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Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory
Syncytial Virus Lin Bai
Huilin Li’s Lab 03/31/2014
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Why I Think You Should Know About This Work
• In this paper, researchers used structural biology to design the key ingredient of a vaccine against a dangerous childhood disease, RSV.
• Three other studies published last fall exploited similar strategies to design a vaccine for another intractable infection, HIV.
• This work was ranked by Science as a runner-up for Breakthrough of the Year 2013. 2
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Why I am Interested in This Work
• I work on macromolecular structural biology and this paper proved the value of structural biology to vaccine design.
• This groundbreaking work may point the way toward vaccines for hepatitis C, dengue, West Nile, and other viruses.
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Background
• Respiratory syncytial virus (RSV) hospitalizes millions of infants and kills 160,000 kids each year.
• RSV attaches to cell via F fusion and G attachment glycoproteins.
• Clinical evidences show that RSV F-specific antibodies can protect against disease.
• A monoclonal antibody on the market, palivizumab, can cut the risk of hospitalization in half.
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• To mediate virus-cell entry, the RSV F glycoprotein transits from a metastable prefusion conformation to a stable postfusion conformation.
J. S. McLellan et al., Science 340, 1113–1117 (2013)
J Virol. Aug 2011; 85(15): 7788–7796.
postfusion Prefusion with antibody D25
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• To mediate virus-cell entry, the RSV F glycoprotein transits from a metastable prefusion conformation to a stable postfusion conformation.
J. S. McLellan et al., Science 340, 1113–1117 (2013)
J Virol. Aug 2011; 85(15): 7788–7796.
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• In this paper, to enhance elicitation of similarly potent antibodies, authors engineered soluble variants of RSV F with stably exposed antigenic site 0.
• These variants were then characterized antigenically and crystallographically and tested for immunogenicity in mice and nonhuman primates (rhesus macaques).
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Structure-Based Vaccine Strategy
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Engineering of RSV F Antigens
• Antigenic site Ø was chosen as the target site
• To stably present antigenic site Ø in the absence of antibody D25, cysteine pairs or cavity-filling hydrophobic substitutions were introduced.
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Antigenic and physical properties of engineered RSV F glycoprotein variants
• More than 100 RSV F variants were constructed, expressed and tested for binding to D25 and motavizumab, and for physical stability.
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Introduction of cysteine pairs
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Antigenic and physical properties of engineered RSV F glycoprotein variants
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Antigenic and physical properties of engineered RSV F glycoprotein variants
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Immunogenicity of Antigenic Site Ø– Stabilized RSV F
• RSV F glycoproteins engineered to display antigenic site Ø elicit neutralizing titers significantly higher than those elicited by postfusion F.
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Physical stability and Structural mimicry of site Ø versus immunogenicity.
• Increasing site Ø stability can increase protective titers elicited upon immunization.
• Enhancing structural mimicry of antigenic site Ø in its D25-bound conformation appears to have similar effect.
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Antigenic analysis of sera from immunized macaques
• Sera with immobilized Ds-Cav1 has the highest binding response.
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Correlation of immunogenicity and antigenic specificity of immunized macaque
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Conclusions
• Structural biology can be used in vaccine development to identify key sites by which to disable a pathogen, to pinpoint residue substitutions that inactivate toxoids, to stabilize select conformations of a subunit antigen, and to determine antibody antigen complexes.
• With site-specific vaccine strategies, selection of an appropriate target site is of crucial importance. Potency played a key role in the selection of site Ø as a vaccine target.
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Take-Home Message
• This paper shows a very important and useful structural biology based vaccine development strategy.
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• That’s all. • Thanks!