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CONFIDENTIAL, NOT FOR DISCLOSURE

This is confidential information of GSK Vaccines. This document is only for review and should not be shared further.

By Canelle Quentin

Dissertation submitted to the Faculty of Sciences of the Université Libre de Bruxelles, in partial fulfillment of the requirements for the degree of

Doctor in agronomy and bioengineering 2015

Jury Member:

Professor Erik Goormaghtigh, Président Professor Michel Vandenbranden, Secrétaire Professor Fabrice Homblé, Promoteur

phD Pol Harvengt

phD Robbert Van Der Most

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Acknowledgment

Avant de vous proposer la lecture de cette dissertation, il me tenait à coeur de remercier les différentes personnes qui ont contribué à la réalisation de celle-ci.

Ce travail n’aurait pu être réalisé sans l’aide du Professeur Fabrice Homblé qui a pris en charge l’encadrement académique ni sans l’aide du Dr Pol Harvengt qui a permis mon insertion au sein GSK vaccines.

Ce travail n’aurait pu se faire sans la société GSK vaccines qui a pris en charge le financement de la recherche. Je tiens à remercier tout particulièrement le département Vaccine Research dans son intégralité et plus particulièrement Marcelle Van Mechelen, Stéphane

Temmerman, Sandrine Tonon, Sofia Buonocore, Philippe Auquier, Nabila Amanchar, Hajar Larbi, Stéphanie Quique pour l’accueil chaleureux qui m’a été réservé au sein du groupe.

I also would like to warmly thank Robbert Van Der Most, Wivine Burny, Vincent Dewar, John Barlow and Benoit Collignon for the science discussions we had and their motivation.

Je désire également exprimer ma gratitude envers le Dr Yvon Corazza pour son initiation à la technologie BIAcore ainsi que pour sa créativité qu’il m’a permis de partager.

Je souhaite également remercier les membres du jury qui prêteront attention à ce manuscrit lors de leur lecture avisée.

Pour leur présence ou leur contribution variée mais néanmoins indispensable, je tiens également à rendre hommage à Muriel Feyssaguet et son équipe, Thierry Ollinger, Michaël Dehottay, Karine Gillard, Philippe Jehoulet, Geneviève Jadot, Sylvie Collignon, Géraldine Minet, Pilar Garcia, Bernard hoyois, Benoit Vincart, Cédric Vanderhaegen, Aurélie Chalon, Catherine Collignon, Carsten Walter, Caroline Hervé, Christel Verachtert, Christine Dantinne, Françoise Villée, Jennifer Dalcq, Laurie Dumont, Loïc Le Gourrierec, Margherita Coccia, Richard Ruez, Sara Lemos, Christine Van Eyck, Maryline Bauthier, Viviane Bechtold, Robert Van Den Berg, Abdelatif Elouahabi, Sandra Morel, Alessandra Ferraro, et l’équipe de Formulation.

D’un point de vue personnel, je tiens également à remercier mes proches et tout d’abord mes parents qui ont tout mis en œuvre pour m’aider à réussir mes entreprises, quelles qu’elles aient été ; ma compagne qui m’a supporté lors des moments de stress, de malheur mais aussi de bonheur; mon frère et ma sœur qui sont des soutiens constants et

indéfectibles ; mes grands–parents qui m’ont toujours encouragé à leur manière ; mes amis qui auront toujours pris la peine de s’inquiéter pour moi et de prendre de mes nouvelles.

À tous, encore une fois, merci.

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i CONFIDENTIAL, NOT FOR DISCLOSURE

This is confidential information of GSK Vaccines. This document is only for review and should not be shared further.

Table of content

GENERAL INTRODUCTION ________________________________________ ERROR! BOOKMARK NOT DEFINED.

B IOMOLECULAR INTERACTION ____________________________________________ E RROR ! B OOKMARK NOT DEFINED . Avidity and affinity ______________________________________________ Error! Bookmark not defined.

Kinetics _______________________________________________________ Error! Bookmark not defined.

Binding interaction assessment ____________________________________ Error! Bookmark not defined.

A NTIBODY AND HUMORAL RESPONSE ________________________________________ E RROR ! B OOKMARK NOT DEFINED . Humoral response and avidity _____________________________________ Error! Bookmark not defined.

Immunological implication of avidity ________________________________ Error! Bookmark not defined.

L ABEL FREE TECHNOLOGY IN SERUM ANALYSIS __________________________________ E RROR ! B OOKMARK NOT DEFINED . Surface Plasmon Resonance (SPR) biosensors _________________________ Error! Bookmark not defined.

Non Specific binding _____________________________________________ Error! Bookmark not defined.

Interaction models ______________________________________________ Error! Bookmark not defined.

P OLYCLONAL ANTIBODY INTERACTION ANALYSIS BY REAL TIME BIOSENSORS ______________ E RROR ! B OOKMARK NOT DEFINED . P ROPOSAL AND AIM OF THE RESEARCH _______________________________________ E RROR ! B OOKMARK NOT DEFINED . Application 1 ___________________________________________________ Error! Bookmark not defined.

Application 2 ___________________________________________________ Error! Bookmark not defined.

D-Pan and Q-Pan application ______________________________________ Error! Bookmark not defined.

MATERIAL AND METHOD _________________________________________ ERROR! BOOKMARK NOT DEFINED.

S ERUM SAMPLES _____________________________________________________ E RROR ! B OOKMARK NOT DEFINED .

S AMPLE TREATMENT ___________________________________________________ E RROR ! B OOKMARK NOT DEFINED .

A NTIGEN L IGANDS ____________________________________________________ E RROR ! B OOKMARK NOT DEFINED .

A NTIGEN IMMOBILIZATION _______________________________________________ E RROR ! B OOKMARK NOT DEFINED .

D ECONVOLUTION STRATEGY ______________________________________________ E RROR ! B OOKMARK NOT DEFINED .

Monoclonal Antibody selection ____________________________________ Error! Bookmark not defined.

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Additivity verification ____________________________________________ Error! Bookmark not defined.

N ON S PECIFIC BINDING OPTIMIZATION _______________________________________ E RROR ! B OOKMARK NOT DEFINED . A PPLICATION 1 EXPERIMENT _____________________________________________ E RROR ! B OOKMARK NOT DEFINED . A PPLICATION 2 EXPERIMENT _____________________________________________ E RROR ! B OOKMARK NOT DEFINED . D-P AN AND Q-P AN EXPERIMENT __________________________________________ E RROR ! B OOKMARK NOT DEFINED . RESULTS _______________________________________________________ ERROR! BOOKMARK NOT DEFINED.

D ECONVOLUTION STRATEGY ______________________________________________ E RROR ! B OOKMARK NOT DEFINED . Monoclonal antibody selection ____________________________________ Error! Bookmark not defined.

Additivity verification ____________________________________________ Error! Bookmark not defined.

Discussion _____________________________________________________ Error! Bookmark not defined.

N ON S PECIFIC BINDING _________________________________________________ E RROR ! B OOKMARK NOT DEFINED . Discussion _____________________________________________________ Error! Bookmark not defined.

A PPLICATION 1 ______________________________________________________ E RROR ! B OOKMARK NOT DEFINED . Specific antibody content _________________________________________ Error! Bookmark not defined.

BIAcore® data’s _________________________________________________ Error! Bookmark not defined.

Association ____________________________________________________ Error! Bookmark not defined.

Dissociation ____________________________________________________ Error! Bookmark not defined.

Statistical analysis _______________________________________________ Error! Bookmark not defined.

Discussion _____________________________________________________ Error! Bookmark not defined.

A PPLICATION 2 ______________________________________________________ E RROR ! B OOKMARK NOT DEFINED . Specific antibody content _________________________________________ Error! Bookmark not defined.

Immobilization _________________________________________________ Error! Bookmark not defined.

BIAcore® Data’s ________________________________________________ Error! Bookmark not defined.

Binding association ______________________________________________ Error! Bookmark not defined.

Dissociation ____________________________________________________ Error! Bookmark not defined.

Discussion _____________________________________________________ Error! Bookmark not defined.

A PPLICATION 3: D-P AN AND Q-P AN ________________________________________ E RROR ! B OOKMARK NOT DEFINED .

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iii CONFIDENTIAL, NOT FOR DISCLOSURE

This is confidential information of GSK Vaccines. This document is only for review and should not be shared further.

HI titers _______________________________________________________ Error! Bookmark not defined.

Measurement of avidity by SPR (BIAcore®) analysis ____________________ Error! Bookmark not defined.

Association ____________________________________________________ Error! Bookmark not defined.

Dissociation ____________________________________________________ Error! Bookmark not defined.

Statistical analysis _______________________________________________ Error! Bookmark not defined.

Discussion _____________________________________________________ Error! Bookmark not defined.

CONCLUSIONS __________________________________________________ ERROR! BOOKMARK NOT DEFINED.

PERSPECTIVES __________________________________________________ ERROR! BOOKMARK NOT DEFINED.

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ANNEXES ______________________________________________________ ERROR! BOOKMARK NOT DEFINED.

A NNEX 1: M ATHEMATICAL TRANSFORMATION OF THE COMPLEX CONCENTRATION AT EQUILIBRIUM E RROR ! B OOKMARK NOT DEFINED .

A NNEX 2: F ITTING OF THE M A BS AND THE M A B MIXTURE __________________________ E RROR ! B OOKMARK NOT DEFINED . A NNEX 3 : C ORRELATION OF END ASSOCIATION LEVEL AT THE 2 CONCENTRATIONS _________ E RROR ! B OOKMARK NOT DEFINED . A NNEX 4: CORRELATION BETWEEN SIMULATED STEADY STATES AT CONCENTRATION 0.05 AND 0.2 IUE RROR ! B OOKMARK NOT DEFINED .

A NNEX : 5 C ORRELATION BETWEEN END ASSOCIATION LEVEL AND SIMULATED STEADY STATE ___ E RROR ! B OOKMARK NOT DEFINED . A NNEX 6: % OF DISSOCIATION FOR ALL THE APPLICATION 1 SAMPLES AT 0.05 AND 0.2 CONCENTRATION E RROR ! B OOKMARK NOT DEFINED .

A NNEX 7: C ORRELATION BETWEEN K

D

GLOBAL FITTING AND % OF DISSOCIATION ___________ E RROR ! B OOKMARK NOT DEFINED . A NNEX 8: RELATION BETWEEN SAMPLE DILUTION AND END ASSOCIATION LEVEL FOR APPLICATION 1E RROR ! B OOKMARK NOT DEFINED .

A NNEX 9: EXAMPLE OF BINDING CURVE ( EXPERIMENTAL + COMPUTED FITTING ) AT 0.2 CONCENTRATION E RROR ! B OOKMARK NOT DEFINED .

A NNEX 10: BINDING CHART OF APPLICATION 1 _________________________________ E RROR ! B OOKMARK NOT DEFINED .

A NNEX 11: E ND ASSOCIATION APPLICATION 2__________________________________ E RROR ! B OOKMARK NOT DEFINED .

A NNEX 12: E ND ASSOCIATION CORRECTION APPLICATION 2 ________________________ E RROR ! B OOKMARK NOT DEFINED .

A NNEX 13: APPLICATION 2 END ASSOCIATION LEVEL AND % OF DISSOCIATION ____________ E RROR ! B OOKMARK NOT DEFINED .

A NNEX 14: DISSOCIATION % FOR BOTH SURFACE AND SERUM SAMPLE _________________ E RROR ! B OOKMARK NOT DEFINED .

A NNEX 15: APPLICATION 2, % DISSOCIATION __________________________________ E RROR ! B OOKMARK NOT DEFINED .

A NNEX 16: DISSOCIATION CURVATURE _______________________________________ E RROR ! B OOKMARK NOT DEFINED .

BIBLIOGRAPHY _________________________________________________ ERROR! BOOKMARK NOT DEFINED.

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