Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus

Autor: Kiyoon Ko, Ivelin S. Georgiev, Yongping Yang, M. Gordon Joyce, Mallika Sastry, Joan O. Ngwuta, Paul V. Thomas, Baoshan Zhang, Lei Chen, Yaroslav Tsybovsky, Tongqing Zhou, Aliaksandr Druz, Peter D. Kwong, Wing-Pui Kong, Guillaume Stewart-Jones, Jeffrey C. Boyington, Man Chen, John R. Mascola, Barney S. Graham
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Protein Conformation
Physiology
Glycobiology
Antibody Response
lcsh:Medicine
Antigen Processing and Recognition
Antibodies
Viral
Biochemistry
Mice
Immunogenicity
Vaccine
Immune Physiology
Medicine and Health Sciences
Public and Occupational Health
lcsh:Science
Immune Response
chemistry.chemical_classification
Mice
Inbred BALB C
Vaccines
Immune System Proteins
Multidisciplinary
Physics
Viral Vaccine
Immunogenicity
Vaccination and Immunization
Respiratory Syncytial Viruses
3. Good health
Physical sciences
Chemistry
Titer
Female
Antibody
Research Article
Chemical physics
Immunology
Biology
complex mixtures
Antibodies
Virus
03 medical and health sciences
Immune system
Antigen
Animals
Humans
Antigens
Glycoproteins
lcsh:R
Biology and Life Sciences
Proteins
Viral Vaccines
Dimers (Chemical physics)
Virology
Mice
Inbred C57BL
HEK293 Cells
030104 developmental biology
chemistry
biology.protein
lcsh:Q
Preventive Medicine
Glycoprotein
Viral Fusion Proteins
Zdroj: PLOS ONE
PLoS ONE, Vol 11, Iss 7, p e0159709 (2016)
PLoS ONE
ISSN: 1932-6203
Popis: Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness worldwide, particularly in infants, young children, and the elderly. Although no licensed vaccine is currently available, an engineered version of the metastable RSV fusion (F) surface glycoprotein—stabilized in the pre-fusion (pre-F) conformation by “DS-Cav1” mutations—elicits high titer RSV-neutralizing responses. Moreover, pre-F-specific antibodies, often against the neutralization-sensitive antigenic site Ø in the membrane-distal head region of trimeric F glycoprotein, comprise a substantial portion of the human response to natural RSV infection. To focus the vaccine-elicited response to antigenic site Ø, we designed a series of RSV F immunogens that comprised the membrane-distal head of the F glycoprotein in its pre-F conformation. These “head-only” immunogens formed monomers, dimers, and trimers. Antigenic analysis revealed that a majority of the 70 engineered head-only immunogens displayed reactivity to site Ø-targeting antibodies, which was similar to that of the parent RSV F DS-Cav1 trimers, often with increased thermostability. We evaluated four of these head-only immunogens in detail, probing their recognition by antibodies, their physical stability, structure, and immunogenicity. When tested in naïve mice, a head-only trimer, half the size of the parent RSV F trimer, induced RSV titers, which were statistically comparable to those induced by DS-Cav1. When used to boost DS-Cav1-primed mice, two head-only RSV F immunogens, a dimer and a trimer, boosted RSV-neutralizing titers to levels that were comparable to those boosted by DS-Cav1, although with higher site Ø-directed responses. Our results provide proof-of-concept for the ability of the smaller head-only RSV F immunogens to focus the vaccine-elicited response to antigenic site Ø. Decent primary immunogenicity, enhanced physical stability, potential ease of manufacture, and potent immunogenicity upon boosting suggest these head-only RSV F immunogens, engineered to retain the pre-fusion conformation, may have advantages as candidate RSV vaccines.
Databáze: OpenAIRE
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