De novo protein design enables the precise induction of RSV-neutralizing antibodies
Fabian Sesterhenn
(1, 2)
,
Che Yang
(1, 2)
,
Jaume Bonet
(1, 2)
,
Johannes T. Cramer
(3)
,
Xiaolin Wen
(4)
,
Yimeng Wang
(5)
,
Chi I. Chiang
(5)
,
Luciano Andres Abriata
(1, 2)
,
Iga Kucharska
(6, 7)
,
Giacomo Castoro
(3)
,
Sabrina S. Vollers
(1, 2)
,
Marie Galloux
(8)
,
Elie Dheilly
(9)
,
Stéphane Rosset
(1, 2)
,
Patricia Corthésy
(1, 2)
,
Sandrine Georgeon
(1, 2)
,
Mélanie Villard
(1, 2)
,
Charles-Adrien Richard
(8)
,
Delphyne Descamps
(8)
,
Teresa Delgado
(10)
,
Elisa Oricchio
(9)
,
Marie Anne Rameix-Welti
(11)
,
Vicente Más
(10)
,
Sean Ervin
(12)
,
Jean Francois Eleouet
(8)
,
Sabine Riffault
(8)
,
John T. Bates
(13)
,
Jean Philippe Julien
(6, 7)
,
Yuxing Li
(5, 14)
,
Theodore S. Jardetzky
(4)
,
Thomas Krey
(3, 15, 16, 17)
,
Bruno Correia
(1, 2)
1
EPFL -
Ecole Polytechnique Fédérale de Lausanne
2 SIB - Swiss Institute of Bioinformatics [Lausanne]
3 MHH - Medizinische Hochschule Hannover = Hannover Medical School
4 Stanford School of Medicine [Stanford]
5 University of Maryland [Baltimore]
6 SickKids - The Hospital for sick children [Toronto]
7 Department of Biochemistry [University of Toronto]
8 VIM (UR 0892) - Virologie et Immunologie Moléculaires
9 ISREC - Swiss Institute for Experimental Cancer Research - Lausanne
10 CNM - Centro Nacional de Microbiología [ISCIII, Madrid, Spain]
11 2I - Infection et inflammation
12 Wake Forest Baptist Medical Center
13 UMMC - University of Mississippi Medical Center
14 University of Maryland School of Medicine
15 DZIF - German Center for Infection Research - partner site Hannover-Braunschweig
16 University of Luebeck
17 INSTITUT FUR ANGEWANDTE BODENBIOLOGIE GMBH HAMBURG DEU
2 SIB - Swiss Institute of Bioinformatics [Lausanne]
3 MHH - Medizinische Hochschule Hannover = Hannover Medical School
4 Stanford School of Medicine [Stanford]
5 University of Maryland [Baltimore]
6 SickKids - The Hospital for sick children [Toronto]
7 Department of Biochemistry [University of Toronto]
8 VIM (UR 0892) - Virologie et Immunologie Moléculaires
9 ISREC - Swiss Institute for Experimental Cancer Research - Lausanne
10 CNM - Centro Nacional de Microbiología [ISCIII, Madrid, Spain]
11 2I - Infection et inflammation
12 Wake Forest Baptist Medical Center
13 UMMC - University of Mississippi Medical Center
14 University of Maryland School of Medicine
15 DZIF - German Center for Infection Research - partner site Hannover-Braunschweig
16 University of Luebeck
17 INSTITUT FUR ANGEWANDTE BODENBIOLOGIE GMBH HAMBURG DEU
Marie Galloux
- Fonction : Auteur
- PersonId : 764302
- ORCID : 0000-0001-7477-8489
- IdRef : 104918055
Charles-Adrien Richard
- Fonction : Auteur
- PersonId : 744278
- IdHAL : charles-adrien-richard
- ORCID : 0000-0001-5306-2297
- IdRef : 204702100
Delphyne Descamps
- Fonction : Auteur
- PersonId : 737945
- IdHAL : delphyne-descamps
- ORCID : 0000-0002-4883-6910
- IdRef : 120011182
Teresa Delgado
- Fonction : Auteur
- PersonId : 795246
- ORCID : 0000-0002-3155-8889
Elisa Oricchio
- Fonction : Auteur
- PersonId : 779813
- ORCID : 0000-0002-1690-0447
Jean Francois Eleouet
- Fonction : Auteur
- PersonId : 1151144
- IdHAL : jean-francois-eleouet
- ORCID : 0000-0002-7361-4885
- IdRef : 128009861
Sabine Riffault
- Fonction : Auteur
- PersonId : 735962
- IdHAL : sabine-riffault
- ORCID : 0000-0003-3154-9162
- IdRef : 121393046
Résumé
De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs. Copyright