A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses

Jon M. Steichen; Ying Cing Lin; Colin Havenar-Daughton; Simone Pecetta; Gabriel Ozorowski; Jordan R. Willis; Laura Toy; Devin Sok; Alessia Liguori; Sven Kratochvil; Jonathan L. Torres; Oleksandr Kalyuzhniy; Eleonora Melzi; Daniel W. Kulp; Sebastian Raemisch; Xiaozhen Hu; Steffen M. Bernard; Erik Georgeson; Nicole Phelps; Yumiko Adachi; Michael Kubitz; Elise Landais; Jeffrey Umotoy; Amanda Robinson; Bryan Briney; Ian A. Wilson; Dennis R. Burton; Andrew B. Ward; Shane Crotty; Facundo D. Batista; William R. Schief

doi:10.1126/science.aax4380

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses

Jon M. Steichen
, Ying Cing Lin
, Colin Havenar-Daughton
, Simone Pecetta
, Gabriel Ozorowski
, Jordan R. Willis
, Laura Toy
, Devin Sok
, Alessia Liguori
, Sven Kratochvil
, Jonathan L. Torres
, Oleksandr Kalyuzhniy
, Eleonora Melzi
, Daniel W. Kulp
, Sebastian Raemisch
, Xiaozhen Hu
, Steffen M. Bernard
, Erik Georgeson
, Nicole Phelps
, Yumiko Adachi

Michael Kubitz, Elise Landais, Jeffrey Umotoy, Amanda Robinson, Bryan Briney, Ian A. Wilson, Dennis R. Burton, Andrew B. Ward, Shane Crotty, Facundo D. Batista, William R. Schief^*

^*Corresponding author for this work

University of Florida
Harvard University
Division of Vaccine Discovery La Jolla Institute for Immunology
Wistar Institute
University of California at San Diego

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.

Original language	English
Article number	eaax4380
Journal	Science
Volume	366
Issue number	6470
DOIs	https://doi.org/10.1126/science.aax4380
Publication status	Published - 6 Dec 2019

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Steichen, J. M., Lin, Y. C., Havenar-Daughton, C., Pecetta, S., Ozorowski, G., Willis, J. R., Toy, L., Sok, D., Liguori, A., Kratochvil, S., Torres, J. L., Kalyuzhniy, O., Melzi, E., Kulp, D. W., Raemisch, S., Hu, X., Bernard, S. M., Georgeson, E., Phelps, N., ... Schief, W. R. (2019). A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses. Science, 366(6470), Article eaax4380. https://doi.org/10.1126/science.aax4380

@article{51c1350566714e3f916dd335d7137c84,

title = "A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses",

abstract = "Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human na{\"i}ve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.",

author = "Steichen, \{Jon M.\} and Lin, \{Ying Cing\} and Colin Havenar-Daughton and Simone Pecetta and Gabriel Ozorowski and Willis, \{Jordan R.\} and Laura Toy and Devin Sok and Alessia Liguori and Sven Kratochvil and Torres, \{Jonathan L.\} and Oleksandr Kalyuzhniy and Eleonora Melzi and Kulp, \{Daniel W.\} and Sebastian Raemisch and Xiaozhen Hu and Bernard, \{Steffen M.\} and Erik Georgeson and Nicole Phelps and Yumiko Adachi and Michael Kubitz and Elise Landais and Jeffrey Umotoy and Amanda Robinson and Bryan Briney and Wilson, \{Ian A.\} and Burton, \{Dennis R.\} and Ward, \{Andrew B.\} and Shane Crotty and Batista, \{Facundo D.\} and Schief, \{William R.\}",

note = "Funding Information: We thank H. Gristick and P. Bjorkman for providing atomic coordinates of unliganded BG18 Fab in advance of publication (17) and C. Corbaci for graphical design assistance for the summary. Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) UM1 Al100663 (Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery) and UM1 AI144462 (Scripps Consortium for HIV/AIDS Vaccine Development) (to W.R.S., F.D.B., S.C., A.B.W., and D.R.B) and NIAID R01 AI113867 (to W.R.S.); by the Ragon Institute of MGH, MIT, and Harvard (to F.D.B., W.R.S., and D.R.B.); by the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium (NAC) and Center (to W.R.S., A.B.W., I.A.W., and D.R.B.); and through the Collaboration for AIDS Vaccine Discovery funding for the IAVI NAC Center (to W.R.S., A.B.W., I.A.W., and D.R.B.). Publisher Copyright: {\textcopyright} 2019 American Association for the Advancement of Science. All rights reserved.",

year = "2019",

month = dec,

day = "6",

doi = "10.1126/science.aax4380",

language = "English",

volume = "366",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6470",

}

Steichen, JM, Lin, YC, Havenar-Daughton, C, Pecetta, S, Ozorowski, G, Willis, JR, Toy, L, Sok, D, Liguori, A, Kratochvil, S, Torres, JL, Kalyuzhniy, O, Melzi, E, Kulp, DW, Raemisch, S, Hu, X, Bernard, SM, Georgeson, E, Phelps, N, Adachi, Y, Kubitz, M, Landais, E, Umotoy, J, Robinson, A, Briney, B, Wilson, IA, Burton, DR, Ward, AB, Crotty, S, Batista, FD & Schief, WR 2019, 'A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses', Science, vol. 366, no. 6470, eaax4380. https://doi.org/10.1126/science.aax4380

TY - JOUR

T1 - A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses

AU - Steichen, Jon M.

AU - Lin, Ying Cing

AU - Havenar-Daughton, Colin

AU - Pecetta, Simone

AU - Ozorowski, Gabriel

AU - Willis, Jordan R.

AU - Toy, Laura

AU - Sok, Devin

AU - Liguori, Alessia

AU - Kratochvil, Sven

AU - Torres, Jonathan L.

AU - Kalyuzhniy, Oleksandr

AU - Melzi, Eleonora

AU - Kulp, Daniel W.

AU - Raemisch, Sebastian

AU - Hu, Xiaozhen

AU - Bernard, Steffen M.

AU - Georgeson, Erik

AU - Phelps, Nicole

AU - Adachi, Yumiko

AU - Kubitz, Michael

AU - Landais, Elise

AU - Umotoy, Jeffrey

AU - Robinson, Amanda

AU - Briney, Bryan

AU - Wilson, Ian A.

AU - Burton, Dennis R.

AU - Ward, Andrew B.

AU - Crotty, Shane

AU - Batista, Facundo D.

AU - Schief, William R.

N1 - Funding Information: We thank H. Gristick and P. Bjorkman for providing atomic coordinates of unliganded BG18 Fab in advance of publication (17) and C. Corbaci for graphical design assistance for the summary. Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) UM1 Al100663 (Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery) and UM1 AI144462 (Scripps Consortium for HIV/AIDS Vaccine Development) (to W.R.S., F.D.B., S.C., A.B.W., and D.R.B) and NIAID R01 AI113867 (to W.R.S.); by the Ragon Institute of MGH, MIT, and Harvard (to F.D.B., W.R.S., and D.R.B.); by the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium (NAC) and Center (to W.R.S., A.B.W., I.A.W., and D.R.B.); and through the Collaboration for AIDS Vaccine Discovery funding for the IAVI NAC Center (to W.R.S., A.B.W., I.A.W., and D.R.B.). Publisher Copyright: © 2019 American Association for the Advancement of Science. All rights reserved.

PY - 2019/12/6

Y1 - 2019/12/6

N2 - Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.

AB - Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.

UR - https://www.scopus.com/pages/publications/85076328637

U2 - 10.1126/science.aax4380

DO - 10.1126/science.aax4380

M3 - Article

C2 - 31672916

SN - 0036-8075

VL - 366

JO - Science

JF - Science

IS - 6470

M1 - eaax4380

ER -

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses

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