Genotype-specific neutralization and protection by antibodies against dengue virus type 3.
Dengue viruses (DENV) comprise a family of related positive-strand RNA viruses that infect up to 100 million people annually. Currently, there is no approved vaccine or therapy to prevent infection or diminish disease severity. Protection against DENV is associated with the development of neutralizing antibodies that recognize the viral envelope (E) protein. Here, with the goal of identifying monoclonal antibodies (MAbs) that can function as postexposure therapy, we generated a panel of 82 new MAbs against DENV-3, including 24 highly neutralizing MAbs. Using yeast surface display, we localized the epitopes of the most strongly neutralizing MAbs to the lateral ridge of domain III (DIII) of the DENV type 3 (DENV-3) E protein. While several MAbs functioned prophylactically to prevent DENV-3-induced lethality in a stringent intracranial-challenge model of mice, only three MAbs exhibited therapeutic activity against a homologous strain when administered 2 days after infection. Remarkably, no MAb in our panel protected prophylactically against challenge by a strain from a heterologous DENV-3 genotype. Consistent with this, no single MAb neutralized efficiently the nine different DENV-3 strains used in this study, likely because of the sequence variation in DIII within and between genotypes. Our studies suggest that strain diversity may limit the efficacy of MAb therapy or tetravalent vaccines against DENV, as neutralization potency generally correlated with a narrowed genotype specificity.
Brien
James D
JD
Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110, USA.
Austin
S Kyle
SK
Sukupolvi-Petty
Soila
S
O'Brien
Katie M
KM
Johnson
Syd
S
Fremont
Daved H
DH
Diamond
Michael S
MS
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000940:Antigenic Variation / Q000235:genetics; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D005838:Genotype; D006801:Humans; D007116:Immunization, Passive; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; C084188:E protein, Dengue virus type 3; D000939:Epitopes; D050505:Mutant Proteins; D014759:Viral Envelope Proteins; D014765:Viral Vaccines