Potent neutralizing antibodies elicited by dengue vaccine in rhesus macaque target diverse epitopes

Autor: Georgina To'a Salazar, Elizabeth Thoryk, Danilo R. Casimiro, Qihui Wang, Benjamin J. Doranz, Weixu Meng, Daniel R. DiStefano, Kalpit A. Vora, Andrew J. Bett, Trevor Barnes, Jennifer M. Pfaff, Ningyan Zhang, Leike Li, Zhiqiang An, Melanie Horton
Jazyk: angličtina
Rok vydání: 2019
Předmět:
RNA viruses
Physiology
Monkeys
Dengue virus
Pathology and Laboratory Medicine
Antibodies
Viral
medicine.disease_cause
Biochemistry
Epitope
Dengue fever
Epitopes
Immune Physiology
Medicine and Health Sciences
Enzyme-Linked Immunoassays
Biology (General)
Neutralizing antibody
Mammals
Vaccines
0303 health sciences
Immune System Proteins
biology
Viral Vaccine
030302 biochemistry & molecular biology
Eukaryota
Antibodies
Monoclonal
Animal Models
Vaccination
Infectious Diseases
Experimental Organism Systems
Medical Microbiology
Viral Pathogens
Viruses
Vertebrates
Pathogens
Antibody
Immunoglobulin Heavy Chains
West Nile virus
Macaque
Research Article
Primates
Infectious Disease Control
QH301-705.5
Immunology
Dengue Vaccines
Research and Analysis Methods
Microbiology
Antibodies
03 medical and health sciences
Virology
Old World monkeys
Genetics
medicine
Animals
Immunoassays
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
Dengue vaccine
030304 developmental biology
Flaviviruses
Rhesus Monkeys
Organisms
Biology and Life Sciences
Proteins
Dengue Virus
RC581-607
medicine.disease
Antibodies
Neutralizing
Macaca mulatta
Amniotes
Immunologic Techniques
Animal Studies
biology.protein
Immunoglobulin Light Chains
Parasitology
Immunologic diseases. Allergy
Cloning
Molecular Cloning
Zdroj: PLoS Pathogens, Vol 15, Iss 6, p e1007716 (2019)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: There is still no safe and effective vaccine against dengue virus infection. Epidemics of dengue virus infection are increasingly a threat to human health around the world. Antibodies generated in response to dengue infection have been shown to impact disease development and effectiveness of dengue vaccine. In this study, we investigated monoclonal antibody responses to an experimental dengue vaccine in rhesus macaques. Variable regions of both heavy chain (VH) and light chain (VL) were cloned from single antibody-secreting B cells. A total of 780 monoclonal antibodies (mAbs) composed of paired VH and VL were characterized. Results show that the vaccination induces mAbs with diverse germline sequences and a wide range of binding affinities. Six potent neutralizing mAbs were identified among 130 dengue envelope protein binders. Critical amino acids for each neutralizing antibody binding to the dengue envelope protein were identified by alanine scanning of mutant libraries. Diverse epitopes were identified, including epitopes on the lateral ridge of DIII, the I-III hinge, the bc loop adjacent to the fusion loop of DII, and the β-strands and loops of DI. Significantly, one of the neutralizing mAbs has a previously unknown epitope in DII at the interface of the envelope and membrane protein and is capable of neutralizing all four dengue serotypes. Taken together, the results of this study not only provide preclinical validation for the tested experimental vaccine, but also shed light on a potential application of the rhesus macaque model for better dengue vaccine evaluation and design of vaccines and immunization strategies.
Author summary Dengue virus (DENV) is a leading cause of human illness in the tropics and subtropics, with about 40% of the world’s population living in areas at risk for infection. There are four DENV serotypes. Patients who have previously been infected by one dengue serotype may develop more severe symptoms such as bleeding and endothelial leakage upon secondary infection with another dengue serotype. This study reports the extensive cloning and analysis of 780 monoclonal antibodies (mAbs) from single B cells of rhesus macaques after immunization with an experimental dengue vaccine. We identified a panel of potent neutralizing mAbs with diverse epitopes on the DENV envelope protein. Antibodies in this panel were found to bind to the lateral ridge of DIII, the I-III hinge, the bc loop adjacent to the fusion loop of DII, and the β-strands and the loops of DI. We also isolated one mAb (d448) that can neutralize all four dengue serotypes and binds to a novel epitope at the interface of the DENV envelope and membrane proteins. Further investigation of these neutralizing monoclonal antibodies is warranted for better vaccine efficacy evaluation and vaccine design.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje