Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2020
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| Online Access: | https://hdl.handle.net/1721.1/128273 |
| _version_ | 1826190504411267072 |
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| author | Sangesland, Maya Ronsard, Larance Kazer, Samuel Weisgurt Bals, Julia Boyoglu-Barnum, Seyhan Yousif, Ashraf S. Barnes, Ralston Feldman, Jared Quirindongo-Crespo, Maricel McTamney, Patrick M. Rohrer, Daniel Lonberg, Nils Chackerian, Bryce Graham, Barney S. Kanekiyo, Masaru Shalek, Alexander K Lingwood, Daniel |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Sangesland, Maya Ronsard, Larance Kazer, Samuel Weisgurt Bals, Julia Boyoglu-Barnum, Seyhan Yousif, Ashraf S. Barnes, Ralston Feldman, Jared Quirindongo-Crespo, Maricel McTamney, Patrick M. Rohrer, Daniel Lonberg, Nils Chackerian, Bryce Graham, Barney S. Kanekiyo, Masaru Shalek, Alexander K Lingwood, Daniel |
| author_sort | Sangesland, Maya |
| collection | MIT |
| description | 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 (VH) 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 VH-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. |
| first_indexed | 2024-09-23T08:41:16Z |
| format | Article |
| id | mit-1721.1/128273 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:41:16Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1282732022-09-23T13:51:37Z Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus Sangesland, Maya Ronsard, Larance Kazer, Samuel Weisgurt Bals, Julia Boyoglu-Barnum, Seyhan Yousif, Ashraf S. Barnes, Ralston Feldman, Jared Quirindongo-Crespo, Maricel McTamney, Patrick M. Rohrer, Daniel Lonberg, Nils Chackerian, Bryce Graham, Barney S. Kanekiyo, Masaru Shalek, Alexander K Lingwood, Daniel Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemistry Broad Institute of MIT and Harvard Koch Institute for Integrative Cancer Research at MIT 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 (VH) 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 VH-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. NIH (Grants 1DP2OD020839, 2U19AI089992, 1U54CA217377, P01AI039671, 5U24AI118672, 2RM1HG006193, 1R33CA202820, 2R01HL095791, 1R01AI138546, 1R01HL126554, 1R01DA046277, 2R01HL095791) Bill and Melinda Gates Foundation (Grants OPP1139972 and BMGF OPP1116944) 2020-10-30T17:10:54Z 2020-10-30T17:10:54Z 2019-10 2019-05 2020-10-19T15:10:45Z Article http://purl.org/eprint/type/JournalArticle 1074-7613 https://hdl.handle.net/1721.1/128273 Sangesland, Maya et al. "Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus." Immunity 51, 4 (October 2019): P735-749.e8 © 2019 Elsevier en http://dx.doi.org/10.1016/j.immuni.2019.09.001 Immunity Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Sangesland, Maya Ronsard, Larance Kazer, Samuel Weisgurt Bals, Julia Boyoglu-Barnum, Seyhan Yousif, Ashraf S. Barnes, Ralston Feldman, Jared Quirindongo-Crespo, Maricel McTamney, Patrick M. Rohrer, Daniel Lonberg, Nils Chackerian, Bryce Graham, Barney S. Kanekiyo, Masaru Shalek, Alexander K Lingwood, Daniel Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus |
| title | Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus |
| title_full | Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus |
| title_fullStr | Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus |
| title_full_unstemmed | Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus |
| title_short | Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus |
| title_sort | germline encoded affinity for cognate antigen enables vaccine amplification of a human broadly neutralizing response against influenza virus |
| url | https://hdl.handle.net/1721.1/128273 |
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