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Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484 and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and the variants of concern, including B.1.1.7 (alpha), P.1 (gamma) and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to wildtype (WT) SARS-CoV-2 do possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern.
Patrick Wilson; Siriruk Changrob; Yanbin Fu; Jenna Guthmiller; Peter Halfmann; Lei Li; Christopher Stamper; Haley Dugan; Molly Accola; William Rehrauer; Nai-Ying Zheng; Min Huang; Jiaolong Wang; Steven Erickson; Henry Utset; Hortencia Graves; Fatima Amanat; D. Noah Sather; Florian Krammer; Yoshihiro Kawaoka. Cross neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike. Research Square 2021, 1 .
AMA StylePatrick Wilson, Siriruk Changrob, Yanbin Fu, Jenna Guthmiller, Peter Halfmann, Lei Li, Christopher Stamper, Haley Dugan, Molly Accola, William Rehrauer, Nai-Ying Zheng, Min Huang, Jiaolong Wang, Steven Erickson, Henry Utset, Hortencia Graves, Fatima Amanat, D. Noah Sather, Florian Krammer, Yoshihiro Kawaoka. Cross neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike. Research Square. 2021; ():1.
Chicago/Turabian StylePatrick Wilson; Siriruk Changrob; Yanbin Fu; Jenna Guthmiller; Peter Halfmann; Lei Li; Christopher Stamper; Haley Dugan; Molly Accola; William Rehrauer; Nai-Ying Zheng; Min Huang; Jiaolong Wang; Steven Erickson; Henry Utset; Hortencia Graves; Fatima Amanat; D. Noah Sather; Florian Krammer; Yoshihiro Kawaoka. 2021. "Cross neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike." Research Square , no. : 1.
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.
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 StyleHenry 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 StyleHenry 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.
Influenza viruses grown in eggs for the purposes of vaccine generation often acquire mutations during egg adaptation or possess different glycosylation patterns than viruses circulating among humans. Here, we report that seasonal influenza virus vaccines possess an egg-derived glycan that is an antigenic decoy, with egg-binding MAbs reacting with a sulfated N -acetyllactosamine (LacNAc).
Jenna J. Guthmiller; Henry A. Utset; Carole Henry; Lei Li; Nai-Ying Zheng; Weina Sun; Marcos Costa Vieira; Seth Zost; Min Huang; Scott E. Hensley; Sarah Cobey; Peter Palese; Patrick C. Wilson. An Egg-Derived Sulfated N -Acetyllactosamine Glycan Is an Antigenic Decoy of Influenza Virus Vaccines. mBio 2021, 12, e0083821 .
AMA StyleJenna J. Guthmiller, Henry A. Utset, Carole Henry, Lei Li, Nai-Ying Zheng, Weina Sun, Marcos Costa Vieira, Seth Zost, Min Huang, Scott E. Hensley, Sarah Cobey, Peter Palese, Patrick C. Wilson. An Egg-Derived Sulfated N -Acetyllactosamine Glycan Is an Antigenic Decoy of Influenza Virus Vaccines. mBio. 2021; 12 (3):e0083821.
Chicago/Turabian StyleJenna J. Guthmiller; Henry A. Utset; Carole Henry; Lei Li; Nai-Ying Zheng; Weina Sun; Marcos Costa Vieira; Seth Zost; Min Huang; Scott E. Hensley; Sarah Cobey; Peter Palese; Patrick C. Wilson. 2021. "An Egg-Derived Sulfated N -Acetyllactosamine Glycan Is an Antigenic Decoy of Influenza Virus Vaccines." mBio 12, no. 3: e0083821.
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.
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 StyleJenna 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 StyleJenna 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.
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.
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 StyleJenna 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 StyleJenna 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.
Antimalarial antibody responses are essential for mediating the clearance of Plasmodium parasite–infected RBCs from infected hosts. However, the rapid appearance of large numbers of plasmablasts in Plasmodium-infected hosts can suppress the development and function of durable humoral immunity. Here, we identify that the formation of plasmablast populations in Plasmodium-infected mice is mechanistically linked to both hemolysis-induced exposure of phosphatidylserine on damaged RBCs and inflammatory cues. We also show that virus and Trypanosoma infections known to trigger hemolytic anemia and high-grade inflammation also induce exuberant plasmablast responses. The induction of hemolysis or administration of RBC membrane ghosts increases plasmablast differentiation. The phosphatidylserine receptor Axl is critical for optimal plasmablast formation, and blocking phosphatidylserine limits plasmablast expansions and reduces Plasmodium parasite burden in vivo. Our findings support that strategies aimed at modulating polyclonal B cell activation and phosphatidylserine exposure may improve immune responses against Plasmodium parasites and potentially other infectious diseases that are associated with anemia.
Rahul Vijay; Jenna J. Guthmiller; Alexandria J. Sturtz; Sequoia Crooks; Jordan T. Johnson; Lei Li; Linda Yu-Ling Lan; Rosemary L. Pope; Yani Chen; Kai J. Rogers; Nirmal Dutta; Jason E. Toombs; Mary E. Wilson; Patrick C. Wilson; Wendy Maury; Rolf A. Brekken; Noah S. Butler. Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation. Journal of Experimental Medicine 2021, 218, 1 .
AMA StyleRahul Vijay, Jenna J. Guthmiller, Alexandria J. Sturtz, Sequoia Crooks, Jordan T. Johnson, Lei Li, Linda Yu-Ling Lan, Rosemary L. Pope, Yani Chen, Kai J. Rogers, Nirmal Dutta, Jason E. Toombs, Mary E. Wilson, Patrick C. Wilson, Wendy Maury, Rolf A. Brekken, Noah S. Butler. Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation. Journal of Experimental Medicine. 2021; 218 (6):1.
Chicago/Turabian StyleRahul Vijay; Jenna J. Guthmiller; Alexandria J. Sturtz; Sequoia Crooks; Jordan T. Johnson; Lei Li; Linda Yu-Ling Lan; Rosemary L. Pope; Yani Chen; Kai J. Rogers; Nirmal Dutta; Jason E. Toombs; Mary E. Wilson; Patrick C. Wilson; Wendy Maury; Rolf A. Brekken; Noah S. Butler. 2021. "Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation." Journal of Experimental Medicine 218, no. 6: 1.
Influenza viruses grown in eggs for the purposes of vaccine generation often acquire mutations during egg adaptation or possess differential glycosylation patterns than viruses circulating amongst humans. Here, we report that seasonal influenza virus vaccines possess an egg-derived sulfated N-acetyllactosamine (LacNAc) that is an antigenic decoy. Half of subjects that received an egg-grown vaccine mounted an antibody response against this egg-derived antigen. Egg-binding monoclonal antibodies specifically bind viruses grown in eggs, but not viruses grown in other chicken derived cells, suggesting only egg-grown vaccines can induce anti-LacNAc antibodies. Notably, antibodies against the sulfated LacNAc utilized a restricted antibody repertoire and possessed features of natural antibodies, as most antibodies were IgM and have simple heavy chain complementarity determining region 3. By analyzing a public dataset of influenza virus vaccine induced plasmablasts, we discovered egg-binding public clonotypes that were shared across studies. Together, this study shows that egg-grown vaccines can induce antibodies against an egg-associated glycan, which may divert the host immune response away from protective epitopes.
Jenna J. Guthmiller; Henry A. Utset; Carole Henry; Lei Li; Nai-Ying Zheng; Weina Sun; Marcos Costa Vieira; Seth Zost; Min Huang; Scott E. Hensley; Sarah Cobey; Peter Palese; Patrick C. Wilson. An egg-derived sulfated N-Acetyllactosamine glycan is an antigenic decoy of influenza virus vaccines. 2021, 1 .
AMA StyleJenna J. Guthmiller, Henry A. Utset, Carole Henry, Lei Li, Nai-Ying Zheng, Weina Sun, Marcos Costa Vieira, Seth Zost, Min Huang, Scott E. Hensley, Sarah Cobey, Peter Palese, Patrick C. Wilson. An egg-derived sulfated N-Acetyllactosamine glycan is an antigenic decoy of influenza virus vaccines. . 2021; ():1.
Chicago/Turabian StyleJenna J. Guthmiller; Henry A. Utset; Carole Henry; Lei Li; Nai-Ying Zheng; Weina Sun; Marcos Costa Vieira; Seth Zost; Min Huang; Scott E. Hensley; Sarah Cobey; Peter Palese; Patrick C. Wilson. 2021. "An egg-derived sulfated N-Acetyllactosamine glycan is an antigenic decoy of influenza virus vaccines." , no. : 1.
Summary Broadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is “anchored” to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an underappreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.
Jenna J. Guthmiller; Julianna Han; Henry A. Utset; Lei Li; Linda Yu-Ling Lan; Carole Henry; Christopher T. Stamper; Olivia Stovicek; Lauren Gentles; Haley L. Dugan; Nai-Ying Zheng; Sara T. Richey; Micah E. Tepora; Dalia J. Bitar; Siriruk Changrob; Shirin Strohmeier; Min Huang; Adolfo García-Sastre; Raffael Nachbagauer; Peter Palese; Jesse D. Bloom; Florian Krammer; Lynda Coughlan; Andrew B. Ward; Patrick C. Wilson. A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin. 2021, 1 .
AMA StyleJenna J. Guthmiller, Julianna Han, Henry A. Utset, Lei Li, Linda Yu-Ling Lan, Carole Henry, Christopher T. Stamper, Olivia Stovicek, Lauren Gentles, Haley L. Dugan, Nai-Ying Zheng, Sara T. Richey, Micah E. Tepora, Dalia J. Bitar, Siriruk Changrob, Shirin Strohmeier, Min Huang, Adolfo García-Sastre, Raffael Nachbagauer, Peter Palese, Jesse D. Bloom, Florian Krammer, Lynda Coughlan, Andrew B. Ward, Patrick C. Wilson. A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin. . 2021; ():1.
Chicago/Turabian StyleJenna J. Guthmiller; Julianna Han; Henry A. Utset; Lei Li; Linda Yu-Ling Lan; Carole Henry; Christopher T. Stamper; Olivia Stovicek; Lauren Gentles; Haley L. Dugan; Nai-Ying Zheng; Sara T. Richey; Micah E. Tepora; Dalia J. Bitar; Siriruk Changrob; Shirin Strohmeier; Min Huang; Adolfo García-Sastre; Raffael Nachbagauer; Peter Palese; Jesse D. Bloom; Florian Krammer; Lynda Coughlan; Andrew B. Ward; Patrick C. Wilson. 2021. "A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin." , no. : 1.
In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
Alec W. Freyn; Julianna Han; Jenna J. Guthmiller; Mark J. Bailey; Karlynn Neu; Hannah L. Turner; Victoria C. Rosado; Veronika Chromikova; Min Huang; Shirin Strohmeier; Sean T. H. Liu; Viviana Simon; Florian Krammer; Andrew B. Ward; Peter Palese; Patrick C. Wilson; Raffael Nachbagauer. Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes. Proceedings of the National Academy of Sciences 2021, 118, 1 .
AMA StyleAlec W. Freyn, Julianna Han, Jenna J. Guthmiller, Mark J. Bailey, Karlynn Neu, Hannah L. Turner, Victoria C. Rosado, Veronika Chromikova, Min Huang, Shirin Strohmeier, Sean T. H. Liu, Viviana Simon, Florian Krammer, Andrew B. Ward, Peter Palese, Patrick C. Wilson, Raffael Nachbagauer. Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes. Proceedings of the National Academy of Sciences. 2021; 118 (8):1.
Chicago/Turabian StyleAlec W. Freyn; Julianna Han; Jenna J. Guthmiller; Mark J. Bailey; Karlynn Neu; Hannah L. Turner; Victoria C. Rosado; Veronika Chromikova; Min Huang; Shirin Strohmeier; Sean T. H. Liu; Viviana Simon; Florian Krammer; Andrew B. Ward; Peter Palese; Patrick C. Wilson; Raffael Nachbagauer. 2021. "Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes." Proceedings of the National Academy of Sciences 118, no. 8: 1.
Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti-Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 was expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria.
Fionna A. Surette; Jenna J. Guthmiller; Lei Li; Alexandria J. Sturtz; Rahul Vijay; Rosemary L. Pope; Brandon L. McClellan; Angela D. Pack; Ryan A. Zander; Peng Shao; Linda Yu-Ling Lan; Daniel Fernandez-Ruiz; William R. Heath; Patrick C. Wilson; Noah S. Butler. Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity. PLOS Pathogens 2021, 17, e1009288 .
AMA StyleFionna A. Surette, Jenna J. Guthmiller, Lei Li, Alexandria J. Sturtz, Rahul Vijay, Rosemary L. Pope, Brandon L. McClellan, Angela D. Pack, Ryan A. Zander, Peng Shao, Linda Yu-Ling Lan, Daniel Fernandez-Ruiz, William R. Heath, Patrick C. Wilson, Noah S. Butler. Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity. PLOS Pathogens. 2021; 17 (2):e1009288.
Chicago/Turabian StyleFionna A. Surette; Jenna J. Guthmiller; Lei Li; Alexandria J. Sturtz; Rahul Vijay; Rosemary L. Pope; Brandon L. McClellan; Angela D. Pack; Ryan A. Zander; Peng Shao; Linda Yu-Ling Lan; Daniel Fernandez-Ruiz; William R. Heath; Patrick C. Wilson; Noah S. Butler. 2021. "Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity." PLOS Pathogens 17, no. 2: e1009288.
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.
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 StyleHaley 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 StyleHaley 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.
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.
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 StyleJenna 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 StyleJenna 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.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity and kinetics of the antibody response mounted against this novel virus are not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and non-structural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike.
Jenna J. Guthmiller; Olivia Stovicek; Jiaolong Wang; Siriruk Changrob; Lei Li; Peter Halfmann; Nai-Ying Zheng; Henry Utset; Christopher T. Stamper; Haley L. Dugan; William D. Miller; Min Huang; Ya-Nan Dai; Christopher A. Nelson; Paige D. Hall; Maud Jansen; Kumaran Shanmugarajah; Jessica S. Donington; Florian Krammer; Daved H. Fremont; Andrzej Joachimiak; Yoshihiro Kawaoka; Vera Tesic; Maria Lucia Madariaga; Patrick C. Wilson. SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike. 2020, 1 .
AMA StyleJenna J. Guthmiller, Olivia Stovicek, Jiaolong Wang, Siriruk Changrob, Lei Li, Peter Halfmann, Nai-Ying Zheng, Henry Utset, Christopher T. Stamper, Haley L. Dugan, William D. Miller, Min Huang, Ya-Nan Dai, Christopher A. Nelson, Paige D. Hall, Maud Jansen, Kumaran Shanmugarajah, Jessica S. Donington, Florian Krammer, Daved H. Fremont, Andrzej Joachimiak, Yoshihiro Kawaoka, Vera Tesic, Maria Lucia Madariaga, Patrick C. Wilson. SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike. . 2020; ():1.
Chicago/Turabian StyleJenna J. Guthmiller; Olivia Stovicek; Jiaolong Wang; Siriruk Changrob; Lei Li; Peter Halfmann; Nai-Ying Zheng; Henry Utset; Christopher T. Stamper; Haley L. Dugan; William D. Miller; Min Huang; Ya-Nan Dai; Christopher A. Nelson; Paige D. Hall; Maud Jansen; Kumaran Shanmugarajah; Jessica S. Donington; Florian Krammer; Daved H. Fremont; Andrzej Joachimiak; Yoshihiro Kawaoka; Vera Tesic; Maria Lucia Madariaga; Patrick C. Wilson. 2020. "SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike." , no. : 1.
Antibodies are critical components of adaptive immunity, binding with high affinity to pathogenic epitopes. Antibodies undergo rigorous selection to achieve this high affinity, yet some maintain an additional basal level of low affinity, broad reactivity to diverse epitopes, a phenomenon termed "polyreactivity". While polyreactivity has been observed in antibodies isolated from various immunological niches, the biophysical properties that allow for promiscuity in a protein selected for high affinity binding to a single target remain unclear. Using a database of nearly 1,500 polyreactive and non-polyreactive antibody sequences, we created a bioinformatic pipeline to isolate key determinants of polyreactivity. These determinants, which include an increase in inter-loop crosstalk and a propensity for an "inoffensive" binding surface, are sufficient to generate a classifier able to identify polyreactive antibodies with over 75% accuracy. The framework from which this classifier was built is generalizable, and represents a powerful, automated pipeline for future immune repertoire analysis.
Christopher T. Boughter; Marta T. Borowska; Jenna J. Guthmiller; Albert Bendelac; Patrick C. Wilson; Benoit Roux; Erin J. Adams. Biochemical Patterns of Antibody Polyreactivity Revealed Through a Bioinformatics-Based Analysis of CDR Loops. 2020, 1 .
AMA StyleChristopher T. Boughter, Marta T. Borowska, Jenna J. Guthmiller, Albert Bendelac, Patrick C. Wilson, Benoit Roux, Erin J. Adams. Biochemical Patterns of Antibody Polyreactivity Revealed Through a Bioinformatics-Based Analysis of CDR Loops. . 2020; ():1.
Chicago/Turabian StyleChristopher T. Boughter; Marta T. Borowska; Jenna J. Guthmiller; Albert Bendelac; Patrick C. Wilson; Benoit Roux; Erin J. Adams. 2020. "Biochemical Patterns of Antibody Polyreactivity Revealed Through a Bioinformatics-Based Analysis of CDR Loops." , no. : 1.
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
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 StyleMaria 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 StyleMaria 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.
Individuals are exposed to influenza viruses throughout their lifetime. Accumulating evidence shows the first viruses an individual is exposed to leaves an imprint on the antibody response induced by subsequent drifted and novel influenza viral exposures. Imprinted humoral immunity against influenza viruses relies on biased immune memory to influenza viruses for which memory B cell responses were initially generated against. Imprinting allows for antibodies to adapt to drifted influenza viruses while maintaining binding potential for the first influenza viruses an individual is exposed to. However, imprinting can increase susceptibility to non-imprinted influenza viruses and mismatched influenza viruses. This review highlights the role of imprinting on the regulation of antibody responses induced by influenza viruses and explores potential vaccine strategies to harness imprinted antibody responses to increase protection against influenza.
Jenna J Guthmiller; Patrick C Wilson. Harnessing immune history to combat influenza viruses. Current Opinion in Immunology 2018, 53, 187 -195.
AMA StyleJenna J Guthmiller, Patrick C Wilson. Harnessing immune history to combat influenza viruses. Current Opinion in Immunology. 2018; 53 ():187-195.
Chicago/Turabian StyleJenna J Guthmiller; Patrick C Wilson. 2018. "Harnessing immune history to combat influenza viruses." Current Opinion in Immunology 53, no. : 187-195.