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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?
GENOME SEQUENCE TO PROTEIN AND PROTEOME…
STRUCTURE
FUNCTION
INTERACTION
DNA/RNA
PROTEIN
COMPOUND
SYSTEMS
INFRASTRUCTURE
APPLICATIONS
RICE
THERAPEUTICS
NANOTECHNOLOGY
DESIGN
EVOLUTION
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.
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.
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.
METHOD
Bayesian probabilities
Scaffold
Distance
bin
Atom type
Atom
type
Chimeric designed protein
Derive interatomic
distances
APPLICATIONS
• HIV
• Influenza
• Syphilis
• Anthrax
HIV
• HIV-1’s 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.
HIV
Epitopes in gp120 of HIV
HIV
Epitopes in gp41 of HIV
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.
INFLUENZA
Epitopes in hemagglutinin of Influenza A virus H3N2
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.
SYPHILIS
TprK of Treponema palladium
SYPHILIS
Discontinuous epitope in TprK protein of Treponema palladium
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.
ANTHRAX
Protective antigen of Bacillus anthracis
ANTHRAX
Discontinuous epitope in protective antigen domain IV of Bacillus anthracis
RESULTS
Epitope in gp120
Epitope in chimeric construct
RESULTS
Epitope in hemagglutinin
Epitope in chimeric construct
ACKNOWLEDGEMENTS
Current group members: Past group members:
•Adrian Laurenzi
•Brian Buttrick
•Chuck Mader
•Dominic Fisher
•Emilia Gan
•Ersin Emre Oren
•Gaurav Chopra
•George White
•Hernan Zamalloa
•Jason North
•Jeremy Horst
•Ling-Hong Hung
•Matthew Clark
•Manish Manish
•Michael Shannon
•Michael Zhou
•Omid Zarei
•Raymond Zhang
•Stewart Moughon
•Thomas Wood
•Weerayuth Kittichotirat
•Aaron Chang
•Aaron Goldman
•Brady Bernard
•Cyrus Hui
•David Nickle
•Duangdao Wichadukul
•Duncan Milburn
•Ekachai Jenwitheesuk
•Gong Cheng
•Imran Rashid
•Jason McDermott
•Juni Lee
•Kai Wang
•Marissa LaMadrid
•Michael Inouye
•Michal Guerquin
•Nipa Jongkon
•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
ACKNOWLEDGEMENTS
Collaborators:
Funding agencies:
•BGI
- Gane Wong
- Jun Yu
- Jun Wang
- et al.
•BIOTEC/KMUTT
•MSE
- Mehmet Sarikaya
- Candan Tamerler
- et al.
•UW Microbiology
- James Staley
- John Mittler
- Michael Lagunoff
- Roger Bumgarner
- Wesley Van Voorhis
- et al.
•National Institutes of Health
•National Science Foundation
-DBI
-IIS
•Searle Scholars Program
•Puget Sound Partners in Global Health
•Washington Research Foundation
•UW
-Advanced Technology Initiative
-TGIF
Budget:
• ~US$1 million/year total costs