DECEPTIVE IMPRINTING OF FMDV: MAPPING OF CAPSID HYPER-VARIABLE REGIONS BETWEEN TWO DISPARATE SAT2 STRAINS Tovhowani Ramulongo Lia Rotherham, Pamela Opperman,

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Presentation transcript:

DECEPTIVE IMPRINTING OF FMDV: MAPPING OF CAPSID HYPER-VARIABLE REGIONS BETWEEN TWO DISPARATE SAT2 STRAINS Tovhowani Ramulongo Lia Rotherham, Pamela Opperman, Jacques Theron, Elizabeth Reider, Francois Maree

Introduction ~ SAT2 is the most prevalent and diverse of all SAT serotypes ~ Recent incursion into North Africa and the Middle East ~ FMDV uses deceptive imprinting to decoy host immune response from vital conserved regions i.e. RGD ~ These decoy epitopes may convey some neutralizing activity or protection, but are largely strain specific ~ Genetically modified viruses provide a valuable tool for the manipulation of the biological properties of field and laboratory strains ~ This present a possible avenue towards design of safe and effective vaccines that provide broader protection against the diverse SAT2 field strains

Introduction ~ Masking of immunodominant epitopes may allow the immune system to refocus and recognize previously subdominant conserved epitopes that induce protection ~ Immune dampening strategy by replacing known hypervariable immunodominant epitope regions between two disparate strains ~ SAT2/ZIM/7/83 (topotype II) previously used as vaccine strain and the devastating SAT2/EGY/9/2012 (topotype VII) ~ This Egypt 2012 outbreak resulted in highest death rate of young animals

Aim To dampen and refocus the immunity towards neutralizing epitope regions of a SAT2 virus

Objectives ~ To predict hypervariable immunodominant epitope regions between two SAT2 viruses ~ To replace predicted antigenic regions of SAT2/ZIM/7/83 with the corresponding regions of SAT2/EGY/9/2012 ~ To characterize the epitope replaced mutants

Prediction of antigenic sites ~ Systematic analysis of the capsid proteins of SAT2/EGY/9/2012 and SAT2/ZIM/7/83 ~ Emphasis on regions of high amino acid variability ~ Flexible exposed structural loops of the viral capsid ~ Previously identified antigenic sites on SAT2/ZIM/7/83 or types A and O ~ Predicted epitope region of SAT2/EGY/9/2012 were introduced into the pSAT2 plasmid; a SAT2/ZIM/7/83 infectious clone

Mutant viruses GH-loop C-terminal VP1 VP3VP2 VAVDQMPS VVL 129 IETDRLPK AVF 189 HTNKTSFV VGDHTRVF 81 LGEHERVW 88 AKGG 108 SHNN 111 VYTKAA 135 KYTQQS 140 GH-loop C-terminal 43 LTNRTAFA 50 GH-loop vEGY HNN SAT2 vEGY epi SAT2 vEGY TQQS SAT2 vEGY site3 SAT2 vEGY EHER SAT2 vEGY VP2/VP3/VP1 SAT2 vEGY GH-loop SAT2 vEGY GH-loopSAT2 SAT2 vEGY C-term SAT2 vEGY GH & Ct SAT2 VP1 VP3VP2 2A Lab 3´UTR polyA IRES polyC S-frag SspIXmaI ZIM/7/83 EGY/9/12

VP1 site3 Visual pentamer display VP1 EHER VP1 HNN VP3 combo VP1 TQQS Cyan : VP1 Magenta : VP3 Green : VP2

Plaques morphology BHK-21IB-RS-2 CHO-K1 no plaques vEGY VP2/VP3/VP1 SAT2 vEGY GH-loopSAT2 SAT2 vEGY C-term SAT2 vEGY GH&Ct SAT2 no plaques ZZ-R-127 vSAT2

Antigenicity of epitope-replaced viruses

Antigenic profiling with mAbs ID5GG1GE11GD12DA10 vEGY epi SAT2 vEGY site3 SAT2 vEGY EHER SAT2 vEGY HNN SAT2 vEGY TQQS SAT2 vEGY GH-loop SAT2 vEGY C-term SAT2 vEGY GH&Ct SAT2 vEGY VP2/VP3/VP1 SAT2 vSAT2 used as reference with 100% binding

DA10 footprint Opperman et al Cyan : VP1 Magenta : VP3 Green : VP2 White : GH-loop

Conclusions ~ CHO-K1 cells were unable to sustain replication of vEGY GH &Ct SAT2 and vEGY GH- loopSAT2 SAT2 mutants ~ vEGY GH-loopSAT2 SAT2 ~ Reduction in cross reactivity against ZIM/7/83 and SAR/03/04 sera ~ vEGY VP3/VP3/VP1 SAT2 ~ Reduction in cross reactivity against ZIM/7/83 and SAR/03/04 sera ~ At least 60% reduction in reactivity to all mAbs ~ vEGY GH&Ct SAT2 ~ Increase in cross reactivity against SAR/03/04 sera ~ 30% reduction in binding to mAbs 1D5 and GD12 ~ vEGY site3 SAT2 ~ Reduction in cross reactivity against ZIM/7/83 and SAR/03/04 sera ~ 70% reduction in reactivity to mAb DA10

Collaborators Oxford University – Drs Elizabeth Fry and Abhay Kotecha Agricultural Research Council University of Pretoria -Prof Jacques Theron Pirbright Institute - Drs Bryan Charleston and Nick Juleaff Plum Island (USDA) – Dr Elizabeth Reider

Thank you Supervision and support: Dr Francois Maree and Team Travel sponsors :DTRA Whitehead Scientific GFRA for platform