Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice.
Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defects during pregnancy. To develop candidate therapeutic agents against ZIKV, we isolated a panel of human monoclonal antibodies from subjects that were previously infected with ZIKV. We show that a subset of antibodies recognize diverse epitopes on the envelope (E) protein and exhibit potent neutralizing activity. One of the most inhibitory antibodies, ZIKV-117, broadly neutralized infection of ZIKV strains corresponding to African and Asian-American lineages. Epitope mapping studies revealed that ZIKV-117 recognized a unique quaternary epitope on the E protein dimer-dimer interface. We evaluated the therapeutic efficacy of ZIKV-117 in pregnant and non-pregnant mice. Monoclonal antibody treatment markedly reduced tissue pathology, placental and fetal infection, and mortality in mice. Thus, neutralizing human antibodies can protect against maternal-fetal transmission, infection and disease, and reveal important determinants for structure-based rational vaccine design efforts.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Gopal
G
Sapparapu
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Estefania
E
Fernandez
The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nurgun
N
Kose
Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri, USA.
Bin Cao
Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Julie M
JM
Fox
The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Robin G
RG
Bombardi
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Haiyan
H
Zhao
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Christopher A
CA
Nelson
Integral Molecular, Philadelphia, Pennsylvania, USA.
Aubrey L
AL
Bryan
Integral Molecular, Philadelphia, Pennsylvania, USA.
Trevor
T
Barnes
Integral Molecular, Philadelphia, Pennsylvania, USA.
Edgar
E
Davidson
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri, USA.|Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri, USA.
Indira U
IU
Mysorekar
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Daved H
DH
Fremont
Integral Molecular, Philadelphia, Pennsylvania, USA.
Benjamin J
BJ
Doranz
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri, USA.|Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.|Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, USA.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, Missouri, USA.
Michael S
MS
Diamond
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
James E
JE
Crowe
D000349:Africa; D000569:Americas; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D000918:Antibody Specificity; D001208:Asia; D001402:B-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D018604:Epitope Mapping; D005260:Female; D005315:Fetal Diseases / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D005333:Fetus / Q000276:immunology / Q000821:virology; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010920:Placenta / Q000276:immunology / Q000821:virology; D011247:Pregnancy; D055503:Protein Multimerization; D015996:Survival Rate; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology; D014765:Viral Vaccines / Q000737:chemistry / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*; D000071244:Zika Virus / Q000254:growth & development* / Q000276:immunology*; D000071243:Zika Virus Infection / Q000276:immunology* / Q000473:pathology / Q000821:virology*
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014764:Viral Proteins; D014765:Viral Vaccines