Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus

被引：62

作者：

Sangesland, Maya ^{[1
,2
]}

Ronsard, Larance ^{[1
,2
]}

Kazer, Samuel W. ^{[1
,2
,3
,4
,5
,6
]}

Bals, Julia ^{[1
,2
]}

Boyoglu-Barnum, Seyhan ^{[7
]}

Yousif, Ashraf S. ^{[1
,2
]}

Barnes, Ralston ^{[8
]}

Feldman, Jared ^{[1
,2
]}

Quirindongo-Crespo, Maricel ^{[8
]}

McTamney, Patrick M. ^{[9
]}

Rohrer, Daniel ^{[8
]}

Lonberg, Nils ^{[8
]}

Chackerian, Bryce ^{[10
]}

Graham, Barney S. ^{[7
]}

Kanekiyo, Masaru ^{[7
]}

Shalek, Alex K. ^{[1
,2
,3
,4
,5
,6
]}

Lingwood, Daniel ^{[1
,2
]}

机构：

[1] MIT, Massachusetts Gen Hosp, Ragon Inst, 400 Technol Sq, Cambridge, MA 02139 USA

[2] Harvard Univ, 400 Technol Sq, Cambridge, MA 02139 USA

[3] MIT, Dept Chem, IMES, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[5] MIT, Broad Inst, 415 Main St, Cambridge, MA 02142 USA

[6] Harvard Univ, 415 Main St, Cambridge, MA 02142 USA

[7] NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA

[8] Bristol Myers Squibb, 700 Bay Rd, Redwood City, CA 94063 USA

[9] Medimmune LLC, One Medimmune Way, Gaithersburg, MD 20878 USA

[10] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, 2425 Camino Salud, Albuquerque, NM 87106 USA

来源：

IMMUNITY | 2019年 / 51卷 / 04期

关键词：

MEMORY B-CELLS; HEMAGGLUTININ-STEM; HUMAN-ANTIBODIES; HIV; IMMUNIZATION; MICE; IMMUNITY; REPERTOIRE; PRECURSORS; EXPRESSION;

D O I：

10.1016/j.immuni.2019.09.001

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Antibody paratopes are formed by hypervariable complementarity-determining regions (CDRH3s) and variable gene-encoded CDRs. The latter show biased usage in human broadly neutralizing antibodies (bnAbs) against both HIV and influenza virus, suggesting the existence of gene-endowed targeting solutions that may be amenable to pathway amplification. To test this, we generated transgenic mice with human CDRH3 diversity but simultaneously constrained to individual user-defined human immunoglobulin variable heavy-chain (V-H) genes, including IGHV1-69, which shows biased usage in human bnAbs targeting the hemagglutinin stalk of group 1 influenza A viruses. Sequential immunization with a stalk-only hemagglutinin nanoparticle elicited group 1 bnAbs, but only in IGHV1-69 mice. This V-H-endowed response required minimal affinity maturation, was elicited alongside pre-existing influenza immunity, and when IGHV1-69 B cells were diluted to match the frequency measured in humans. These results indicate that the human repertoire could, in principle, support germline-encoded bnAb elicitation using a single recombinant hemagglutinin immunogen.

引用

页码：735 / +

页数：23

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