Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate

Kwinten Sliepen; Laura Radić; Joan Capella-Pujol; Yasunori Watanabe; Ian Zon; Ana Chumbe; Wen-Hsin Lee; Marlon de Gast; Jelle Koopsen; Sylvie Koekkoek; Iván del Moral-Sánchez; Philip J. M. Brouwer; Rashmi Ravichandran; Gabriel Ozorowski; Neil P. King; Andrew B. Ward; Marit J. van Gils; Max Crispin; Janke Schinkel; Rogier W. Sanders

doi:https://doi.org/10.1038/s41467-022-34961-8

Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate

Kwinten Sliepen, Laura Radić, Joan Capella-Pujol, Yasunori Watanabe, Ian Zon, Ana Chumbe, Wen-Hsin Lee, Marlon de Gast, Jelle Koopsen, Sylvie Koekkoek, Iván del Moral-Sánchez, Philip J. M. Brouwer, Rashmi Ravichandran, Gabriel Ozorowski, Neil P. King, Andrew B. Ward, Marit J. van Gils, Max Crispin, Janke Schinkel, Rogier W. Sanders

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

18 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.

Original language	English
Article number	7271
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34961-8
Publication status	Published - 1 Dec 2022

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Sliepen, K., Radić, L., Capella-Pujol, J., Watanabe, Y., Zon, I., Chumbe, A., Lee, W.-H., de Gast, M., Koopsen, J., Koekkoek, S., del Moral-Sánchez, I., Brouwer, P. J. M., Ravichandran, R., Ozorowski, G., King, N. P., Ward, A. B., van Gils, M. J., Crispin, M., Schinkel, J., & Sanders, R. W. (2022). Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate. Nature communications, 13(1), Article 7271. https://doi.org/10.1038/s41467-022-34961-8

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title = "Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate",

abstract = "Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.",

author = "Kwinten Sliepen and Laura Radi{\'c} and Joan Capella-Pujol and Yasunori Watanabe and Ian Zon and Ana Chumbe and Wen-Hsin Lee and {de Gast}, Marlon and Jelle Koopsen and Sylvie Koekkoek and {del Moral-S{\'a}nchez}, Iv{\'a}n and Brouwer, {Philip J. M.} and Rashmi Ravichandran and Gabriel Ozorowski and King, {Neil P.} and Ward, {Andrew B.} and {van Gils}, {Marit J.} and Max Crispin and Janke Schinkel and Sanders, {Rogier W.}",

note = "Funding Information: We thank Mitch Brinkkemper, Marielle van Breemen, Jonne Snitselaar, and Tom Bijl for experimental support. We thank Steven Foung for donating the CBH-4B, CBH-4D, and CBH-4G antibodies and Tim Beaumont and Sabrina Merat for donating the AT1209 and AT1211 antibodies. We thank Dietmar Katinger and Philipp Mundsperger for providing the squalene emulsion adjuvant. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. Kewal Raman. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. This research was supported by the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), an AMC Fellowship from Amsterdam UMC (M.J.v.G.), Vici grant from the Netherlands Organization for Scientific Research (NWO) (R.W.S), a Vidi and Aspasia grant from the NWO (grant numbers 91719372 and 015.015.042) (J.S.), the Bill & Melinda Gates Foundation (OPP1156262 to N.P.K. and R.W.S.), an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.), and an AMC PhD Scholarship (A.C.M.). Mass spectrometry and electron microscopy (M.C. and A.B.W.) were supported by Bill and Melinda Gates Foundation grant INV-008352/OPP1153692. Y.W. has taken up a position at AstraZeneca; all experimental work was performed prior to this development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank Mitch Brinkkemper, Marielle van Breemen, Jonne Snitselaar, and Tom Bijl for experimental support. We thank Steven Foung for donating the CBH-4B, CBH-4D, and CBH-4G antibodies and Tim Beaumont and Sabrina Merat for donating the AT1209 and AT1211 antibodies. We thank Dietmar Katinger and Philipp Mundsperger for providing the squalene emulsion adjuvant. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. Kewal Raman. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. This research was supported by the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), an AMC Fellowship from Amsterdam UMC (M.J.v.G.), Vici grant from the Netherlands Organization for Scientific Research (NWO) (R.W.S), a Vidi and Aspasia grant from the NWO (grant numbers 91719372 and 015.015.042) (J.S.), the Bill & Melinda Gates Foundation (OPP1156262 to N.P.K. and R.W.S.), an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.), and an AMC PhD Scholarship (A.C.M.). Mass spectrometry and electron microscopy (M.C. and A.B.W.) were supported by Bill and Melinda Gates Foundation grant INV-008352/OPP1153692. Y.W. has taken up a position at AstraZeneca; all experimental work was performed prior to this development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "1",

doi = "https://doi.org/10.1038/s41467-022-34961-8",

language = "English",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

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number = "1",

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Sliepen, K, Radić, L, Capella-Pujol, J, Watanabe, Y, Zon, I, Chumbe, A, Lee, W-H, de Gast, M , Koopsen, J , Koekkoek, S , del Moral-Sánchez, I, Brouwer, PJM, Ravichandran, R, Ozorowski, G, King, NP, Ward, AB, van Gils, MJ, Crispin, M, Schinkel, J & Sanders, RW 2022, 'Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate', Nature communications, vol. 13, no. 1, 7271. https://doi.org/10.1038/s41467-022-34961-8

TY - JOUR

T1 - Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate

AU - Sliepen, Kwinten

AU - Radić, Laura

AU - Capella-Pujol, Joan

AU - Watanabe, Yasunori

AU - Zon, Ian

AU - Chumbe, Ana

AU - Lee, Wen-Hsin

AU - de Gast, Marlon

AU - Koopsen, Jelle

AU - Koekkoek, Sylvie

AU - del Moral-Sánchez, Iván

AU - Brouwer, Philip J. M.

AU - Ravichandran, Rashmi

AU - Ozorowski, Gabriel

AU - King, Neil P.

AU - Ward, Andrew B.

AU - van Gils, Marit J.

AU - Crispin, Max

AU - Schinkel, Janke

AU - Sanders, Rogier W.

N1 - Funding Information: We thank Mitch Brinkkemper, Marielle van Breemen, Jonne Snitselaar, and Tom Bijl for experimental support. We thank Steven Foung for donating the CBH-4B, CBH-4D, and CBH-4G antibodies and Tim Beaumont and Sabrina Merat for donating the AT1209 and AT1211 antibodies. We thank Dietmar Katinger and Philipp Mundsperger for providing the squalene emulsion adjuvant. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. Kewal Raman. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. This research was supported by the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), an AMC Fellowship from Amsterdam UMC (M.J.v.G.), Vici grant from the Netherlands Organization for Scientific Research (NWO) (R.W.S), a Vidi and Aspasia grant from the NWO (grant numbers 91719372 and 015.015.042) (J.S.), the Bill & Melinda Gates Foundation (OPP1156262 to N.P.K. and R.W.S.), an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.), and an AMC PhD Scholarship (A.C.M.). Mass spectrometry and electron microscopy (M.C. and A.B.W.) were supported by Bill and Melinda Gates Foundation grant INV-008352/OPP1153692. Y.W. has taken up a position at AstraZeneca; all experimental work was performed prior to this development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank Mitch Brinkkemper, Marielle van Breemen, Jonne Snitselaar, and Tom Bijl for experimental support. We thank Steven Foung for donating the CBH-4B, CBH-4D, and CBH-4G antibodies and Tim Beaumont and Sabrina Merat for donating the AT1209 and AT1211 antibodies. We thank Dietmar Katinger and Philipp Mundsperger for providing the squalene emulsion adjuvant. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. Kewal Raman. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. This research was supported by the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), an AMC Fellowship from Amsterdam UMC (M.J.v.G.), Vici grant from the Netherlands Organization for Scientific Research (NWO) (R.W.S), a Vidi and Aspasia grant from the NWO (grant numbers 91719372 and 015.015.042) (J.S.), the Bill & Melinda Gates Foundation (OPP1156262 to N.P.K. and R.W.S.), an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.), and an AMC PhD Scholarship (A.C.M.). Mass spectrometry and electron microscopy (M.C. and A.B.W.) were supported by Bill and Melinda Gates Foundation grant INV-008352/OPP1153692. Y.W. has taken up a position at AstraZeneca; all experimental work was performed prior to this development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.

AB - Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.

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U2 - https://doi.org/10.1038/s41467-022-34961-8

DO - https://doi.org/10.1038/s41467-022-34961-8

M3 - Article

C2 - 36434005

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 7271

ER -

Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate

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