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1. Vaccination induces broadly neutralizing antibody precursors to HIV gp41

Author

Schiffner, Torben, Phung, Ivy, Ray, Rashmi, Irimia, Adriana, Tian, Ming, Swanson, Olivia, Lee, Jeong Hyun, Lee, Chang-Chun D., Marina-Zárate, Ester, Cho, So Yeon, Huang, Jiachen, Ozorowski, Gabriel, Skog, Patrick D., Serra, Andreia M., Rantalainen, Kimmo, Allen, Joel D., Baboo, Sabyasachi, Rodriguez, Oscar L., Himansu, Sunny, Zhou, Jianfu, Hurtado, Jonathan, Flynn, Claudia T., McKenney, Katherine, Havenar-Daughton, Colin, Saha, Swati, Shields, Kaitlyn, Schultze, Steven, Smith, Melissa L., Liang, Chi-Hui, Toy, Laura, Pecetta, Simone, Lin, Ying-Cing, Willis, Jordan R., Sesterhenn, Fabian, Kulp, Daniel W., Hu, Xiaozhen, Cottrell, Christopher A., Zhou, Xiaoya, Ruiz, Jennifer, Wang, Xuesong, Nair, Usha, Kirsch, Kathrin H., Cheng, Hwei-Ling, Davis, Jillian, Kalyuzhniy, Oleksandr, Liguori, Alessia, Diedrich, Jolene K., Ngo, Julia T., Lewis, Vanessa, Phelps, Nicole, Tingle, Ryan D., Spencer, Skye, Georgeson, Erik, Adachi, Yumiko, Kubitz, Michael, Eskandarzadeh, Saman, Elsliger, Marc A., Amara, Rama R., Landais, Elise, Briney, Bryan, Burton, Dennis R., Carnathan, Diane G., Silvestri, Guido, Watson, Corey T., Yates, III, John R., Paulson, James C., Crispin, Max, Grigoryan, Gevorg, Ward, Andrew B., Sok, Devin, Alt, Frederick W., Wilson, Ian A., Batista, Facundo D., Crotty, Shane, and Schief, William R.

Published
2024
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3. Priming antibody responses to the fusion peptide in rhesus macaques

Author

Cottrell, Christopher A., Pratap, Payal P., Cirelli, Kimberly M., Carnathan, Diane G., Enemuo, Chiamaka A., Antanasijevic, Aleksandar, Ozorowski, Gabriel, Sewall, Leigh M., Gao, Hongmei, Allen, Joel D., Nogal, Bartek, Silva, Murillo, Bhiman, Jinal, Pauthner, Matthias, Irvine, Darrell J., Montefiori, David, Crispin, Max, Burton, Dennis R., Silvestri, Guido, Crotty, Shane, and Ward, Andrew B.

Published
2024
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4. Triple tandem trimer immunogens for HIV-1 and influenza nucleic acid-based vaccines

Author

del Moral-Sánchez, Iván, Wee, Edmund G., Xian, Yuejiao, Lee, Wen-Hsin, Allen, Joel D., Torrents de la Peña, Alba, Fróes Rocha, Rebeca, Ferguson, James, León, André N., Koekkoek, Sylvie, Schermer, Edith E., Burger, Judith A., Kumar, Sanjeev, Zwolsman, Robby, Brinkkemper, Mitch, Aartse, Aafke, Eggink, Dirk, Han, Julianna, Yuan, Meng, Crispin, Max, Ozorowski, Gabriel, Ward, Andrew B., Wilson, Ian A., Hanke, Tomáš, Sliepen, Kwinten, and Sanders, Rogier W.

Published
2024
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5. Improving the secretion of designed protein assemblies through negative design of cryptic transmembrane domains

Author

Wang, Jing Yang, Khmelinskaia, Alena, Sheffler, William, Miranda, Marcos C, Antanasijevic, Aleksandar, Borst, Andrew J, Torres, Susana V, Shu, Chelsea, Hsia, Yang, Nattermann, Una, Ellis, Daniel, Walkey, Carl, Ahlrichs, Maggie, Chan, Sidney, Kang, Alex, Nguyen, Hannah, Sydeman, Claire, Sankaran, Banumathi, Wu, Mengyu, Bera, Asim K, Carter, Lauren, Fiala, Brooke, Murphy, Michael, Baker, David, Ward, Andrew B, and King, Neil P

Subjects
Medical Biotechnology, Biological Sciences, Biomedical and Clinical Sciences, Bioengineering, Vaccine Related, Biotechnology, Nanotechnology, Generic health relevance, Proteins, Nanoparticles, Vaccines, biochemistry, protein design, nanoparticles
Abstract

Computationally designed protein nanoparticles have recently emerged as a promising platform for the development of new vaccines and biologics. For many applications, secretion of designed nanoparticles from eukaryotic cells would be advantageous, but in practice, they often secrete poorly. Here we show that designed hydrophobic interfaces that drive nanoparticle assembly are often predicted to form cryptic transmembrane domains, suggesting that interaction with the membrane insertion machinery could limit efficient secretion. We develop a general computational protocol, the Degreaser, to design away cryptic transmembrane domains without sacrificing protein stability. The retroactive application of the Degreaser to previously designed nanoparticle components and nanoparticles considerably improves secretion, and modular integration of the Degreaser into design pipelines results in new nanoparticles that secrete as robustly as naturally occurring protein assemblies. Both the Degreaser protocol and the nanoparticles we describe may be broadly useful in biotechnological applications.

Published
2023

7. Structural insights into the broad protection against H1 influenza viruses by a computationally optimized hemagglutinin vaccine

Author

Dzimianski, John V, Han, Julianna, Sautto, Giuseppe A, O’Rourke, Sara M, Cruz, Joseph M, Pierce, Spencer R, Ecker, Jeffrey W, Carlock, Michael A, Nagashima, Kaito A, Mousa, Jarrod J, Ross, Ted M, Ward, Andrew B, and DuBois, Rebecca M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Influenza, Vaccine Related, Immunization, Infectious Diseases, Biodefense, Biotechnology, Prevention, Emerging Infectious Diseases, Pneumonia & Influenza, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Humans, Orthomyxoviridae Infections, Influenza Vaccines, Hemagglutinins, Influenza A Virus, H1N1 Subtype, Antibodies, Viral, Hemagglutinin Glycoproteins, Influenza Virus, Biological sciences, Biomedical and clinical sciences
Abstract

Influenza virus poses an ongoing human health threat with pandemic potential. Due to mutations in circulating strains, formulating effective vaccines remains a challenge. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins is a promising vaccine strategy to protect against a wide range of current and future influenza viruses. Though effective in preclinical studies, the mechanistic basis driving the broad reactivity of COBRA proteins remains to be elucidated. Here, we report the crystal structure of the COBRA HA termed P1 and identify antigenic and glycosylation properties that contribute to its immunogenicity. We further report the cryo-EM structure of the P1-elicited broadly neutralizing antibody 1F8 bound to COBRA P1, revealing 1F8 to recognize an atypical receptor binding site epitope via an unexpected mode of binding.

Published
2023

8. Author Correction: Vaccination induces broadly neutralizing antibody precursors to HIV gp41

Author

Schiffner, Torben, Phung, Ivy, Ray, Rashmi, Irimia, Adriana, Tian, Ming, Swanson, Olivia, Lee, Jeong Hyun, Lee, Chang-Chun D., Marina-Zárate, Ester, Cho, So Yeon, Huang, Jiachen, Ozorowski, Gabriel, Skog, Patrick D., Serra, Andreia M., Rantalainen, Kimmo, Allen, Joel D., Baboo, Sabyasachi, Rodriguez, Oscar L., Himansu, Sunny, Zhou, Jianfu, Hurtado, Jonathan, Flynn, Claudia T., McKenney, Katherine, Havenar-Daughton, Colin, Saha, Swati, Shields, Kaitlyn, Schultze, Steven, Smith, Melissa L., Liang, Chi-Hui, Toy, Laura, Pecetta, Simone, Lin, Ying-Cing, Willis, Jordan R., Sesterhenn, Fabian, Kulp, Daniel W., Hu, Xiaozhen, Cottrell, Christopher A., Zhou, Xiaoya, Ruiz, Jennifer, Wang, Xuesong, Nair, Usha, Kirsch, Kathrin H., Cheng, Hwei-Ling, Davis, Jillian, Kalyuzhniy, Oleksandr, Liguori, Alessia, Diedrich, Jolene K., Ngo, Julia T., Lewis, Vanessa, Phelps, Nicole, Tingle, Ryan D., Spencer, Skye, Georgeson, Erik, Adachi, Yumiko, Kubitz, Michael, Eskandarzadeh, Saman, Elsliger, Marc A., Amara, Rama R., Landais, Elise, Briney, Bryan, Burton, Dennis R., Carnathan, Diane G., Silvestri, Guido, Watson, Corey T., Yates, III, John R., Paulson, James C., Crispin, Max, Grigoryan, Gevorg, Ward, Andrew B., Sok, Devin, Alt, Frederick W., Wilson, Ian A., Batista, Facundo D., Crotty, Shane, and Schief, William R.

Published
2024
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10. Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques

Author

He, Wan-Ting, Yuan, Meng, Callaghan, Sean, Musharrafieh, Rami, Song, Ge, Silva, Murillo, Beutler, Nathan, Lee, Wen-Hsin, Yong, Peter, Torres, Jonathan L, Melo, Mariane, Zhou, Panpan, Zhao, Fangzhu, Zhu, Xueyong, Peng, Linghang, Huang, Deli, Anzanello, Fabio, Ricketts, James, Parren, Mara, Garcia, Elijah, Ferguson, Melissa, Rinaldi, William, Rawlings, Stephen A, Nemazee, David, Smith, Davey M, Briney, Bryan, Safonova, Yana, Rogers, Thomas F, Dan, Jennifer M, Zhang, Zeli, Weiskopf, Daniela, Sette, Alessandro, Crotty, Shane, Irvine, Darrell J, Ward, Andrew B, Wilson, Ian A, Burton, Dennis R, and Andrabi, Raiees

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Vaccine Related, Pneumonia & Influenza, Emerging Infectious Diseases, Biotechnology, Biodefense, Prevention, Immunization, Vaccine Related (AIDS), Pneumonia, Lung, Infectious Diseases, Infection, Good Health and Well Being, Animals, Antibodies, Neutralizing, Antibodies, Viral, Broadly Neutralizing Antibodies, COVID-19, Epitopes, Humans, Macaca mulatta, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS-related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.

Published
2022

11. The Pre-Existing Human Antibody Repertoire to Computationally Optimized Influenza H1 Hemagglutinin Vaccines.

Author

Nagashima, Kaito, Dzimianski, John V, Han, Julianna, Abbadi, Nada, Gingerich, Aaron D, Royer, Fredejah, O'Rourke, Sara, Sautto, Giuseppe A, Ross, Ted M, Ward, Andrew B, DuBois, Rebecca M, and Mousa, Jarrod J

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Biodefense, Biotechnology, Pneumonia & Influenza, Emerging Infectious Diseases, Prevention, Immunization, Vaccine Related, Influenza, Infectious Diseases, Infection, Good Health and Well Being, Antibodies, Monoclonal, Antibodies, Viral, B-Lymphocytes, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza Vaccines, Influenza, Human, Biochemistry and cell biology
Abstract

Computationally optimized broadly reactive Ag (COBRA) hemagglutinin (HA) immunogens have previously been generated for several influenza subtypes to improve vaccine-elicited Ab breadth. As nearly all individuals have pre-existing immunity to influenza viruses, influenza-specific memory B cells will likely be recalled upon COBRA HA vaccination. We determined the epitope specificity and repertoire characteristics of pre-existing human B cells to H1 COBRA HA Ags. Cross-reactivity between wild-type HA and H1 COBRA HA proteins P1, X6, and Y2 were observed for isolated mAbs. The mAbs bound five distinct epitopes on the pandemic A/California/04/2009 HA head and stem domains, and most mAbs had hemagglutination inhibition and neutralizing activity against 2009 pandemic H1 strains. Two head-directed mAbs, CA09-26 and CA09-45, had hemagglutination inhibition and neutralizing activity against a prepandemic H1 strain. One mAb, P1-05, targeted the stem region of H1 HA, but did not compete with a known stem-targeting H1 mAb. We determined that mAb P1-05 recognizes a recently discovered HA epitope, the anchor epitope, and we identified similar mAbs using B cell repertoire sequencing. In addition, the trimerization domain distance from HA was critical to recognition of this epitope by mAb P1-05, suggesting the importance of protein design for vaccine formulations. Overall, these data indicate that seasonally vaccinated individuals possess a population of functional H1 COBRA HA-reactive B cells that target head, central stalk, and anchor epitopes, and they demonstrate the importance of structure-based assessment of subunit protein vaccine candidates to ensure accessibility of optimal protein epitopes.

Published
2022

12. Targeted isolation of diverse human protective broadly neutralizing antibodies against SARS-like viruses

Author

He, Wan-ting, Musharrafieh, Rami, Song, Ge, Dueker, Katharina, Tse, Longping V, Martinez, David R, Schäfer, Alexandra, Callaghan, Sean, Yong, Peter, Beutler, Nathan, Torres, Jonathan L, Volk, Reid M, Zhou, Panpan, Yuan, Meng, Liu, Hejun, Anzanello, Fabio, Capozzola, Tazio, Parren, Mara, Garcia, Elijah, Rawlings, Stephen A, Smith, Davey M, Wilson, Ian A, Safonova, Yana, Ward, Andrew B, Rogers, Thomas F, Baric, Ralph S, Gralinski, Lisa E, Burton, Dennis R, and Andrabi, Raiees

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Vaccine Related, Biodefense, Lung, Pneumonia & Influenza, Emerging Infectious Diseases, Infectious Diseases, Prevention, Pneumonia, Immunization, Biotechnology, Good Health and Well Being, Antibodies, Neutralizing, Antibodies, Viral, Broadly Neutralizing Antibodies, COVID-19, Humans, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Biochemistry and cell biology
Abstract

The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.

Published
2022

13. Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface

Author

Wolters, Rachael M., Ferguson, James A., Nuñez, Ivette A., Chen, Elaine E., Sornberger, Ty, Myers, Luke, Oeverdieck, Svearike, Raghavan, Sai Sundar Rajan, Kona, Chandrahaas, Handal, Laura S., Esilu, Trevor E., Davidson, Edgar, Doranz, Benjamin J., Engdahl, Taylor B., Kose, Nurgun, Williamson, Lauren E., Creech, C. Buddy, Gibson-Corley, Katherine N., Ward, Andrew B., and Crowe, James E., Jr.

Published
2024
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15. A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates

Author

Phung, Ivy, Rodrigues, Kristen A., Marina-Zárate, Ester, Maiorino, Laura, Pahar, Bapi, Lee, Wen-Hsin, Melo, Mariane, Kaur, Amitinder, Allers, Carolina, Fahlberg, Marissa, Grasperge, Brooke F., Dufour, Jason P., Schiro, Faith, Aye, Pyone P., Lopez, Paul G., Torres, Jonathan L., Ozorowski, Gabriel, Eskandarzadeh, Saman, Kubitz, Michael, Georgeson, Erik, Groschel, Bettina, Nedellec, Rebecca, Bick, Michael, Kaczmarek Michaels, Katarzyna, Gao, Hongmei, Shen, Xiaoying, Carnathan, Diane G., Silvestri, Guido, Montefiori, David C., Ward, Andrew B., Hangartner, Lars, Veazey, Ronald S., Burton, Dennis R., Schief, William R., Irvine, Darrell J., and Crotty, Shane

Published
2023
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16. A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection

Author

Ronk, Adam J., Lloyd, Nicole M., Zhang, Min, Atyeo, Caroline, Perrett, Hailee R., Mire, Chad E., Hastie, Kathryn M., Sanders, Rogier W., Brouwer, Philip J. M., Saphire, Erica Olmann, Ward, Andrew B., Ksiazek, Thomas G., Alvarez Moreno, Juan Carlos, Thaker, Harshwardhan M., Alter, Galit, Himansu, Sunny, Carfi, Andrea, and Bukreyev, Alexander

Published
2023
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17. Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection

Author

Martin, Gregory M., Torres, Jonathan L., Pholcharee, Tossapol, Oyen, David, Flores-Garcia, Yevel, Gibson, Grace, Moskovitz, Re’em, Beutler, Nathan, Jung, Diana D., Copps, Jeffrey, Lee, Wen-Hsin, Gonzalez-Paez, Gonzalo, Emerling, Daniel, MacGill, Randall S., Locke, Emily, King, C. Richter, Zavala, Fidel, Wilson, Ian A., and Ward, Andrew B.

Published
2023
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18. Profound structural conservation of chemically cross-linked HIV-1 envelope glycoprotein experimental vaccine antigens

Author

Martin, Gregory M., Russell, Rebecca A., Mundsperger, Philip, Harris, Scarlett, Jovanoska, Lu, Trajano, Luiza Farache, Schiffner, Torben, Fabian, Katalin, Tolazzi, Monica, Scarlatti, Gabriella, McFarlane, Leon, Cheeseman, Hannah, Aldon, Yoann, Schermer, Edith E., Breemen, Marielle, Sliepen, Kwinten, Katinger, Dietmar, Kunert, Renate, Sanders, Rogier W., Shattock, Robin, Ward, Andrew B., and Sattentau, Quentin J.

Published
2023
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21. Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates

Author

Zhang, Yi-Nan, Paynter, Jennifer, Antanasijevic, Aleksandar, Allen, Joel D., Eldad, Mor, Lee, Yi-Zong, Copps, Jeffrey, Newby, Maddy L., He, Linling, Chavez, Deborah, Frost, Pat, Goodroe, Anna, Dutton, John, Lanford, Robert, Chen, Christopher, Wilson, Ian A., Crispin, Max, Ward, Andrew B., and Zhu, Jiang

Published
2023
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23. Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses

Author

Ray, Rashmi, Nait Mohamed, Faez Amokrane, Maurer, Daniel P., Huang, Jiachen, Alpay, Berk A., Ronsard, Larance, Xie, Zhenfei, Han, Julianna, Fernandez-Quintero, Monica, Phan, Quynh Anh, Ursin, Rebecca L., Vu, Mya, Kirsch, Kathrin H., Prum, Thavaleak, Rosado, Victoria C., Bracamonte-Moreno, Thalia, Okonkwo, Vintus, Bals, Julia, McCarthy, Caitlin, Nair, Usha, Kanekiyo, Masaru, Ward, Andrew B., Schmidt, Aaron G., Batista, Facundo D., and Lingwood, Daniel

Published
2024
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25. Cross-reactive serum and memory B-cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection.

Author

Song, Ge, He, Wan-Ting, Callaghan, Sean, Anzanello, Fabio, Huang, Deli, Ricketts, James, Torres, Jonathan L, Beutler, Nathan, Peng, Linghang, Vargas, Sirena, Cassell, Jon, Parren, Mara, Yang, Linlin, Ignacio, Caroline, Smith, Davey M, Voss, James E, Nemazee, David, Ward, Andrew B, Rogers, Thomas, Burton, Dennis R, and Andrabi, Raiees

Subjects
B-Lymphocytes, Humans, SARS Virus, Antibodies, Viral, Cross Reactions, Immunologic Memory, Female, Male, Cross Protection, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus, COVID-19, SARS-CoV-2
Abstract

Pre-existing immunity to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, induced from natural infection or vaccination. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. Here we compare serum antibody and memory B cell responses to coronavirus spike proteins from pre-pandemic and SARS-CoV-2 convalescent donors using binding and functional assays. We show weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we find evidence of pre-existing cross-reactive memory B cells that are activated during SARS-CoV-2 infection. Monoclonal antibodies show varying degrees of cross-reactivity with betacoronaviruses, including SARS-CoV-1 and endemic coronaviruses. We identify one cross-reactive neutralizing antibody specific to the S2 subunit of the S protein. Our results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2.

Published
2021

26. Broad SARS-CoV-2 neutralization by monoclonal and bispecific antibodies derived from a Gamma-infected individual

Author

Guerra, Denise, Beaumont, Tim, Radić, Laura, Kerster, Gius, van der Straten, Karlijn, Yuan, Meng, Torres, Jonathan L., Lee, Wen-Hsin, Liu, Hejun, Poniman, Meliawati, Bontjer, Ilja, Burger, Judith A., Claireaux, Mathieu, Caniels, Tom G., Snitselaar, Jonne L., Bijl, Tom P.L., Kruijer, Sabine, Ozorowski, Gabriel, Gideonse, David, Sliepen, Kwinten, Ward, Andrew B., Eggink, Dirk, de Bree, Godelieve J., Wilson, Ian A., Sanders, Rogier W., and van Gils, Marit J.

Published
2023
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27. Human anti-N1 monoclonal antibodies elicited by pandemic H1N1 virus infection broadly inhibit HxN1 viruses in vitro and in vivo

Author

Hansen, Lena, McMahon, Meagan, Turner, Hannah L., Zhu, Xueyong, Turner, Jackson S., Ozorowski, Gabriel, Stadlbauer, Daniel, Vahokoski, Juha, Schmitz, Aaron J., Rizk, Amena A., Alsoussi, Wafaa B., Strohmeier, Shirin, Yu, Wenli, Choreño-Parra, José Alberto, Jiménez-Alvarez, Luis, Cruz-Lagunas, Alfredo, Zúñiga, Joaquín, Mudd, Philip A., Cox, Rebecca J., Wilson, Ian A., Ward, Andrew B., Ellebedy, Ali H., and Krammer, Florian

Published
2023
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29. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

Author

Clausen, Thomas Mandel, Sandoval, Daniel R, Spliid, Charlotte B, Pihl, Jessica, Perrett, Hailee R, Painter, Chelsea D, Narayanan, Anoop, Majowicz, Sydney A, Kwong, Elizabeth M, McVicar, Rachael N, Thacker, Bryan E, Glass, Charles A, Yang, Zhang, Torres, Jonathan L, Golden, Gregory J, Bartels, Phillip L, Porell, Ryan N, Garretson, Aaron F, Laubach, Logan, Feldman, Jared, Yin, Xin, Pu, Yuan, Hauser, Blake M, Caradonna, Timothy M, Kellman, Benjamin P, Martino, Cameron, Gordts, Philip LSM, Chanda, Sumit K, Schmidt, Aaron G, Godula, Kamil, Leibel, Sandra L, Jose, Joyce, Corbett, Kevin D, Ward, Andrew B, Carlin, Aaron F, and Esko, Jeffrey D

Subjects
Biochemistry and Cell Biology, Biological Sciences, Coronaviruses, Emerging Infectious Diseases, Infectious Diseases, Coronaviruses Therapeutics and Interventions, Infection, Amino Acid Sequence, Angiotensin-Converting Enzyme 2, Betacoronavirus, Binding Sites, COVID-19, Cell Line, Coronavirus Infections, Heparin, Heparitin Sulfate, Humans, Kidney, Lung, Molecular Dynamics Simulation, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, Protein Binding, Protein Domains, Recombinant Proteins, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Virus Internalization, coronavirus, heparan sulfate, heparan sulfate-binding proteins, heparin, lung epithelial cells, pseudotyped virus, spike proteins, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

Published
2020

30. Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Author

Song, Ge, He, Wan-Ting, Callaghan, Sean, Anzanello, Fabio, Huang, Deli, Ricketts, James, Torres, Jonathan L, Beutler, Nathan, Peng, Linghang, Vargas, Sirena, Cassell, Jon, Parren, Mara, Yang, Linlin, Ignacio, Caroline, Smith, Davey M, Voss, James E, Nemazee, David, Ward, Andrew B, Rogers, Thomas, Burton, Dennis R, and Andrabi, Raiees

Subjects
Infectious Diseases, Vaccine Related, Biotechnology, Immunization, Pneumonia, Lung, Pneumonia & Influenza, Biodefense, Prevention, Emerging Infectious Diseases, Infection, Good Health and Well Being
Abstract

Pre-existing immune responses to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, either induced in natural infection or through vaccination. Such consequences are well established in the influenza and flavivirus fields. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. We compared serum antibody and memory B cell responses to coronavirus spike (S) proteins from pre-pandemic and SARS-CoV-2 convalescent donors using a series of binding and functional assays. We found weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we found stronger evidence of pre-existing cross-reactive memory B cells that were activated on SARS-CoV-2 infection. Monoclonal antibodies (mAbs) isolated from the donors showed varying degrees of cross-reactivity with betacoronaviruses, including SARS and endemic coronaviruses. None of the cross-reactive mAbs were neutralizing except for one that targeted the S2 subunit of the S protein. The results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2.

Published
2020

31. 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

32. Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies

Author

Perrett, Hailee R., Brouwer, Philip J.M., Hurtado, Jonathan, Newby, Maddy L., Liu, Lin, Müller-Kräuter, Helena, Müller Aguirre, Sarah, Burger, Judith A., Bouhuijs, Joey H., Gibson, Grace, Messmer, Terrence, Schieffelin, John S., Antanasijevic, Aleksandar, Boons, Geert-Jan, Strecker, Thomas, Crispin, Max, Sanders, Rogier W., Briney, Bryan, and Ward, Andrew B.

Published
2023
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33. Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses

Author

Radić, Laura, Sliepen, Kwinten, Yin, Victor, Brinkkemper, Mitch, Capella-Pujol, Joan, Schriek, Angela I., Torres, Jonathan L., Bangaru, Sandhya, Burger, Judith A., Poniman, Meliawati, Bontjer, Ilja, Bouhuijs, Joey H., Gideonse, David, Eggink, Dirk, Ward, Andrew B., Heck, Albert J.R., Van Gils, Marit J., Sanders, Rogier W., and Schinkel, Janke

Published
2023
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34. Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Author

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

Published
2023
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35. Long-primed germinal centres with enduring affinity maturation and clonal migration

Author

Lee, Jeong Hyun, Sutton, Henry J., Cottrell, Christopher A., Phung, Ivy, Ozorowski, Gabriel, Sewall, Leigh M., Nedellec, Rebecca, Nakao, Catherine, Silva, Murillo, Richey, Sara T., Torre, Jonathan L., Lee, Wen-Hsin, Georgeson, Erik, Kubitz, Michael, Hodges, Sam, Mullen, Tina-Marie, Adachi, Yumiko, Cirelli, Kimberly M., Kaur, Amitinder, Allers, Carolina, Fahlberg, Marissa, Grasperge, Brooke F., Dufour, Jason P., Schiro, Faith, Aye, Pyone P., Kalyuzhniy, Oleksandr, Liguori, Alessia, Carnathan, Diane G., Silvestri, Guido, Shen, Xiaoying, Montefiori, David C., Veazey, Ronald S., Ward, Andrew B., Hangartner, Lars, Burton, Dennis R., Irvine, Darrell J., Schief, William R., and Crotty, Shane

Published
2022
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36. Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes

Author

Hurtado, Jonathan, primary, Rogers, Thomas F., additional, Jaffe, David B., additional, Adams, Bruce A., additional, Bangaru, Sandhya, additional, Garcia, Elijah, additional, Capozzola, Tazio, additional, Messmer, Terrence, additional, Sharma, Pragati, additional, Song, Ge, additional, Beutler, Nathan, additional, He, Wanting, additional, Dueker, Katharina, additional, Musharrafieh, Rami, additional, Burbach, Sarah, additional, Truong, Alina, additional, Stubbington, Michael J.T., additional, Burton, Dennis R., additional, Andrabi, Raiees, additional, Ward, Andrew B., additional, McDonnell, Wyatt J., additional, and Briney, Bryan, additional

Published
2024
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37. Co-display of diverse spike proteins on nanoparticles broadens sarbecovirus neutralizing antibody responses

Author

Brinkkemper, Mitch, Veth, Tim S., Brouwer, Philip J.M., Turner, Hannah, Poniman, Meliawati, Burger, Judith A., Bouhuijs, Joey H., Olijhoek, Wouter, Bontjer, Ilja, Snitselaar, Jonne L., Caniels, Tom G., van der Linden, Cynthia A., Ravichandran, Rashmi, Villaudy, Julien, van der Velden, Yme U., Sliepen, Kwinten, van Gils, Marit J., Ward, Andrew B., King, Neil P., Heck, Albert J.R., and Sanders, Rogier W.

Published
2022
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38. Antigen- and scaffold-specific antibody responses to protein nanoparticle immunogens

Author

Kraft, John C., Pham, Minh N., Shehata, Laila, Brinkkemper, Mitch, Boyoglu-Barnum, Seyhan, Sprouse, Kaitlin R., Walls, Alexandra C., Cheng, Suna, Murphy, Mike, Pettie, Deleah, Ahlrichs, Maggie, Sydeman, Claire, Johnson, Max, Blackstone, Alyssa, Ellis, Daniel, Ravichandran, Rashmi, Fiala, Brooke, Wrenn, Samuel, Miranda, Marcos, Sliepen, Kwinten, Brouwer, Philip J.M., Antanasijevic, Aleksandar, Veesler, David, Ward, Andrew B., Kanekiyo, Masaru, Pepper, Marion, Sanders, Rogier W., and King, Neil P.

Published
2022
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39. Innate cell markers that predict anti-HIV neutralizing antibody titers in vaccinated macaques

Author

Van Tilbeurgh, Matthieu, Maisonnasse, Pauline, Palgen, Jean-Louis, Tolazzi, Monica, Aldon, Yoann, Dereuddre-Bosquet, Nathalie, Cavarelli, Mariangela, Beignon, Anne-Sophie, Marcos-Lopez, Ernesto, Gallouet, Anne-Sophie, Gilson, Emmanuel, Ozorowski, Gabriel, Ward, Andrew B., Bontjer, Ilja, McKay, Paul F., Shattock, Robin J., Scarlatti, Gabriella, Sanders, Rogier W., and Le Grand, Roger

Published
2022
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40. Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape pathways

Author

Zhao, Fangzhu, Keating, Celina, Ozorowski, Gabriel, Shaabani, Namir, Francino-Urdaniz, Irene M., Barman, Shawn, Limbo, Oliver, Burns, Alison, Zhou, Panpan, Ricciardi, Michael J., Woehl, Jordan, Tran, Quoc, Turner, Hannah L., Peng, Linghang, Huang, Deli, Nemazee, David, Andrabi, Raiees, Sok, Devin, Teijaro, John R., Whitehead, Timothy A., Ward, Andrew B., Burton, Dennis R., and Jardine, Joseph G.

Published
2022
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42. Molecular insights into antibody-mediated protection against the prototypic simian immunodeficiency virus

Author

Zhao, Fangzhu, Berndsen, Zachary T., Pedreño-Lopez, Nuria, Burns, Alison, Allen, Joel D., Barman, Shawn, Lee, Wen-Hsin, Chakraborty, Srirupa, Gnanakaran, Sandrasegaram, Sewall, Leigh M., Ozorowski, Gabriel, Limbo, Oliver, Song, Ge, Yong, Peter, Callaghan, Sean, Coppola, Jessica, Weisgrau, Kim L., Lifson, Jeffrey D., Nedellec, Rebecca, Voigt, Thomas B., Laurino, Fernanda, Louw, Johan, Rosen, Brandon C., Ricciardi, Michael, Crispin, Max, Desrosiers, Ronald C., Rakasz, Eva G., Watkins, David I., Andrabi, Raiees, Ward, Andrew B., Burton, Dennis R., and Sok, Devin

Published
2022
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43. Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

Author

van Schooten, Jelle, Farokhi, Elinaz, Schorcht, Anna, van den Kerkhof, Tom L. G. M., Gao, Hongmei, van der Woude, Patricia, Burger, Judith A., Meesters, Tim G. Rijkhold, Bijl, Tom, Ghalaiyini, Riham, Turner, Hannah L., Dorning, Jessica, van Schaik, Barbera D. C., van Kampen, Antoine H. C., Labranche, Celia C., Stanfield, Robyn L., Sok, Devin, Montefiori, David C., Burton, Dennis R., Seaman, Michael S., Ozorowski, Gabriel, Wilson, Ian A., Sanders, Rogier W., Ward, Andrew B., and van Gils, Marit J.

Published
2022
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44. A public antibody class recognizes an S2 epitope exposed on open conformations of SARS-CoV-2 spike

Author

Claireaux, Mathieu, Caniels, Tom G., de Gast, Marlon, Han, Julianna, Guerra, Denise, Kerster, Gius, van Schaik, Barbera D. C., Jongejan, Aldo, Schriek, Angela I., Grobben, Marloes, Brouwer, Philip J. M., van der Straten, Karlijn, Aldon, Yoann, Capella-Pujol, Joan, Snitselaar, Jonne L., Olijhoek, Wouter, Aartse, Aafke, Brinkkemper, Mitch, Bontjer, Ilja, Burger, Judith A., Poniman, Meliawati, Bijl, Tom P. L., Torres, Jonathan L., Copps, Jeffrey, Martin, Isabel Cuella, de Taeye, Steven W., de Bree, Godelieve J., Ward, Andrew B., Sliepen, Kwinten, van Kampen, Antoine H. C., Moerland, Perry D., Sanders, Rogier W., and van Gils, Marit J.

Published
2022
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49. Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate

Author

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

Published
2022
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50. Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire.

Author

Altman, Pilar X., Ozorowski, Gabriel, Stanfield, Robyn L., Haakenson, Jeremy, Appel, Michael, Parren, Mara, Lee, Wen-Hsin, Sang, Huldah, Woehl, Jordan, Saye-Francisco, Karen, Sewall, Leigh M., Joyce, Collin, Song, Ge, Porter, Katelyn, Landais, Elise, Andrabi, Raiees, Wilson, Ian A., Ward, Andrew B., Mwangi, Waithaka, and Smider, Vaughn V.

Subjects
SIMIAN immunodeficiency virus, HIV infections, ANTIBODY formation, AIDS vaccines, BLOOD serum analysis, MONOCLONAL antibodies
Abstract

The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response. Author summary: The elicitation of epitope-specific broadly neutralizing antibodies is highly desirable for an HIV vaccine as bnAbs can prevent HIV infection in robust animal challenge models and humans, but to date, cows are the only model shown to reliably produce HIV bnAb responses by Envelope (Env) immunization. Previously, these responses involve Abs with ultralong CDRH3s and are all directed to a single site, the CD4 binding site. To determine whether this is a unique phenomenon or whether cow antibodies can target further bnAb sites on Env, we employed an immunization protocol that generated cow bnAbs to a second site, the V2-apex. We conclude that ultralong CDRH3s are well adapted to penetrate the glycan shield of HIV Env and recognize conserved regions and may constitute protein units, either in the context of antibodies or in other engineered proteins, that could be deployed as anti-HIV reagents. [ABSTRACT FROM AUTHOR]

Published
2024
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