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Henry Utset
Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA

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Review
Published: 01 July 2021 in Vaccines
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The generation of high affinity antibodies is a crucial aspect of immunity induced by vaccination or infection. Investigation into the B cells that produce these antibodies grants key insights into the effectiveness of novel immunogens to induce a lasting protective response against endemic or pandemic pathogens, such as influenza viruses, human immunodeficiency virus, or severe acute respiratory syndrome coronavirus-2. However, humoral immunity has largely been studied at the serological level, limiting our knowledge on the specificity and function of B cells recruited to respond to pathogens. In this review, we cover a number of recent innovations in the field that have increased our ability to connect B cell function to the B cell repertoire and antigen specificity. Moreover, we will highlight recent advances in the development of both ex vivo and in vivo models to study human B cell responses. Together, the technologies highlighted in this review can be used to help design and validate new vaccine designs and platforms.

ACS Style

Henry Utset; Jenna Guthmiller; Patrick Wilson. Bridging the B Cell Gap: Novel Technologies to Study Antigen-Specific Human B Cell Responses. Vaccines 2021, 9, 711 .

AMA Style

Henry Utset, Jenna Guthmiller, Patrick Wilson. Bridging the B Cell Gap: Novel Technologies to Study Antigen-Specific Human B Cell Responses. Vaccines. 2021; 9 (7):711.

Chicago/Turabian Style

Henry Utset; Jenna Guthmiller; Patrick Wilson. 2021. "Bridging the B Cell Gap: Novel Technologies to Study Antigen-Specific Human B Cell Responses." Vaccines 9, no. 7: 711.

Research article
Published: 02 June 2021 in Science Translational Medicine
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Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls memory B cells that are specific to the conserved receptor-binding site (RBS) or lateral patch epitopes of the hemagglutinin (HA) head domain. Monoclonal antibodies (mAbs) generated against these epitopes are broadly neutralizing against H1N1 viruses spanning 40 years of viral evolution and provide potent protection in vivo. Lateral patch-targeting antibodies demonstrated near universal binding to H1 viruses, and RBS-binding antibodies commonly cross-reacted with H3N2 viruses and influenza B viruses. Lateral patch-targeting mAbs were restricted to expressing the variable heavy-chain gene VH3-23 with or without the variable kappa-chain gene VK1-33 and often had a Y-x-R motif within the heavy-chain complementarity determining region 3 to make key contacts with HA. Moreover, lateral patch antibodies that used both VH3-23 and VK1-33 maintained neutralizing capability with recent pH1N1 strains that acquired mutations near the lateral patch. RBS-binding mAbs used a diverse repertoire but targeted the RBS epitope similarly and made extensive contacts with the major antigenic site Sb. Together, our data indicate that RBS- and lateral patch-targeting clones are abundant within the human memory B cell pool, and universal vaccine strategies should aim to drive antibodies against both conserved head and stalk epitopes.

ACS Style

Jenna J. Guthmiller; Julianna Han; Lei Li; Alec W. Freyn; Sean T. H. Liu; Olivia Stovicek; Christopher T. Stamper; Haley L. Dugan; Micah E. Tepora; Henry A. Utset; Dalia J. Bitar; Natalie J. Hamel; Siriruk Changrob; Nai-Ying Zheng; Min Huang; Florian Krammer; Raffael Nachbagauer; Peter Palese; Andrew B. Ward; Patrick C. Wilson. First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes. Science Translational Medicine 2021, 13, eabg4535 .

AMA Style

Jenna J. Guthmiller, Julianna Han, Lei Li, Alec W. Freyn, Sean T. H. Liu, Olivia Stovicek, Christopher T. Stamper, Haley L. Dugan, Micah E. Tepora, Henry A. Utset, Dalia J. Bitar, Natalie J. Hamel, Siriruk Changrob, Nai-Ying Zheng, Min Huang, Florian Krammer, Raffael Nachbagauer, Peter Palese, Andrew B. Ward, Patrick C. Wilson. First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes. Science Translational Medicine. 2021; 13 (596):eabg4535.

Chicago/Turabian Style

Jenna J. Guthmiller; Julianna Han; Lei Li; Alec W. Freyn; Sean T. H. Liu; Olivia Stovicek; Christopher T. Stamper; Haley L. Dugan; Micah E. Tepora; Henry A. Utset; Dalia J. Bitar; Natalie J. Hamel; Siriruk Changrob; Nai-Ying Zheng; Min Huang; Florian Krammer; Raffael Nachbagauer; Peter Palese; Andrew B. Ward; Patrick C. Wilson. 2021. "First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes." Science Translational Medicine 13, no. 596: eabg4535.

Journal article
Published: 01 June 2021 in Immunity
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Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.

ACS Style

Haley L. Dugan; Christopher T. Stamper; Lei Li; Siriruk Changrob; Nicholas W. Asby; Peter J. Halfmann; Nai-Ying Zheng; Min Huang; Dustin G. Shaw; Mari S. Cobb; Steven A. Erickson; Jenna J. Guthmiller; Olivia Stovicek; Jiaolong Wang; Emma S. Winkler; Maria Lucia Madariaga; Kumaran Shanmugarajah; Maud O. Jansen; Fatima Amanat; Isabelle Stewart; Henry A. Utset; Jun Huang; Christopher A. Nelson; Ya-Nan Dai; Paige D. Hall; Robert P. Jedrzejczak; Andrzej Joachimiak; Florian Krammer; Michael S. Diamond; Daved H. Fremont; Yoshihiro Kawaoka; Patrick C. Wilson. Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets. Immunity 2021, 54, 1290 -1303.e7.

AMA Style

Haley L. Dugan, Christopher T. Stamper, Lei Li, Siriruk Changrob, Nicholas W. Asby, Peter J. Halfmann, Nai-Ying Zheng, Min Huang, Dustin G. Shaw, Mari S. Cobb, Steven A. Erickson, Jenna J. Guthmiller, Olivia Stovicek, Jiaolong Wang, Emma S. Winkler, Maria Lucia Madariaga, Kumaran Shanmugarajah, Maud O. Jansen, Fatima Amanat, Isabelle Stewart, Henry A. Utset, Jun Huang, Christopher A. Nelson, Ya-Nan Dai, Paige D. Hall, Robert P. Jedrzejczak, Andrzej Joachimiak, Florian Krammer, Michael S. Diamond, Daved H. Fremont, Yoshihiro Kawaoka, Patrick C. Wilson. Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets. Immunity. 2021; 54 (6):1290-1303.e7.

Chicago/Turabian Style

Haley L. Dugan; Christopher T. Stamper; Lei Li; Siriruk Changrob; Nicholas W. Asby; Peter J. Halfmann; Nai-Ying Zheng; Min Huang; Dustin G. Shaw; Mari S. Cobb; Steven A. Erickson; Jenna J. Guthmiller; Olivia Stovicek; Jiaolong Wang; Emma S. Winkler; Maria Lucia Madariaga; Kumaran Shanmugarajah; Maud O. Jansen; Fatima Amanat; Isabelle Stewart; Henry A. Utset; Jun Huang; Christopher A. Nelson; Ya-Nan Dai; Paige D. Hall; Robert P. Jedrzejczak; Andrzej Joachimiak; Florian Krammer; Michael S. Diamond; Daved H. Fremont; Yoshihiro Kawaoka; Patrick C. Wilson. 2021. "Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets." Immunity 54, no. 6: 1290-1303.e7.

Review
Published: 22 May 2021 in Viruses
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Antibodies are critical for providing protection against influenza virus infections. However, protective humoral immunity against influenza viruses is limited by the antigenic drift and shift of the major surface glycoproteins, hemagglutinin and neuraminidase. Importantly, people are exposed to influenza viruses throughout their life and tend to reuse memory B cells from prior exposure to generate antibodies against new variants. Despite this, people tend to recall memory B cells against constantly evolving variable epitopes or non-protective antigens, as opposed to recalling them against broadly neutralizing epitopes of hemagglutinin. In this review, we discuss the factors that impact the generation and recall of memory B cells against distinct viral antigens, as well as the immunological limitations preventing broadly neutralizing antibody responses. Lastly, we discuss how next-generation vaccine platforms can potentially overcome these obstacles to generate robust and long-lived protection against influenza A viruses.

ACS Style

Jenna Guthmiller; Henry Utset; Patrick Wilson. B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat. Viruses 2021, 13, 965 .

AMA Style

Jenna Guthmiller, Henry Utset, Patrick Wilson. B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat. Viruses. 2021; 13 (6):965.

Chicago/Turabian Style

Jenna Guthmiller; Henry Utset; Patrick Wilson. 2021. "B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat." Viruses 13, no. 6: 965.

Research article
Published: 09 December 2020 in Science Translational Medicine
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Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection–induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes.

ACS Style

Haley L. Dugan; Jenna J. Guthmiller; Philip Arevalo; Min Huang; Yao-Qing Chen; Karlynn E. Neu; Carole Henry; Nai-Ying Zheng; Linda Yu-Ling Lan; Micah E. Tepora; Olivia Stovicek; Dalia Bitar; Anna-Karin E. Palm; Christopher T. Stamper; Siriruk Changrob; Henry A. Utset; Lynda Coughlan; Florian Krammer; Sarah Cobey; Patrick C. Wilson. Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans. Science Translational Medicine 2020, 12, eabd3601 .

AMA Style

Haley L. Dugan, Jenna J. Guthmiller, Philip Arevalo, Min Huang, Yao-Qing Chen, Karlynn E. Neu, Carole Henry, Nai-Ying Zheng, Linda Yu-Ling Lan, Micah E. Tepora, Olivia Stovicek, Dalia Bitar, Anna-Karin E. Palm, Christopher T. Stamper, Siriruk Changrob, Henry A. Utset, Lynda Coughlan, Florian Krammer, Sarah Cobey, Patrick C. Wilson. Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans. Science Translational Medicine. 2020; 12 (573):eabd3601.

Chicago/Turabian Style

Haley L. Dugan; Jenna J. Guthmiller; Philip Arevalo; Min Huang; Yao-Qing Chen; Karlynn E. Neu; Carole Henry; Nai-Ying Zheng; Linda Yu-Ling Lan; Micah E. Tepora; Olivia Stovicek; Dalia Bitar; Anna-Karin E. Palm; Christopher T. Stamper; Siriruk Changrob; Henry A. Utset; Lynda Coughlan; Florian Krammer; Sarah Cobey; Patrick C. Wilson. 2020. "Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans." Science Translational Medicine 12, no. 573: eabd3601.

Journal article
Published: 22 October 2020 in Immunity
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Summary Polyreactivity is the ability of a single antibody to bind to multiple molecularly distinct antigens and is a common feature of antibodies induced upon pathogen exposure. However, little is known about the role of polyreactivity during anti-influenza virus antibody responses. By analyzing more than 500 monoclonal antibodies (mAbs) derived from B cells induced by numerous influenza virus vaccines and infections, we found mAbs targeting conserved neutralizing influenza virus hemagglutinin epitopes were polyreactive. Polyreactive mAbs were preferentially induced by novel viral exposures due to their broad viral binding breadth. Polyreactivity augmented mAb viral binding strength by increasing antibody flexibility, allowing for adaption to imperfectly conserved epitopes. Lastly, we found affinity-matured polyreactive B cells were typically derived from germline polyreactive B cells that were preferentially selected to participate in B cell responses over time. Together, our data reveal that polyreactivity is a beneficial feature of antibodies targeting conserved epitopes.

ACS Style

Jenna J. Guthmiller; Linda Yu-Ling Lan; Monica L. Fernández-Quintero; Julianna Han; Henry A. Utset; Dalia J. Bitar; Natalie J. Hamel; Olivia Stovicek; Lei Li; Micah Tepora; Carole Henry; Karlynn E. Neu; Haley L. Dugan; Marta T. Borowska; Yao-Qing Chen; Sean T.H. Liu; Christopher T. Stamper; Nai-Ying Zheng; Min Huang; Anna-Karin E. Palm; Adolfo García-Sastre; Raffael Nachbagauer; Peter Palese; Lynda Coughlan; Florian Krammer; Andrew B. Ward; Klaus R. Liedl; Patrick C. Wilson. Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses. Immunity 2020, 53, 1230 -1244.e5.

AMA Style

Jenna J. Guthmiller, Linda Yu-Ling Lan, Monica L. Fernández-Quintero, Julianna Han, Henry A. Utset, Dalia J. Bitar, Natalie J. Hamel, Olivia Stovicek, Lei Li, Micah Tepora, Carole Henry, Karlynn E. Neu, Haley L. Dugan, Marta T. Borowska, Yao-Qing Chen, Sean T.H. Liu, Christopher T. Stamper, Nai-Ying Zheng, Min Huang, Anna-Karin E. Palm, Adolfo García-Sastre, Raffael Nachbagauer, Peter Palese, Lynda Coughlan, Florian Krammer, Andrew B. Ward, Klaus R. Liedl, Patrick C. Wilson. Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses. Immunity. 2020; 53 (6):1230-1244.e5.

Chicago/Turabian Style

Jenna J. Guthmiller; Linda Yu-Ling Lan; Monica L. Fernández-Quintero; Julianna Han; Henry A. Utset; Dalia J. Bitar; Natalie J. Hamel; Olivia Stovicek; Lei Li; Micah Tepora; Carole Henry; Karlynn E. Neu; Haley L. Dugan; Marta T. Borowska; Yao-Qing Chen; Sean T.H. Liu; Christopher T. Stamper; Nai-Ying Zheng; Min Huang; Anna-Karin E. Palm; Adolfo García-Sastre; Raffael Nachbagauer; Peter Palese; Lynda Coughlan; Florian Krammer; Andrew B. Ward; Klaus R. Liedl; Patrick C. Wilson. 2020. "Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses." Immunity 53, no. 6: 1230-1244.e5.

Other
Published: 23 June 2020
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BackgroundConvalescent plasma therapy for COVID-19 relies on the transfer of anti-viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID-19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial.MethodsMultivariable analysis of clinical and serological parameters in 103 confirmed COVID-19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID-19.FindingsMean symptom duration of plasma donors was 11.9±5.9 days and 7.8% (8/103) had been hospitalized. Antibody titers ranged from 0 to 1:3,892 (anti-receptor binding domain (RBD)) and 0 to 1:3,289 (anti-spike). Multivariable analysis demonstrated that higher anti-RBD and anti-spike titer were associated with increased age, hospitalization for COVID-19, fever, and absence of myalgia (all pInterpretationAdvanced age, fever, absence of myalgia, fatigue, blood type and hospitalization were associated with higher convalescent antibody titer to COVID-19. Despite variability in donor titer, 80% of convalescent plasma recipients showed significant increase in antibody levels post-transfusion. A more complete understanding of the dose-response effect of plasma transfusion among COVID-19 patients is needed to determine the clinical efficacy of this therapy.Trial RegistrationNCT04340050FundingDepartment of Surgery University of Chicago, National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051

ACS Style

Maria Lucia L. Madariaga; Jenna J. Guthmiller; Stephen Schrantz; Maud O. Jansen; Chancey Christensen; Madan Kumar; Micah Prochaska; Geoffrey Wool; Amy Durkin-Celauro; Won Hee Oh; Laura Trockman; Janani Vigneswaran; Robert Keskey; Dustin G. Shaw; Haley Dugan; Nai-Ying Zheng; Mari Cobb; Henry Utset; Jiaolong Wang; Olivia Stovicek; Cindy Bethel; Scott Matushek; Mihai Giurcanu; Kathleen G. Beavis; Diego Di Sabato; David Meltzer; Mark K. Ferguson; John P. Kress; Kumaran Shanmugarajah; Jeffrey B. Matthews; John F. Fung; Patrick C. Wilson; John C. Alverdy; Jessica S. Donington. Clinical predictors of donor antibody titer and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial. 2020, 1 .

AMA Style

Maria Lucia L. Madariaga, Jenna J. Guthmiller, Stephen Schrantz, Maud O. Jansen, Chancey Christensen, Madan Kumar, Micah Prochaska, Geoffrey Wool, Amy Durkin-Celauro, Won Hee Oh, Laura Trockman, Janani Vigneswaran, Robert Keskey, Dustin G. Shaw, Haley Dugan, Nai-Ying Zheng, Mari Cobb, Henry Utset, Jiaolong Wang, Olivia Stovicek, Cindy Bethel, Scott Matushek, Mihai Giurcanu, Kathleen G. Beavis, Diego Di Sabato, David Meltzer, Mark K. Ferguson, John P. Kress, Kumaran Shanmugarajah, Jeffrey B. Matthews, John F. Fung, Patrick C. Wilson, John C. Alverdy, Jessica S. Donington. Clinical predictors of donor antibody titer and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial. . 2020; ():1.

Chicago/Turabian Style

Maria Lucia L. Madariaga; Jenna J. Guthmiller; Stephen Schrantz; Maud O. Jansen; Chancey Christensen; Madan Kumar; Micah Prochaska; Geoffrey Wool; Amy Durkin-Celauro; Won Hee Oh; Laura Trockman; Janani Vigneswaran; Robert Keskey; Dustin G. Shaw; Haley Dugan; Nai-Ying Zheng; Mari Cobb; Henry Utset; Jiaolong Wang; Olivia Stovicek; Cindy Bethel; Scott Matushek; Mihai Giurcanu; Kathleen G. Beavis; Diego Di Sabato; David Meltzer; Mark K. Ferguson; John P. Kress; Kumaran Shanmugarajah; Jeffrey B. Matthews; John F. Fung; Patrick C. Wilson; John C. Alverdy; Jessica S. Donington. 2020. "Clinical predictors of donor antibody titer and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial." , no. : 1.