies elicited by DENV1 vaccination
Our results indicate that the type-specific DENV1 response is remarkably focused on just two regions of the DENV1 envelope protein
Summary
Dengue virus (DENV) is a mosquito-transmitted flavivirus responsible for 390 million human infections each year [1]. Four related serotypes (DENV1-4) circulate in virtually all tropical and sub-tropical regions of the world [2]. While DENV infection is often subclinical, clinical symptoms of dengue fever (DF) include a self-limiting febrile illness, myalgia, rash, and retro-orbital pain [3]. A more severe clinical illness (dengue shock syndrome/dengue hemorrhagic fever) involving capillary leakage, thrombocytopenia, and hemorrhage has been associated with secondary infections by a heterologous DENV serotype and higher viral loads in vivo [4,5]. The incidence of severe DENV disease is rising globally due to increasing co-circulation of multiple DENV serotypes in endemic areas [2,6]. There are no specific treatments or approved vaccines for DENV infection
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