mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models

被引：3

作者：

Wang, Xuesong ^{[1
]}

Cottrell, Christopher A. ^{[2
,3
,4
]}

Hu, Xiaozhen ^{[2
,3
,4
,5
]}

Ray, Rashmi ^{[1
]}

Bottermann, Maria ^{[1
]}

Villavicencio, Paula Maldonado ^{[1
]}

Yan, Yu ^{[1
]}

Xie, Zhenfei ^{[1
]}

Warner, John E. ^{[1
]}

Ellis-Pugh, Jordan Renae ^{[1
]}

Kalyuzhniy, Oleksandr ^{[2
,3
,4
]}

Liguori, Alessia ^{[2
,3
,4
]}

Willis, Jordan R. ^{[2
,3
,4
]}

Menis, Sergey ^{[2
,3
,4
]}

Raemisch, Sebastian ^{[2
,3
,4
,7
]}

Eskandarzadeh, Saman ^{[2
,3
,4
]}

Kubitz, Michael ^{[2
,3
,4
]}

Tingle, Ryan ^{[2
,3
,4
]}

Phelps, Nicole ^{[2
,3
,4
]}

Groschel, Bettina ^{[2
,3
,4
]}

Himansu, Sunny ^{[5
]}

Carfi, Andrea ^{[5
]}

Kirsch, Kathrin H. ^{[1
]}

Weldon, Stephanie R. ^{[1
]}

Nair, Usha ^{[1
]}

Schief, William R. ^{[1
,2
,3
,4
,5
]}

Batista, Facundo D. ^{[1
,6
]}

机构：

[1] Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USA

[2] Scripps Res Inst, Dept Immunol & Microbiol, La Jolla, CA 92037 USA

[3] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discovery, La Jolla, CA 92037 USA

[5] Moderna Inc, Cambridge, MA 02139 USA

[6] MIT, Dept Biol, Cambridge, MA 02139 USA

[7] Max Planck Unit Sci Pathogens, D-10117 Berlin, Germany

来源：

SCIENCE IMMUNOLOGY | 2024年 / 9卷 / 95期

关键词：

CENTER B-CELLS; AFFINITY MATURATION; STRUCTURAL BASIS; HIV; GERMLINE; MEMORY; ANTIGEN; IG; SEQUENCE; DESIGN;

D O I：

10.1126/sciimmunol.adn0622

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.

引用

页数：15

共 1 条

[1] Vaccination induces maturation of diverse unmutated VRC01-class precursors to HIV-1 broadly neutralizing antibodies in an Ig-humanized mouse model
Chen, X.
Zhou, T.
Schmidt, S.
Duan, H.
Cheng, C.
Chuang, G. -Y.
Gu, Y.
Louder, M.
Lin, B.
Shen, C. -H.
Sheng, Z.
Joyce, M. G.
Doria-Rose, N.
Shapiro, L.
Tian, M.
JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, 2021, 24

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