Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution.
The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ∼43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. Here, we used a well-characterized nonimmune human Ab-phage library and a panning strategy with proteoliposomes and cells to identify seven human nAbs against the receptor-binding domain (RBD) of the MERS-CoV Spike protein. These nAbs bind to three different epitopes in the RBD and human dipeptidyl peptidase 4 (hDPP4) interface with subnanomolar/nanomolar binding affinities and block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Escape mutant assays identified five amino acid residues that are critical for neutralization escape. Despite the close proximity of the three epitopes on the RBD interface, escape from one epitope did not have a major impact on neutralization with Abs directed to a different epitope. Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Xian-Chun
XC
Tang
Departments of Microbiology and Immunology and.
Sudhakar S
SS
Agnihothram
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Yongjun
Y
Jiao
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Jeremy
J
Stanhope
Departments of Microbiology and Immunology and.
Rachel L
RL
Graham
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Eric C
EC
Peterson
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Yuval
Y
Avnir
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Aimee St Clair
AS
Tallarico
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Jared
J
Sheehan
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and.
Quan
Q
Zhu
Departments of Microbiology and Immunology andEpidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 rbaric@ad.unc.edu wayne_marasco@dfci.harvard.edu.
Ralph S
RS
Baric
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and rbaric@ad.unc.edu wayne_marasco@dfci.harvard.edu.
Wayne A
WA
Marasco
D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000302:isolation & purification*; D000914:Antibodies, Viral / Q000276:immunology / Q000302:isolation & purification*; D000998:Antiviral Agents / Q000276:immunology / Q000302:isolation & purification; D005075:Biological Evolution; D021821:Communicable Diseases, Emerging / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D017934:Coronavirus / Q000235:genetics / Q000276:immunology*; D018352:Coronavirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008969:Molecular Sequence Data; D010802:Phylogeny; D064370:Spike Glycoprotein, Coronavirus / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*; D015047:Zoonoses / Q000188:drug therapy / Q000276:immunology / Q000401:mortality
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D007074:Immunoglobulin G; D064370:Spike Glycoprotein, Coronavirus; D014765:Viral Vaccines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
IGHV1–69; biodefense; emerging pathogen; humoral immunity; zoonosis