COMPUTATIONAL VACCINE DESIGN

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COMPUTATIONAL VACCINE DESIGN RAM
SAMUDRALA ASSOCIATE PROFESSOR UNIVERSITY OF
WASHINGTON How can we design vaccines based on
conformational epitopes and protein structure
prediction simulations?
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GENOME SEQUENCE TO PROTEIN AND PROTEOME
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INTRODUCTION

• Conformational epitopes are two or more nonlocal
  regions of an antigen that interact structurally
  at the atomic level, together with each other and
  with the antibody.
• Majority of B-cell epitopes are conformational.
• Protective antibodies recognize structural
  elements in the context of complete antigen
  structure.

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PROBLEMS

• Linear peptides corresponding to the epitopes are
  devoid of structural context of native antigen.
• Immune evasion mechanisms
• Conformational flexibility.
• Steric masking.
• Antigen variation.
• Presence of immunodominant decoy elements.

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RESEARCH DESIGN

• Aim
• Transform an immunological region (i.e., region
  which can induce antibody) to an antigenic region
  (i.e., region which can bind with antibody).
• Objectives
• Retaining the native structure of epitopes.
• Presenting the epitopes exposed to aqueous
  environment.
• Method
• Computational design of chimeric constructs by
  grafting epitopes in soluble/stable scaffolds.

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METHOD
Bayesian probabilities

• 
  Scaffold
• 
  
• 
  
• Chimeric designed protein

Derive interatomic distances
Atom type
Distance bin
Atom type
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APPLICATIONS

• HIV
• Influenza
• Syphilis
• Anthrax

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HIV

• HIV-1s extensive diversity is a major challenge
  for vaccine design strategies.
• The presence of segments that are nearly
  invariant in all HIV-1 M group strongly suggests
  that these conserved elements are both obligatory
  for viral viability and are therefore potential
  Achilles Heel of the virus.
• Our scaffold based vaccine design is based on
  conserved elements of viral spike protein gp120
  and gp41.

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HIV
Epitopes in gp120 of HIV
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Epitopes in gp41 of HIV
HIV
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INFLUENZA

• For Influenza, we are utilizing the epitopes in
  viral surface protein hemagglutinin(HA).
• Hemagglutin is responsible for receptor binding
  and membrane fusion of viral particles.
• We have selected 3 protective epitopes from HA1
  of Influenza A virus H3N2 A/Wuhan/359/95 strain.

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INFLUENZA
Epitopes in hemagglutinin of Influenza A virus
H3N2
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SYPHILIS

• Syphilis is caused by Treponema pallidum subsp.
  pallidum (T.pallidum), a highly virulent,
  invasive and genetically intractable spirochete.
• For Syphilis, our design is based on N-terminal
  region of outer membrane protein TprK, which has
  been shown to elicit opsonizing antibodies
  response.
• We have utilized a combination of structure
  prediction methods, immunological assays and a
  support vector machine based method for analyzing
  amino acid composition (CBTOPE) for the
  determination of discontinuous epitopes in TprK.

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TprK of Treponema palladium
SYPHILIS
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SYPHILIS
Discontinuous epitope in TprK protein of
Treponema palladium
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ANTHRAX

• Anthrax is caused by Bacillus anthracis, a
  gram-positive, spore forming, and rod-shaped
  bacterium.
• Anthrax toxin belongs to the family of bacterial
  AB toxins, composed of a single B subunit,
  protective antigen and two alternative A
  subunits edema factor and lethal factor.
• Protective antigen (PA) is the dominant antigen
  in both natural and vaccine-induced immunity to
  anthrax infection.
• We are exploiting the epitopes from receptor
  binding domain (Domain IV) of protective antigen.
  

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Protective antigen of Bacillus anthracis
ANTHRAX
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ANTHRAX
Discontinuous epitope in protective antigen
domain IV of Bacillus anthracis
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Epitope in gp120
Epitope in chimeric construct
RESULTS
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Epitope in hemagglutinin
Epitope in chimeric construct
RESULTS
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ACKNOWLEDGEMENTS

• Rob Braiser
• Renee Ireton
• Shu Feng
• Sarunya Suebtragoon
• Shing-Chung Ngan
• Shyamala Iyer
• Siriphan Manocheewa
• Somsak Phattarasukol
• Tianyun Liu
• Vanessa Steinhilb
• Vania Wang
• Yi-Ling Cheng
• Zach Frazier

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ACKNOWLEDGEMENTS

• Budget
• US1 million/year total costs