Proof of principle for epitope-focused vaccine design.
Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] PhD Program in Computational Biology, Instituto Gulbenkian Ciência and Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras 2780-157, Portugal [3] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Bruno E
BE
Correia
The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
John T
JT
Bates
The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA.
Rebecca J
RJ
Loomis
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Gretchen
G
Baneyx
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Chris
C
Carrico
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Joseph G
JG
Jardine
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Peter
P
Rupert
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Colin
C
Correnti
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Oleksandr
O
Kalyuzhniy
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Vinayak
V
Vittal
The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA.
Mary J
MJ
Connell
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Eric
E
Stevens
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Alexandria
A
Schroeter
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Man
M
Chen
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Skye
S
Macpherson
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Andreia M
AM
Serra
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Yumiko
Y
Adachi
1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA [2].
Margaret A
MA
Holmes
1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Yuxing
Y
Li
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Rachel E
RE
Klevit
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Barney S
BS
Graham
1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
Richard T
RT
Wyatt
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
David
D
Baker
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Roland K
RK
Strong
1] The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pathology, Microbiology and Immunology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA [3] Department of Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA.
James E
JE
Crowe
The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA.
Philip R
PR
Johnson
1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
William R
WR
Schief
D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000032:analysis / Q000276:immunology; D000914:Antibodies, Viral / Q000032:analysis / Q000276:immunology; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009500:Neutralization Tests; D011487:Protein Conformation; D055550:Protein Stability; D022261:Respiratory Syncytial Virus Vaccines / Q000737:chemistry* / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000737:chemistry / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes; D022261:Respiratory Syncytial Virus Vaccines