Precise targeting of HIV broadly neutralizing antibody precursors in humans

Tom G. Caniels; Madhu Prabhakaran; Gabriel Ozorowski; Kellie J. MacPhee; Weiwei Wu; Karlijn van der Straten; Sashank Agrawal; Ronald Derking; Emma I. M. M. Reiss; Katrina Millard; Martina Turroja; Aimee Desrosiers; Jeffrey Bethony; Elissa Malkin; Marinus H. Liesdek; Annelou van der Veen; Michelle Klouwens; Jonne L. Snitselaar; Joey H. Bouhuijs; Rhianna Bronson; Jalen Jean-Baptiste; Suprabhath Gajjala; Zahra Rikhtegaran Tehrani; Alison Benner; Mukundhan Ramaswami; Michael O. Duff; Yung-Wen Liu; Alicia H. Sato; Ju Yeong Kim; Isabel J. L. Baken; Catarina Mendes Silva; Tom P. L. Bijl; Jacqueline van Rijswijk; Judith A. Burger; Albert Cupo; Anila Yasmeen; Swastik Phulera; Wen-Hsin Lee; Kipchoge N. Randall; Shiyu Zhang; Martin M. Corcoran; Isabel Regadas; Alex C. Sullivan; David M. Brown; Jennifer A. Bohl; Kelli M. Greene; Hongmei Gao; Nicole L. Yates; Sheetal Sawant; Jan M. Prins; Neeltje A. Kootstra; Stephen M. Kaminsky; Burc Barin; Farhad Rahaman; Margaret Meller; Vince Philiponis; Dagna S. Laufer; Angela Lombardo; Lindsey Mwoga; Solmaz Shotorbani; Drienna Holman; Richard A. Koup; Per Johan Klasse; Gunilla B. Karlsson Hedestam; Georgia D. Tomaras; Marit J. van Gils; David C. Montefiori; Adrian B. McDermott; Ollivier Hyrien; John P. Moore; Ian A. Wilson; Andrew B. Ward; David J. Diemert; Godelieve J. de Bree; Sarah F. Andrews; Marina Caskey; Rogier W. Sanders

doi:10.1126/science.adv5572

Precise targeting of HIV broadly neutralizing antibody precursors in humans

Tom G. Caniels
, Madhu Prabhakaran
, Gabriel Ozorowski
, Kellie J. MacPhee
, Weiwei Wu
, Karlijn van der Straten
, Sashank Agrawal
, Ronald Derking
, Emma I. M. M. Reiss
, Katrina Millard
, Martina Turroja
, Aimee Desrosiers
, Jeffrey Bethony
, Elissa Malkin
, Marinus H. Liesdek
, Annelou van der Veen
, Michelle Klouwens
, Jonne L. Snitselaar
, Joey H. Bouhuijs
, Rhianna Bronson

Jalen Jean-Baptiste, Suprabhath Gajjala, Zahra Rikhtegaran Tehrani, Alison Benner, Mukundhan Ramaswami, Michael O. Duff, Yung-Wen Liu, Alicia H. Sato, Ju Yeong Kim, Isabel J. L. Baken, Catarina Mendes Silva, Tom P. L. Bijl, Jacqueline van Rijswijk, Judith A. Burger, Albert Cupo, Anila Yasmeen, Swastik Phulera, Wen-Hsin Lee, Kipchoge N. Randall, Shiyu Zhang, Martin M. Corcoran, Isabel Regadas, Alex C. Sullivan, David M. Brown, Jennifer A. Bohl, Kelli M. Greene, Hongmei Gao, Nicole L. Yates, Sheetal Sawant, Jan M. Prins, Neeltje A. Kootstra, Stephen M. Kaminsky, Burc Barin, Farhad Rahaman, Margaret Meller, Vince Philiponis, Dagna S. Laufer, Angela Lombardo, Lindsey Mwoga, Solmaz Shotorbani, Drienna Holman, Richard A. Koup, Per Johan Klasse, Gunilla B. Karlsson Hedestam, Georgia D. Tomaras, Marit J. van Gils, David C. Montefiori, Adrian B. McDermott, Ollivier Hyrien, John P. Moore, Ian A. Wilson, Andrew B. Ward, David J. Diemert, Godelieve J. de Bree, Sarah F. Andrews, Marina Caskey^*, Rogier W. Sanders^*

^*Corresponding author for this work

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

Abstract

A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01B, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.

Original language	English
Article number	eadv5572
Journal	Science
Volume	389
Issue number	6759
DOIs	https://doi.org/10.1126/science.adv5572
Publication status	Published - 31 Jul 2025

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10.1126/science.adv5572

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Caniels, T. G., Prabhakaran, M., Ozorowski, G., MacPhee, K. J., Wu, W., van der Straten, K., Agrawal, S., Derking, R., Reiss, E. I. M. M., Millard, K., Turroja, M., Desrosiers, A., Bethony, J., Malkin, E., Liesdek, M. H., van der Veen, A., Klouwens, M., Snitselaar, J. L., Bouhuijs, J. H., ... Sanders, R. W. (2025). Precise targeting of HIV broadly neutralizing antibody precursors in humans. Science, 389(6759), Article eadv5572. https://doi.org/10.1126/science.adv5572

@article{90744b709d8146869fad734bd7d4bf2d,

title = "Precise targeting of HIV broadly neutralizing antibody precursors in humans",

abstract = "A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01B, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.",

author = "Caniels, \{Tom G.\} and Madhu Prabhakaran and Gabriel Ozorowski and MacPhee, \{Kellie J.\} and Weiwei Wu and \{van der Straten\}, Karlijn and Sashank Agrawal and Ronald Derking and Reiss, \{Emma I. M. M.\} and Katrina Millard and Martina Turroja and Aimee Desrosiers and Jeffrey Bethony and Elissa Malkin and Liesdek, \{Marinus H.\} and \{van der Veen\}, Annelou and Michelle Klouwens and Snitselaar, \{Jonne L.\} and Bouhuijs, \{Joey H.\} and Rhianna Bronson and Jalen Jean-Baptiste and Suprabhath Gajjala and Tehrani, \{Zahra Rikhtegaran\} and Alison Benner and Mukundhan Ramaswami and Duff, \{Michael O.\} and Yung-Wen Liu and Sato, \{Alicia H.\} and Kim, \{Ju Yeong\} and Baken, \{Isabel J. L.\} and Silva, \{Catarina Mendes\} and Bijl, \{Tom P. L.\} and \{van Rijswijk\}, Jacqueline and Burger, \{Judith A.\} and Albert Cupo and Anila Yasmeen and Swastik Phulera and Wen-Hsin Lee and Randall, \{Kipchoge N.\} and Shiyu Zhang and Corcoran, \{Martin M.\} and Isabel Regadas and Sullivan, \{Alex C.\} and Brown, \{David M.\} and Bohl, \{Jennifer A.\} and Greene, \{Kelli M.\} and Hongmei Gao and Yates, \{Nicole L.\} and Sheetal Sawant and Prins, \{Jan M.\} and Kootstra, \{Neeltje A.\} and Kaminsky, \{Stephen M.\} and Burc Barin and Farhad Rahaman and Margaret Meller and Vince Philiponis and Laufer, \{Dagna S.\} and Angela Lombardo and Lindsey Mwoga and Solmaz Shotorbani and Drienna Holman and Koup, \{Richard A.\} and Klasse, \{Per Johan\} and \{Karlsson Hedestam\}, \{Gunilla B.\} and Tomaras, \{Georgia D.\} and \{van Gils\}, \{Marit J.\} and Montefiori, \{David C.\} and McDermott, \{Adrian B.\} and Ollivier Hyrien and Moore, \{John P.\} and Wilson, \{Ian A.\} and Ward, \{Andrew B.\} and Diemert, \{David J.\} and \{de Bree\}, \{Godelieve J.\} and Andrews, \{Sarah F.\} and Marina Caskey and Sanders, \{Rogier W.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the authors, some rights reserved.",

year = "2025",

month = jul,

day = "31",

doi = "10.1126/science.adv5572",

language = "English",

volume = "389",

journal = "Science",

issn = "0036-8075",

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

number = "6759",

}

Caniels, TG, Prabhakaran, M, Ozorowski, G, MacPhee, KJ, Wu, W, van der Straten, K, Agrawal, S, Derking, R, Reiss, EIMM, Millard, K, Turroja, M, Desrosiers, A, Bethony, J, Malkin, E, Liesdek, MH, van der Veen, A, Klouwens, M, Snitselaar, JL, Bouhuijs, JH, Bronson, R, Jean-Baptiste, J, Gajjala, S, Tehrani, ZR, Benner, A, Ramaswami, M, Duff, MO, Liu, Y-W, Sato, AH, Kim, JY, Baken, IJL, Silva, CM, Bijl, TPL, van Rijswijk, J , Burger, JA, Cupo, A, Yasmeen, A, Phulera, S, Lee, W-H, Randall, KN, Zhang, S, Corcoran, MM, Regadas, I, Sullivan, AC, Brown, DM, Bohl, JA, Greene, KM, Gao, H, Yates, NL, Sawant, S, Prins, JM , Kootstra, NA, Kaminsky, SM, Barin, B, Rahaman, F, Meller, M, Philiponis, V, Laufer, DS, Lombardo, A, Mwoga, L, Shotorbani, S, Holman, D, Koup, RA, Klasse, PJ, Karlsson Hedestam, GB, Tomaras, GD, van Gils, MJ, Montefiori, DC, McDermott, AB, Hyrien, O, Moore, JP, Wilson, IA, Ward, AB, Diemert, DJ, de Bree, GJ, Andrews, SF, Caskey, M & Sanders, RW 2025, 'Precise targeting of HIV broadly neutralizing antibody precursors in humans', Science, vol. 389, no. 6759, eadv5572. https://doi.org/10.1126/science.adv5572

TY - JOUR

T1 - Precise targeting of HIV broadly neutralizing antibody precursors in humans

AU - Caniels, Tom G.

AU - Prabhakaran, Madhu

AU - Ozorowski, Gabriel

AU - MacPhee, Kellie J.

AU - Wu, Weiwei

AU - van der Straten, Karlijn

AU - Agrawal, Sashank

AU - Derking, Ronald

AU - Reiss, Emma I. M. M.

AU - Millard, Katrina

AU - Turroja, Martina

AU - Desrosiers, Aimee

AU - Bethony, Jeffrey

AU - Malkin, Elissa

AU - Liesdek, Marinus H.

AU - van der Veen, Annelou

AU - Klouwens, Michelle

AU - Snitselaar, Jonne L.

AU - Bouhuijs, Joey H.

AU - Bronson, Rhianna

AU - Jean-Baptiste, Jalen

AU - Gajjala, Suprabhath

AU - Tehrani, Zahra Rikhtegaran

AU - Benner, Alison

AU - Ramaswami, Mukundhan

AU - Duff, Michael O.

AU - Liu, Yung-Wen

AU - Sato, Alicia H.

AU - Kim, Ju Yeong

AU - Baken, Isabel J. L.

AU - Silva, Catarina Mendes

AU - Bijl, Tom P. L.

AU - van Rijswijk, Jacqueline

AU - Burger, Judith A.

AU - Cupo, Albert

AU - Yasmeen, Anila

AU - Phulera, Swastik

AU - Lee, Wen-Hsin

AU - Randall, Kipchoge N.

AU - Zhang, Shiyu

AU - Corcoran, Martin M.

AU - Regadas, Isabel

AU - Sullivan, Alex C.

AU - Brown, David M.

AU - Bohl, Jennifer A.

AU - Greene, Kelli M.

AU - Gao, Hongmei

AU - Yates, Nicole L.

AU - Sawant, Sheetal

AU - Prins, Jan M.

AU - Kootstra, Neeltje A.

AU - Kaminsky, Stephen M.

AU - Barin, Burc

AU - Rahaman, Farhad

AU - Meller, Margaret

AU - Philiponis, Vince

AU - Laufer, Dagna S.

AU - Lombardo, Angela

AU - Mwoga, Lindsey

AU - Shotorbani, Solmaz

AU - Holman, Drienna

AU - Koup, Richard A.

AU - Klasse, Per Johan

AU - Karlsson Hedestam, Gunilla B.

AU - Tomaras, Georgia D.

AU - van Gils, Marit J.

AU - Montefiori, David C.

AU - McDermott, Adrian B.

AU - Hyrien, Ollivier

AU - Moore, John P.

AU - Wilson, Ian A.

AU - Ward, Andrew B.

AU - Diemert, David J.

AU - de Bree, Godelieve J.

AU - Andrews, Sarah F.

AU - Caskey, Marina

AU - Sanders, Rogier W.

PY - 2025/7/31

Y1 - 2025/7/31

N2 - A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01B, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.

AB - A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01B, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.

UR - https://www.scopus.com/pages/publications/105012855664

U2 - 10.1126/science.adv5572

DO - 10.1126/science.adv5572

M3 - Article

C2 - 40373114

SN - 0036-8075

VL - 389

JO - Science

JF - Science

IS - 6759

M1 - eadv5572

ER -

Precise targeting of HIV broadly neutralizing antibody precursors in humans

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