Persistence of Circulating Memory B Cell Clones with Potential for Dengue Virus Disease Enhancement for Decades following Infection

Abstract

Symptomatic dengue virus infection ranges in disease severity from an influenza-like illness to life-threatening shock. One model of the mechanism underlying severe disease proposes that weakly neutralizing, dengue serotype cross-reactive antibodies induced during a primary infection facilitate virus entry into Fc receptor-bearing cells during a subsequent secondary infection, increasing viral replication and the release of cytokines and vasoactive mediators, culminating in shock. This process has been termed antibody-dependent enhancement of infection and has significantly hindered vaccine development. Much of our understanding of this process has come from studies using mouse monoclonal antibodies (MAbs); however, antibody responses in mice typically exhibit less complexity than those in humans. A better understanding of the humoral immune response to natural dengue virus infection in humans is sorely needed. Using a high-efficiency human hybridoma technology, we isolated 37 hybridomas secreting human MAbs to dengue viruses from 12 subjects years or even decades following primary or secondary infection. The majority of the human antibodies recovered were broadly cross-reactive, directed against either envelope or premembrane proteins, and capable of enhancement of infection in vitro; few exhibited serotype-specific binding or potent neutralizing activity. Memory B cells encoding enhancing antibodies predominated in the circulation, even two or more decades following infection. Mapping the epitopes and activity of naturally occurring dengue antibodies should prove valuable in determining whether the enhancing and neutralizing activity of antibodies can be separated. Such principles could be used in the rational design of vaccines that enhance the induction of neutralizing antibodies, while lowering the risk of dengue shock syndrome. D engue viruses (DENV) are expanding globally with an estimated 50 to 100 million cases of DENV infection occurring worldwide annually, and more than 20,000 associated deaths. It is now estimated that approximately one-fifth of the world population is at risk of infection by DENV (9, 12, 13). Dengue is also threatening the continental United States. More than 25 cases of locally acquired infection were reported in Key West, Florida, in 2009 and 2010 (1). Symptomatic dengue disease ranges in severity from an influenza-like illness to life-threatening hemorrhagic fever or shock. Understanding the pathogenesis of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is of central importance in the rational development of antiviral for treatment and vaccines to prevent dengue disease (11,49).The DENV complex consists of four serotypes. Infection with a single serotype leads to antibody responses that cross-react with all serotypes (14). Despite the cross-reactivity, individuals only develop protective immunity against the serotype responsible for infection (14,43). Human studies have established clearly that the risk of progressing to DHF is greater during secondary than during prim...

RETRACTED: Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity

“…To more fully explore the significance of the EDI/EDII region, we examined the epitope target of the potently neutralizing DENV-3-specific human monoclonal NAb 5J7 (8,10), which was recovered from a donor (donor 105) previously infected with DENV-3. To identify the 5J7 epitope, we generated a comprehensive library of DENV-3 E proteins, in which every residue was separately mutated (1,400 total mutants).…”

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

“…With other Ags this may not be the case. For example, in dengue virus, subneutralizing cross-reactive Abs and crossreactive memory B cells are thought to play a major pathogenic role in dengue hemorrhagic fever during secondary infections (70)(71)(72). Our findings suggest that polyvalent vaccines may be a double-edged sword: effective in cases in which there are no shared epitopes or if conserved epitopes are neutralizing and detrimental in cases in which conserved epitopes are present, but polymorphic or strain-specific epitopes are critical for neutralization.…”

Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus

“…We tested the ability of five dengue sera and 11 plasmablast-derived mAbs to enhance ZIKV infection using a human FcγR-bearing monocytic cell line, U937. The U937 cell line is widely used to study ADE of DENV infection, and it is not typically permissive to high levels of DENV infection in the absence of enhancing antibodies (17). The five dengue sera tested were all acute samples from DENV2-infected patients, including patients 31, 32, 33, and 39 from whose plasmablasts the mAbs in this study were derived.…”