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2. Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens.

Author

Ueda, George, Antanasijevic, Aleksandar, Fallas, Jorge A, Sheffler, William, Copps, Jeffrey, Ellis, Daniel, Hutchinson, Geoffrey B, Moyer, Adam, Yasmeen, Anila, Tsybovsky, Yaroslav, Park, Young-Jun, Bick, Matthew J, Sankaran, Banumathi, Gillespie, Rebecca A, Brouwer, Philip Jm, Zwart, Peter H, Veesler, David, Kanekiyo, Masaru, Graham, Barney S, Sanders, Rogier W, Moore, John P, Klasse, Per Johan, Ward, Andrew B, King, Neil P, and Baker, David

Subjects
Humans, Glycoproteins, Influenza Vaccines, Antigens, Viral, Cryoelectron Microscopy, Vaccination, Nanoparticles, Immunity, Humoral, B lymphocytes, BL21, E. coli, HEK293F, Lemo21, computational biology, human, immunology, inflammation, systems biology, virus, Antigens, Viral, Immunity, Humoral, Biochemistry and Cell Biology
Abstract

Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.

Published
2020

3. Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike

Author

Derking, Ronald, Allen, Joel D., Cottrell, Christopher A., Sliepen, Kwinten, Seabright, Gemma E., Lee, Wen-Hsin, Aldon, Yoann, Rantalainen, Kimmo, Antanasijevic, Aleksandar, Copps, Jeffrey, Yasmeen, Anila, Cupo, Albert, Cruz Portillo, Victor M., Poniman, Meliawati, Bol, Niki, van der Woude, Patricia, de Taeye, Steven W., van den Kerkhof, Tom L.G.M., Klasse, P.J., Ozorowski, Gabriel, van Gils, Marit J., Moore, John P., Ward, Andrew B., Crispin, Max, and Sanders, Rogier W.

Published
2021
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4. Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.

Author

Caniels, Tom G., Medina-Ramìrez, Max, Zhang, Shiyu, Kratochvil, Sven, Xian, Yuejiao, Koo, Ja-Hyun, Derking, Ronald, Samsel, Jakob, van Schooten, Jelle, Pecetta, Simone, Lamperti, Edward, Yuan, Meng, Carrasco, María Ríos, del Moral Sánchez, Iván, Allen, Joel D., Bouhuijs, Joey H., Yasmeen, Anila, Ketas, Thomas J., Snitselaar, Jonne L., and Bijl, Tom P. L.

Subjects
AIDS vaccines, BINDING sites, B cells, VACCINE development, IMMUNOGLOBULINS
Abstract

Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers. Editor's summary: HIV vaccine efforts include developing immunogens that induce broadly neutralizing antibodies (bnAbs). Two studies highlight advances in inducing VRC01-class bnAbs that bind to the conserved CD4 binding site (CD4bs) epitope of the HIV envelope (Env). Caniels et al. used structure-based design to optimize a trimeric HIV Env antigen called BG505 SOSIP GT1.1 (GT1.1). Adult nonhuman primates (NHPs) immunized with GT1.1 produced antibodies that neutralized fully glycosylated viruses by specifically binding to the CD4bs. Nelson et al. evaluated GT1.1 in infant NHPs compared with a predecessor immunogen, BG505 SOSIP. Both immunogens induced neutralizing antibodies against autologous viruses, but only infants primed with GT1.1 generated VRC01-like CD4bs bnAb precursors upon boosting with BG505 SOSIP. These findings indicate that trimeric germline-targeting immunogens can elicit neutralizing antibodies toward conserved HIV Env epitopes. (See accompanying Research Article by Nelson et al. and accompanying Focus by Amara.) —Christiana Fogg [ABSTRACT FROM AUTHOR]

Published
2024
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5. A Hybrid Bat-Crow Search Algorithm Based Home Energy Management in Smart Grid

Author

Pamir, Javaid, Nadeem, Mohsin, Syed Muhammad, Iqbal, Arshad, Yasmeen, Anila, Ali, Ihsan, Kacprzyk, Janusz, Series Editor, Pal, Nikhil R., Advisory Editor, Bello Perez, Rafael, Advisory Editor, Corchado, Emilio S., Advisory Editor, Hagras, Hani, Advisory Editor, Kóczy, László T., Advisory Editor, Kreinovich, Vladik, Advisory Editor, Lin, Chin-Teng, Advisory Editor, Lu, Jie, Advisory Editor, Melin, Patricia, Advisory Editor, Nedjah, Nadia, Advisory Editor, Nguyen, Ngoc Thanh, Advisory Editor, Wang, Jun, Advisory Editor, Barolli, Leonard, editor, Javaid, Nadeem, editor, Ikeda, Makoto, editor, and Takizawa, Makoto, editor

Published
2019
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6. Fog Computing Based Energy Management System Model for Smart Buildings

Author

Zahoor, Saman, Javaid, Nadeem, Khalid, Adia, Yasmeen, Anila, Nadeem, Zunaira, Kacprzyk, Janusz, Series Editor, Pal, Nikhil R., Advisory Editor, Bello Perez, Rafael, Advisory Editor, Corchado, Emilio S., Advisory Editor, Hagras, Hani, Advisory Editor, Kóczy, László T., Advisory Editor, Kreinovich, Vladik, Advisory Editor, Lin, Chin-Teng, Advisory Editor, Lu, Jie, Advisory Editor, Melin, Patricia, Advisory Editor, Nedjah, Nadia, Advisory Editor, Nguyen, Ngoc Thanh, Advisory Editor, Wang, Jun, Advisory Editor, Barolli, Leonard, editor, Xhafa, Fatos, editor, Javaid, Nadeem, editor, and Enokido, Tomoya, editor

Published
2019
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7. Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

Author

Brouwer, Philip J. M., Antanasijevic, Aleksandar, de Gast, Marlon, Allen, Joel D., Bijl, Tom P. L., Yasmeen, Anila, Ravichandran, Rashmi, Burger, Judith A., Ozorowski, Gabriel, Torres, Jonathan L., LaBranche, Celia, Montefiori, David C., Ringe, Rajesh P., van Gils, Marit J., Moore, John P., Klasse, Per Johan, Crispin, Max, King, Neil P., Ward, Andrew B., and Sanders, Rogier W.

Published
2021
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8. Germline-targeting SOSIP trimer immunization elicits precursor CD4 binding-site targeting broadly neutralizing antibodies in infant macaques.

Author

Nelson, Ashley N, primary, Shen, Xiaoying, additional, Venkatayogi, Sravani, additional, Zhang, Shiyu, additional, Ozorowski, Gabriel, additional, Dennis, Maria, additional, Sewall, Leigh M, additional, Milligan, Emma, additional, Davis, Dominique, additional, Cross, Kaitlyn, additional, Chen, Yue, additional, van Schooten, Jelle, additional, Eudaily, Joshua, additional, Isaac, John, additional, Memon, Saad, additional, Weinbaum, Carolyn, additional, Stanfield-Oakley, Sherry, additional, Byrd, Alliyah, additional, Chutkan, Suni, additional, Berendam, Stella, additional, Cronin, Kenneth, additional, Yasmeen, Anila, additional, Alam, S.Munir, additional, LeBranche, Celia, additional, Rogers, Kenneth, additional, Shirreff, Lisa, additional, Cupo, Albert, additional, Derking, Ronlad, additional, Villinger, Francois, additional, Klasse, Per Johan, additional, Ferrari, Guido, additional, Williams, Wilton B, additional, Hudgens, Michael G, additional, Ward, Andrew B, additional, Montefiori, David C, additional, VanRompay, Koen, additional, Wiehe, Kevin, additional, Moore, John P, additional, Sanders, Rogier W, additional, De Paris, Kristina, additional, and Permar, Sallie R, additional

Published
2023
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16. Fuzzy Energy Management Controller for Smart Homes

Author

Khalid, Rabiya, Abid, Samia, Zafar, Ayesha, Yasmeen, Anila, Khan, Zahoor Ali, Qasim, Umar, Javaid, Nadeem, Kacprzyk, Janusz, Series editor, Pal, Nikhil R., Advisory editor, Bello Perez, Rafael, Advisory editor, Corchado, Emilio S., Advisory editor, Hagras, Hani, Advisory editor, Kóczy, László T., Advisory editor, Kreinovich, Vladik, Advisory editor, Lin, Chin-Teng, Advisory editor, Lu, Jie, Advisory editor, Melin, Patricia, Advisory editor, Nedjah, Nadia, Advisory editor, Nguyen, Ngoc Thanh, Advisory editor, Wang, Jun, Advisory editor, Barolli, Leonard, editor, and Enokido, Tomoya, editor

Published
2018
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17. Glycan heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

Author

Ringe, Rajesh P., primary, Colin, Philippe, additional, Ozorowski, Gabriel, additional, Allen, Joel D., additional, Yasmeen, Anila, additional, Seabright, Gemma E., additional, Lee, Jeong Hyun, additional, Antanasijevic, Aleksandar, additional, Rantalainen, Kimmo, additional, Ketas, Thomas, additional, Moore, John P., additional, Ward, Andrew B., additional, Crispin, Max, additional, and Klasse, P. J., additional

Published
2023
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18. Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Author

Torrents de la Peña, Alba, Julien, Jean-Philippe, de Taeye, Steven W., Garces, Fernando, Guttman, Miklos, Ozorowski, Gabriel, Pritchard, Laura K., Behrens, Anna-Janina, Go, Eden P., Burger, Judith A., Schermer, Edith E., Sliepen, Kwinten, Ketas, Thomas J., Pugach, Pavel, Yasmeen, Anila, Cottrell, Christopher A., Torres, Jonathan L., Vavourakis, Charlotte D., van Gils, Marit J., LaBranche, Celia, Montefiori, David C., Desaire, Heather, Crispin, Max, Klasse, Per Johan, Lee, Kelly K., Moore, John P., Ward, Andrew B., Wilson, Ian A., and Sanders, Rogier W.

Published
2017
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19. A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure

Author

Lee, Jeong Hyun, Andrabi, Raiees, Su, Ching-Yao, Yasmeen, Anila, Julien, Jean-Philippe, Kong, Leopold, Wu, Nicholas C., McBride, Ryan, Sok, Devin, Pauthner, Matthias, Cottrell, Christopher A., Nieusma, Travis, Blattner, Claudia, Paulson, James C., Klasse, Per Johan, Wilson, Ian A., Burton, Dennis R., and Ward, Andrew B.

Published
2017
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21. Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle

Author

Brouwer, Philip J. M., Antanasijevic, Aleksandar, Berndsen, Zachary, Yasmeen, Anila, Fiala, Brooke, Bijl, Tom P. L., Bontjer, Ilja, Bale, Jacob B., Sheffler, William, Allen, Joel D., Schorcht, Anna, Burger, Judith A., Camacho, Miguel, Ellis, Daniel, Cottrell, Christopher A., Behrens, Anna-Janina, Catalano, Marco, del Moral-Sánchez, Iván, Ketas, Thomas J., LaBranche, Celia, van Gils, Marit J., Sliepen, Kwinten, Stewart, Lance J., Crispin, Max, Montefiori, David C., Baker, David, Moore, John P., Klasse, Per Johan, Ward, Andrew B., King, Neil P., and Sanders, Rogier W.

Published
2019
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22. Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Author

Caniels, Tom G., primary, Medina-Ramírez, Max, additional, Zhang, Jinsong, additional, Sarkar, Anita, additional, Kumar, Sonu, additional, LaBranche, Alex, additional, Derking, Ronald, additional, Allen, Joel D., additional, Snitselaar, Jonne L., additional, Capella-Pujol, Joan, additional, Sánchez, Iván del Moral, additional, Yasmeen, Anila, additional, Diaz, Marilyn, additional, Aldon, Yoann, additional, Bijl, Tom P.L., additional, Venkatayogi, Sravani, additional, Martin Beem, Joshua S., additional, Newman, Amanda, additional, Jiang, Chuancang, additional, Lee, Wen-Hsin, additional, Pater, Maarten, additional, Burger, Judith A., additional, van Breemen, Mariëlle J., additional, de Taeye, Steven W., additional, Rantalainen, Kimmo, additional, LaBranche, Celia, additional, Saunders, Kevin O., additional, Montefiori, David, additional, Ozorowski, Gabriel, additional, Ward, Andrew B., additional, Crispin, Max, additional, Moore, John P., additional, Klasse, Per Johan, additional, Haynes, Barton F., additional, Wilson, Ian A., additional, Wiehe, Kevin, additional, Verkoczy, Laurent, additional, and Sanders, Rogier W., additional

Published
2023
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24. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Author

de Taeye, Steven W., Ozorowski, Gabriel, Torrents de la Peña, Alba, Guttman, Miklos, Julien, Jean-Philippe, van den Kerkhof, Tom L.G.M., Burger, Judith A., Pritchard, Laura K., Pugach, Pavel, Yasmeen, Anila, Crampton, Jordan, Hu, Joyce, Bontjer, Ilja, Torres, Jonathan L., Arendt, Heather, DeStefano, Joanne, Koff, Wayne C., Schuitemaker, Hanneke, Eggink, Dirk, Berkhout, Ben, Dean, Hansi, LaBranche, Celia, Crotty, Shane, Crispin, Max, Montefiori, David C., Klasse, P.J., Lee, Kelly K., Moore, John P., Wilson, Ian A., Ward, Andrew B., and Sanders, Rogier W.

Published
2015
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34. An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability

Author

van Gils, Marit J., van den Kerkhof, Tom L. G. M., Ozorowski, Gabriel, Cottrell, Christopher A., Sok, Devin, Pauthner, Matthias, Pallesen, Jesper, de Val, Natalia, Yasmeen, Anila, de Taeye, Steven W., Schorcht, Anna, Gumbs, Stephanie, Johanna, Inez, Saye-Francisco, Karen, Liang, Chi-Hui, Landais, Elise, Nie, Xiaoyan, Pritchard, Laura K., Crispin, Max, Kelsoe, Garnett, Wilson, Ian A., Schuitemaker, Hanneke, Klasse, Per Johan, Moore, John P., Burton, Dennis R., Ward, Andrew B., and Sanders, Rogier W.

Published
2017
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35. HIV-1 Germline-Targeting Vaccine Regimen Selects for Rare Immunoglobulin Insertions and Deletions Typical of VRC01-Class Antibodies

Author

Caniels, Tom G., primary, Medina-Ramírez, Max, additional, Zhang, Jinsong, additional, Sarkar, Anita, additional, Kumar, Sonu, additional, LaBranche, Alex, additional, Derking, Ronald, additional, Allen, Joel D., additional, Snitselaar, Jonne L., additional, Capella-Pujol, Joan, additional, del Moral Sánchez, Iván, additional, Yasmeen, Anila, additional, Diaz, Marilyn, additional, Aldon, Yoann, additional, Bijl, Tom PL, additional, Venkatayogi, Sravani, additional, Martin Beem, Joshua S., additional, Newman, Amanda, additional, Jiang, Chuancang, additional, Lee, Wen-Hsin, additional, Pater, Maarten, additional, Burger, Judith A., additional, van Breemen, Mariëlle J., additional, LaBranche, Celia C., additional, Saunders, Kevin O., additional, Montefiori, David C., additional, Ozorowski, Gabriel, additional, Ward, Andrew B., additional, Crispin, Max, additional, Moore, John P., additional, Klasse, Per Johan, additional, Haynes, Barton F., additional, Wilson, Ian, additional, Wiehe, Kevin, additional, Verkoczy, Laurent, additional, and Sanders, Rogier, additional

Published
2022
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37. Antibody Responses to SARS-CoV-2 mRNA Vaccines Are Detectable in Saliva

Author

Ketas, Thomas J., primary, Chaturbhuj, Devidas, additional, Cruz Portillo, Victor M., additional, Francomano, Erik, additional, Golden, Encouse, additional, Chandrasekhar, Sharanya, additional, Debnath, Gargi, additional, Diaz-Tapia, Randy, additional, Yasmeen, Anila, additional, Kramer, Kyle D., additional, Munawar, Tarek, additional, Leconet, Wilhem, additional, Zhao, Zhen, additional, Brouwer, Philip J.M., additional, Cushing, Melissa M., additional, Sanders, Rogier W., additional, Cupo, Albert, additional, Klasse, P.J., additional, Formenti, Silvia C., additional, and Moore, John P., additional

Published
2021
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38. Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

Author

Brouwer, Philip J. M., primary, Antanasijevic, Aleksandar, additional, de Gast, Marlon, additional, Allen, Joel D., additional, Bijl, Tom P. L., additional, Yasmeen, Anila, additional, Ravichandran, Rashmi, additional, Burger, Judith A., additional, Ozorowski, Gabriel, additional, Torres, Jonathan L., additional, LaBranche, Celia, additional, Montefiori, David C., additional, Ringe, Rajesh P., additional, van Gils, Marit J., additional, Moore, John P., additional, Klasse, Per Johan, additional, Crispin, Max, additional, King, Neil P., additional, Ward, Andrew B., additional, and Sanders, Rogier W., additional

Published
2020
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39. Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Author

Schorcht, Anna, primary, van den Kerkhof, Tom L. G. M., additional, Cottrell, Christopher A., additional, Allen, Joel D., additional, Torres, Jonathan L., additional, Behrens, Anna-Janina, additional, Schermer, Edith E., additional, Burger, Judith A., additional, de Taeye, Steven W., additional, Torrents de la Peña, Alba, additional, Bontjer, Ilja, additional, Gumbs, Stephanie, additional, Ozorowski, Gabriel, additional, LaBranche, Celia C., additional, de Val, Natalia, additional, Yasmeen, Anila, additional, Klasse, Per Johan, additional, Montefiori, David C., additional, Moore, John P., additional, Schuitemaker, Hanneke, additional, Crispin, Max, additional, van Gils, Marit J., additional, Ward, Andrew B., additional, and Sanders, Rogier W., additional

Published
2020
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40. Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens

Author

Antanasijevic, Aleksandar, primary, Ueda, George, additional, Brouwer, Philip J. M., additional, Copps, Jeffrey, additional, Huang, Deli, additional, Allen, Joel D., additional, Cottrell, Christopher A., additional, Yasmeen, Anila, additional, Sewall, Leigh M., additional, Bontjer, Ilja, additional, Ketas, Thomas J., additional, Turner, Hannah L., additional, Berndsen, Zachary T., additional, Montefiori, David C., additional, Klasse, Per Johan, additional, Crispin, Max, additional, Nemazee, David, additional, Moore, John P., additional, Sanders, Rogier W., additional, King, Neil P., additional, Baker, David, additional, and Ward, Andrew B., additional

Published
2020
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41. Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

Author

Ueda, George, primary, Antanasijevic, Aleksandar, additional, Fallas, Jorge A, additional, Sheffler, William, additional, Copps, Jeffrey, additional, Ellis, Daniel, additional, Hutchinson, Geoffrey B, additional, Moyer, Adam, additional, Yasmeen, Anila, additional, Tsybovsky, Yaroslav, additional, Park, Young-Jun, additional, Bick, Matthew J, additional, Sankaran, Banumathi, additional, Gillespie, Rebecca A, additional, Brouwer, Philip JM, additional, Zwart, Peter H, additional, Veesler, David, additional, Kanekiyo, Masaru, additional, Graham, Barney S, additional, Sanders, Rogier W, additional, Moore, John P, additional, Klasse, Per Johan, additional, Ward, Andrew B, additional, King, Neil P, additional, and Baker, David, additional

Published
2020
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42. Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike

Author

Derking, Ronald, primary, Allen, Joel D., additional, Cottrell, Christopher A., additional, Sliepen, Kwinten, additional, Seabright, Gemma E., additional, Lee, Wen-Hsin, additional, Rantalainen, Kimmo, additional, Antanasijevic, Aleksandar, additional, Copps, Jeffrey, additional, Yasmeen, Anila, additional, van der Woude, Patricia, additional, de Taeye, Steven W., additional, van den Kerkhof, Tom L.G.M., additional, Klasse, P.J., additional, Ozorowski, Gabriel, additional, van Gils, Marit J., additional, Moore, John P., additional, Ward, Andrew B., additional, Crispin, Max, additional, and Sanders, Rogier W., additional

Published
2020
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43. Author response: Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

Author

Ueda, George, primary, Antanasijevic, Aleksandar, additional, Fallas, Jorge A, additional, Sheffler, William, additional, Copps, Jeffrey, additional, Ellis, Daniel, additional, Hutchinson, Geoffrey B, additional, Moyer, Adam, additional, Yasmeen, Anila, additional, Tsybovsky, Yaroslav, additional, Park, Young-Jun, additional, Bick, Matthew J, additional, Sankaran, Banumathi, additional, Gillespie, Rebecca A, additional, Brouwer, Philip JM, additional, Zwart, Peter H, additional, Veesler, David, additional, Kanekiyo, Masaru, additional, Graham, Barney S, additional, Sanders, Rogier W, additional, Moore, John P, additional, Klasse, Per Johan, additional, Ward, Andrew B, additional, King, Neil P, additional, and Baker, David, additional

Published
2020
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45. cGMP production and analysis of BG505 SOSIP.664, an extensively glycosylated, trimeric HIV-1 envelope glycoprotein vaccine candidate

Author

dey, Antu K., Cupo, Albert, Ozorowski, Gabriel, Sharma, Vaneet K., Behrens, Anna-Janina, Go, Eden P., Ketas, Thomas J., Yasmeen, Anila, Klasse, Per J., Sayeed, Eddy, Desaire, Heather, Crispin, Max, Wilson, Ian A., Sanders, Rogier W., Hassell, Thomas, Ward, Andrew B., Moore, John P., AII - Infectious diseases, Medical Microbiology and Infection Prevention, and AII - Amsterdam institute for Infection and Immunity

Abstract

We describe the properties of BG505 SOSIP.664 HIV-1 envelope glycoprotein trimers produced under current Good Manufacturing Practice (cGMP) conditions. These proteins are the first of a new generation of native-like trimers that are the basis for many structure-guided immunogen development programs aimed at devising how to induce broadly neutralizing antibodies (bNAbs) to HIV-1 by vaccination. The successful translation of this prototype demonstrates the feasibility of producing similar immunogens on an appropriate scale and of an acceptable quality for Phase I experimental medicine clinical trials. BG505 SOSIP.664 trimers are extensively glycosylated, contain numerous disulfide bonds and require proteolytic cleavage, all properties that pose a substantial challenge to cGMP production. Our strategy involved creating a stable CHO cell line that was adapted to serum-free culture conditions to produce envelope glycoproteins. The trimers were then purified by chromatographic methods using a 2G12 bNAb affinity column and size-exclusion chromatography. The chosen procedures allowed any adventitious viruses to be cleared from the final product to the required extent of >12 log10. The final cGMP production run yielded 3.52 g (peptidic mass) of fully purified trimers (Drug Substance) from a 200 L bioreactor, a notable yield for such a complex glycoprotein. The purified trimers were fully native-like as judged by negative-stain electron microscopy, and were stable over a multi-month period at room temperature or below and for at least 1 week at 50°C. Their antigenicity, disulfide bond patterns, and glycan composition were consistent with trimers produced on a research laboratory scale. The methods reported here should pave the way for the cGMP production of other native-like Env glycoprotein trimers of various designs and genotypes.

Published
2018

48. Reducing V3 antigenicity and immunogenicity on soluble, native-like HIV-1 Env SOSIP trimers

Author

Ringe, Rajesh P., Ozorowski, Gabriel, Rantalainen, Kimmo, Struwe, Weston B., Matthews, Katie, Torres, Jonathan L., Yasmeen, Anila, Cottrell, Christopher A., Ketas, Thomas J., LaBranche, Celia C., Montefiori, David C., Cupo, Albert, Crispin, Max, Wilson, Ian A., Ward, Andrew B., Sanders, Rogier W., Klasse, P. J., Moore, John P., AII - Infectious diseases, Medical Microbiology and Infection Prevention, and AII - Amsterdam institute for Infection and Immunity

Abstract

Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such "off-target" immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man(6)GlcNAc(2) form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan-and E64K-modified trimer variant, BG505 SOSIP. 664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP. 664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes

Published
2017

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