477 results on '"Crowe JE"'
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2. Mouse and Human Monoclonal Antibodies Protect against Infection by Multiple Genotypes of Japanese Encephalitis Virus.
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Nabel, GJ, Fernandez, E, Kose, N, Edeling, MA, Adhikari, J, Sapparapu, G, Lazarte, SM, Nelson, CA, Govero, J, Gross, ML, Fremont, DH, Crowe, JE, Diamond, MS, Nabel, GJ, Fernandez, E, Kose, N, Edeling, MA, Adhikari, J, Sapparapu, G, Lazarte, SM, Nelson, CA, Govero, J, Gross, ML, Fremont, DH, Crowe, JE, and Diamond, MS
- Abstract
Japanese encephalitis virus (JEV) remains a leading cause of viral encephalitis worldwide. Although JEV-specific antibodies have been described, an assessment of their ability to neutralize multiple genotypes of JEV has been limited. Here, we describe the development of a panel of mouse and human neutralizing monoclonal antibodies (MAbs) that inhibit infection in cell culture of four different JEV genotypes tested. Mechanism-of-action studies showed that many of these MAbs inhibited infection at a postattachment step, including blockade of virus fusion. Mapping studies using site-directed mutagenesis and hydrogen-deuterium exchange with mass spectrometry revealed that the lateral ridge on domain III of the envelope protein was a primary recognition epitope for our panel of strongly neutralizing MAbs. Therapeutic studies in mice demonstrated protection against lethality caused by genotype I and III strains when MAbs were administered as a single dose even 5 days after infection. This information may inform the development of vaccines and therapeutic antibodies as emerging strains and genotypic shifts become more prevalent.IMPORTANCE Although Japanese encephalitis virus (JEV) is a vaccine-preventable cause of viral encephalitis, the inactivated and live attenuated platforms available are derived from strains belonging to a single genotype (GIII) due to its historical prevalence in areas of JEV epidemics. Related to this, studies with vaccines and antibodies have focused on assessing the in vitro and in vivo protective responses to homologous or heterologous GIII strains. An epidemiological shift in JEV genotype distribution warrants the induction of broadly neutralizing antibody responses that inhibit infection of multiple JEV genotypes. Here, we generated a panel of mouse and human neutralizing monoclonal antibodies and evaluated their inhibitory activity, epitope location, and capacity for protection against multiple JEV genotypes in mice.
- Published
- 2018
3. Acute bowing fractures of the forearm in children: a frequently missed injury
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Crowe, JE, primary and Swischuk, LE, additional
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- 1977
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4. Combined esophageal and duodenal atresia without tracheoesophageal fustula: characteristic radiographic changes
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Crowe, JE, primary and Sumner, TE, additional
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- 1978
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5. Pulmonary blastoma in a child
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Sumner, TE, primary, Phelps, CR, additional, Crowe, JE, additional, Poolos, SP, additional, and Shaffner, LD, additional
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- 1979
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6. High frequency of shared clonotypes in human T cell receptor repertoires
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Soto, C, primary, Bombardi, RG, additional, Kozhevnikov, M, additional, Sinkovits, RS, additional, Chen, EC, additional, Branchizio, A, additional, Kose, N, additional, Day, SB, additional, Pilkinton, M, additional, Gujral, M, additional, Mallal, S, additional, and Crowe, JE, additional
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7. Rapid evolution of fluoroquinolone-resistant Escherichia coli in Nigeria is temporally associated with fluoroquinolone use
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Lamikanra Adebayo, Crowe Jennifer L, Lijek Rebeccah S, Odetoyin Babatunde W, Wain John, Aboderin A Oladipo, and Okeke Iruka N
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antimicrobial resistance ,antimicrobial use ,quinolone resistance ,drug resistance ,ciprofloxacin ,fluoroquinolones ,selective pressure ,Nigeria ,chloroquine ,antimalarial ,fluoroquinolone-resistant ,Escherichia coli ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Antibiotic resistance has necessitated fluoroquinolone use but little is known about the selective forces and resistance trajectory in malaria-endemic settings, where selection from the antimalarial chloroquine for fluoroquinolone-resistant bacteria has been proposed. Methods Antimicrobial resistance was studied in fecal Escherichia coli isolates in a Nigerian community. Quinolone-resistance determining regions of gyrA and parC were sequenced in nalidixic acid resistant strains and horizontally-transmitted quinolone-resistance genes were sought by PCR. Antimicrobial prescription practices were compared with antimicrobial resistance rates over a period spanning three decades. Results Before 2005, quinolone resistance was limited to low-level nalixidic acid resistance in fewer than 4% of E. coli isolates. In 2005, the proportion of isolates demonstrating low-level quinolone resistance due to elevated efflux increased and high-level quinolone resistance and resistance to the fluoroquinolones appeared. Fluoroquinolone resistance was attributable to single nucleotide polymorphisms in quinolone target genes gyrA and/or parC. By 2009, 35 (34.5%) of isolates were quinolone non-susceptible with nine carrying gyrA and parC SNPs and six bearing identical qnrS1 alleles. The antimalarial chloroquine was heavily used throughout the entire period but E. coli with quinolone-specific resistance mechanisms were only detected in the final half decade, immediately following the introduction of the fluoroquinolone antibacterial ciprofloxacin. Conclusions Fluoroquinolones, and not chloroquine, appear to be the selective force for fluoroquinolone-resistant fecal E. coli in this setting. Rapid evolution to resistance following fluoroquinolone introduction points the need to implement resistant containment strategies when new antibacterials are introduced into resource-poor settings with high infectious disease burdens.
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- 2011
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8. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children.
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Williams JV, Harris PA, Tollefson SJ, Halburnt-Rush LL, Pingsterhaus JM, Edwards KM, Wright PF, Crowe JE Jr., Williams, John V, Harris, Paul A, Tollefson, Sharon J, Halburnt-Rush, Lisa L, Pingsterhaus, Joyce M, Edwards, Kathryn M, Wright, Peter F, and Crowe, James E Jr
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Background: We sought to determine the role of human metapneumovirus in lower respiratory tract illness in previously healthy infants and children.Methods: We tested nasal-wash specimens, obtained over a 25-year period from otherwise healthy children presenting with acute respiratory tract illness, for human metapneumovirus.Results: A viral cause other than human metapneumovirus was determined for 279 of 687 visits for acute lower respiratory tract illness (41 percent) by 463 children in a population of 2009 infants and children prospectively seen from 1976 to 2001. There were 408 visits for lower respiratory tract illness by 321 children for which no cause was identified. Of these 321 children, specimens from 248 were available. Forty-nine of these 248 specimens (20 percent) contained human metapneumovirus RNA or viable virus. Thus, 20 percent of all previously virus-negative lower respiratory tract illnesses were attributable to human metapneumovirus, which means that 12 percent of all lower respiratory tract illnesses in this cohort were most likely due to this virus. The mean age of human metapneumovirus-infected children was 11.6 months, the male:female ratio was 1.8:1, 78 percent of illnesses occurred between December and April, and the hospitalization rate was 2 percent. The virus was associated with bronchiolitis in 59 percent of cases, pneumonia in 8 percent, croup in 18 percent, and an exacerbation of asthma in 14 percent. We also detected human metapneumovirus in 15 percent of samples from 261 patients with upper respiratory tract infection but in only 1 of 86 samples from asymptomatic children.Conclusions: Human metapneumovirus infection is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to that of respiratory syncytial virus. [ABSTRACT FROM AUTHOR]- Published
- 2004
9. Human metapneumovirus and lower respiratory tract disease in children.
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Ho H, Principi N, Esposito S, Bosis S, Williams JV, and Crowe JE Jr.
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- 2004
10. Discovery and characterization of a pan-betacoronavirus S2-binding antibody.
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Johnson NV, Wall SC, Kramer KJ, Holt CM, Periasamy S, Richardson SI, Manamela NP, Suryadevara N, Andreano E, Paciello I, Pierleoni G, Piccini G, Huang Y, Ge P, Allen JD, Uno N, Shiakolas AR, Pilewski KA, Nargi RS, Sutton RE, Abu-Shmais AA, Parks R, Haynes BF, Carnahan RH, Crowe JE Jr, Montomoli E, Rappuoli R, Bukreyev A, Ross TM, Sautto GA, McLellan JS, and Georgiev IS
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The continued emergence of deadly human coronaviruses from animal reservoirs highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq), we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryoelectron microscopy (cryo-EM) structure of 54043-5 bound to the prefusion S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses in vitro, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit., Competing Interests: Declaration of interests A.R.S. and I.S.G. are co-founders of AbSeek Bio. K.J.K., A.R.S., N.V.J., I.S.G., J.S.M., R.H.C., and J.E.C. are listed as inventors on patents filed describing the antibodies discovered here. R.H.C. is an inventor on patents related to other SARS-CoV-2 antibodies. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory has received funding support in sponsored research agreements from AstraZeneca, IDBiologics, and Takeda. The Georgiev laboratory at VUMC has received unrelated funding from Takeda Pharmaceuticals., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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11. Potent neutralizing human monoclonal antibodies protect from Rift Valley fever encephalitis.
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Connors KA, Chapman NS, McMillen CM, Hoehl RM, McGaughey JJ, Frey ZD, Midgett M, Williams C, Reed DS, Crowe JE Jr, and Hartman AL
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- Animals, Rats, Humans, Female, Mice, Rift Valley Fever immunology, Rift Valley Fever prevention & control, Antibodies, Neutralizing immunology, Antibodies, Neutralizing pharmacology, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal pharmacology, Rift Valley fever virus immunology, Disease Models, Animal, Antibodies, Viral immunology
- Abstract
Rift Valley fever (RVF) is an emerging arboviral disease affecting both humans and livestock. In humans, RVF displays a spectrum of clinical manifestations, including encephalitis. To date, there are no FDA-approved vaccines or therapeutics for human use, although several are in preclinical development. Few small-animal models of RVF encephalitis exist, further complicating countermeasure assessment. Human mAbs RVFV-140, RVFV-268, and RVFV-379 are recombinant potently neutralizing antibodies that prevent infection by binding the RVFV surface glycoproteins. Previous studies showed that both RVFV-268 and RVFV-140 improve survival in a lethal mouse model of disease, and RVFV-268 has prevented vertical transmission in a pregnant rat model of infection. Despite these successes, evaluation of mAbs in the context of brain disease has been limited. This is the first study to our knowledge to assess neutralizing antibodies for prevention of RVF neurologic disease using a rat model. Administration of RVFV-140, RVFV-268, or RVFV-379 24 hours prior to aerosol exposure to the virulent ZH501 strain of RVFV resulted in substantially enhanced survival and lack of neurological signs of disease. These results using a stringent and highly lethal aerosol infection model support the potential use of human mAbs to prevent the development of RVF encephalitis.
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- 2024
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12. Functional and structural basis of human parainfluenza virus type 3 neutralization with human monoclonal antibodies.
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Suryadevara N, Otrelo-Cardoso AR, Kose N, Hu YX, Binshtein E, Wolters RM, Greninger AL, Handal LS, Carnahan RH, Moscona A, Jardetzky TS, and Crowe JE Jr
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- Animals, Humans, Disease Models, Animal, Neutralization Tests, B-Lymphocytes immunology, Models, Molecular, Parainfluenza Virus 3, Human immunology, Parainfluenza Virus 3, Human genetics, Antibodies, Monoclonal immunology, Antibodies, Monoclonal chemistry, Antibodies, Neutralizing immunology, Antibodies, Neutralizing chemistry, Antibodies, Viral immunology, Antibodies, Viral chemistry, Sigmodontinae, Viral Fusion Proteins immunology, Viral Fusion Proteins chemistry, HN Protein immunology, HN Protein chemistry, HN Protein genetics, Respirovirus Infections immunology, Respirovirus Infections virology
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Human parainfluenza virus type 3 (hPIV3) is a respiratory pathogen that can cause severe disease in older people and infants. Currently, vaccines against hPIV3 are in clinical trials but none have been approved yet. The haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Here we describe naturally occurring potently neutralizing human antibodies directed against both surface glycoproteins of hPIV3. We isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. One HN-binding monoclonal antibody (mAb), designated PIV3-23, exhibited functional attributes including haemagglutination and neuraminidase inhibition. We also delineated the structural basis of neutralization for two HN and one F mAbs. MAbs that neutralized hPIV3 in vitro protected against infection and disease in vivo in a cotton rat model of hPIV3 infection, suggesting correlates of protection for hPIV3 and the potential clinical utility of these mAbs., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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13. Author Correction: Antibodies targeting the glycan cap of Ebola virus glycoprotein are potent inducers of the complement system.
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Ilinykh PA, Huang K, Gunn BM, Kuzmina NA, Kedarinath K, Jurado-Cobena E, Zhou F, Subramani C, Hyde MA, Velazquez JV, Williamson LE, Gilchuk P, Carnahan RH, Alter G, Crowe JE Jr, and Bukreyev A
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- 2024
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14. Comparison of uridine and N1-methylpseudouridine mRNA platforms in development of an Andes virus vaccine.
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Kuzmin IV, Soto Acosta R, Pruitt L, Wasdin PT, Kedarinath K, Hernandez KR, Gonzales KA, Hill K, Weidner NG, Mire C, Engdahl TB, Moon WJ, Popov V, Crowe JE Jr, Georgiev IS, Garcia-Blanco MA, Abbott RK, and Bukreyev A
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- Animals, Female, Mice, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Messenger immunology, Antibodies, Viral immunology, Orthohantavirus immunology, Orthohantavirus genetics, Antibodies, Neutralizing immunology, Germinal Center immunology, Pseudouridine immunology, Cricetinae, mRNA Vaccines, Hemorrhagic Fever, American prevention & control, Hemorrhagic Fever, American immunology, Hemorrhagic Fever, American virology, RNA, Viral genetics, RNA, Viral immunology, B-Lymphocytes immunology, Humans, Vaccine Development, Mesocricetus, Uridine, Viral Vaccines immunology, Viral Vaccines administration & dosage
- Abstract
The rodent-borne Andes virus (ANDV) causes a severe disease in humans. We developed an ANDV mRNA vaccine based on the M segment of the viral genome, either with regular uridine (U-mRNA) or N1-methylpseudouridine (m1Ψ-mRNA). Female mice immunized by m1Ψ-mRNA developed slightly greater germinal center (GC) responses than U-mRNA-immunized mice. Single cell RNA and BCR sequencing of the GC B cells revealed similar levels of activation, except an additional cluster of cells exhibiting interferon response in animals vaccinated with U-mRNA but not m1Ψ-mRNA. Similar immunoglobulin class-switching and somatic hypermutations were observed in response to the vaccines. Female Syrian hamsters were immunized via a prime-boost regimen with two doses of each vaccine. The titers of glycoprotein-binding antibodies were greater for U-mRNA construct than for m1Ψ-mRNA construct; however, the titers of ANDV-neutralizing antibodies were similar. Vaccinated animals were challenged with a lethal dose of ANDV, along with a naïve control group. All control animals and two animals vaccinated with a lower dose of m1Ψ-mRNA succumbed to infection whereas other vaccinated animals survived without evidence of virus replication. The data demonstrate the development of a protective vaccine against ANDV and the lack of a substantial effect of m1Ψ modification on immunogenicity and protection in rodents., (© 2024. The Author(s).)
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- 2024
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15. Antibodies targeting the glycan cap of Ebola virus glycoprotein are potent inducers of the complement system
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Ilinykh PA, Huang K, Gunn BM, Kuzmina NA, Kedarinath K, Jurado-Cobena E, Zhou F, Subramani C, Hyde MA, Velazquez JV, Williamson LE, Gilchuk P, Carnahan RH, Alter G, Crowe JE Jr, and Bukreyev A
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- Animals, Mice, Humans, Complement Activation, Mice, Inbred BALB C, Female, Complement System Proteins immunology, Complement System Proteins metabolism, Glycoproteins immunology, Ebolavirus immunology, Antibodies, Monoclonal immunology, Hemorrhagic Fever, Ebola immunology, Hemorrhagic Fever, Ebola virology, Hemorrhagic Fever, Ebola prevention & control, Polysaccharides immunology, Antibodies, Viral immunology, Viral Envelope Proteins immunology, Viral Envelope Proteins metabolism
- Abstract
Antibodies to Ebola virus glycoprotein (EBOV GP) represent an important correlate of the vaccine efficiency and infection survival. Both neutralization and some of the Fc-mediated effects are known to contribute the protection conferred by antibodies of various epitope specificities. At the same time, the role of the complement system remains unclear. Here, we compare complement activation by two groups of representative monoclonal antibodies (mAbs) interacting with the glycan cap (GC) or the membrane-proximal external region (MPER) of GP. Binding of GC-specific mAbs to GP induces complement-dependent cytotoxicity (CDC) in the GP-expressing cell line via C3 deposition on GP in contrast to MPER-specific mAbs. In the mouse model of EBOV infection, depletion of the complement system leads to an impairment of protection exerted by one of the GC-specific, but not MPER-specific mAbs. Our data suggest that activation of the complement system represents an important mechanism of antiviral protection by GC antibodies., (© 2024. The Author(s).)
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- 2024
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16. Structural Mapping of Polyclonal IgG Responses to HA After Influenza Virus Vaccination or Infection.
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León AN, Rodriguez AJ, Richey ST, de la Peña AT, Wolters RM, Jackson AM, Webb K, Creech CB, Yoder S, Mudd PA, Crowe JE Jr, Han J, and Ward AB
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Cellular and molecular characterization of immune responses elicited by influenza virus infection and seasonal vaccination have informed efforts to improve vaccine efficacy, breadth, and longevity. Here, we use negative stain electron microscopy polyclonal epitope mapping (nsEMPEM) to structurally characterize the humoral IgG antibody responses to hemagglutinin (HA) from human patients vaccinated with a seasonal quadrivalent flu vaccine or infected with influenza A viruses. Our data show that both vaccinated and infected patients had humoral IgGs targeting highly conserved regions on both H1 and H3 subtype HAs, including the stem and anchor, which are targets for universal influenza vaccine design. Responses against H1 predominantly targeted the central stem epitope in infected patients and vaccinated donors, whereas head epitopes were more prominently targeted on H3. Responses against H3 were less abundant, but a greater diversity of H3 epitopes were targeted relative to H1. While our analysis is limited by sample size, on average, vaccinated donors responded to a greater diversity of epitopes on both H1 and H3 than infected patients. These data establish a baseline for assessing polyclonal antibody responses in vaccination and infection, providing context for future vaccine trials and emphasizing the importance of carefully designing vaccines to boost protective responses towards conserved epitopes.
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- 2024
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17. Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface.
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Wolters RM, Ferguson JA, Nuñez IA, Chen EE, Sornberger T, Myers L, Oeverdieck S, Raghavan SSR, Kona C, Handal LS, Esilu TE, Davidson E, Doranz BJ, Engdahl TB, Kose N, Williamson LE, Creech CB, Gibson-Corley KN, Ward AB, and Crowe JE Jr
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- Humans, Animals, Influenza Vaccines immunology, Mice, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections prevention & control, Viral Proteins immunology, Virus Replication drug effects, Neuraminidase immunology, Influenza B virus immunology, Antibodies, Monoclonal immunology, Antibodies, Viral immunology, Influenza, Human immunology, Influenza, Human prevention & control
- Abstract
Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized the IBV neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Competition-binding experiments suggested the antibodies recognized two major antigenic sites. One group, which included mAb FluB-393, broadly inhibited IBV NA sialidase activity, protected prophylactically in vivo, and bound to the lateral corner of NA. The second group contained an active site mAb, FluB-400, that broadly inhibited IBV NA sialidase activity and virus replication in vitro in primary human respiratory epithelial cell cultures and protected against IBV in vivo when administered systemically or intranasally. Overall, the findings described here shape our mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates., Competing Interests: Declaration of interests L.E.W. serves as a consultant for BigHat Biosciences. The content of this article is solely the responsibility of the authors and does not represent the official views of BigHat Biosciences. C.B.C. serves as a consultant to GlaxoSmithKline, Sanofi, TDCowen Investments, Guidepoint Global, Debiopharm, and CommenseBio and receives royalties from UpToDate. The laboratory of C.B.C. receives funding for unrelated work from Moderna. J.E.C. has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, Emergent Biosolutions, GlaxoSmithKline, and BTG International Inc; is a member of the Scientific Advisory Board of Meissa Vaccines; a former member of the Scientific Advisory Board of Gigagen (Grifols); and is founder of IDBiologics. The laboratory of J.E.C. received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. The opinions, interpretations, conclusions, and recommendations contained herein are those of the authors and are not necessarily endorsed by the US Department of Defense. E.D., T.E.E., and B.J.D. are employees of Integral Molecular, B.J.D. is a shareholder of Integral Molecular. Vanderbilt University has applied for a patent pertinent to some of the materials in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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18. Imprinting of serum neutralizing antibodies by Wuhan-1 mRNA vaccines.
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Liang CY, Raju S, Liu Z, Li Y, Asthagiri Arunkumar G, Case JB, Scheaffer SM, Zost SJ, Acreman CM, Gagne M, Andrew SF, Carvalho Dos Anjos DC, Foulds KE, McLellan JS, Crowe JE Jr, Douek DC, Whelan SPJ, Elbashir SM, Edwards DK, and Diamond MS
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- Adult, Animals, Female, Humans, Male, Mice, 2019-nCoV Vaccine mRNA-1273 administration & dosage, 2019-nCoV Vaccine mRNA-1273 immunology, China, Cross Reactions immunology, Epitopes, B-Lymphocyte immunology, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus genetics, Vaccination, Antibodies, Neutralizing immunology, Antibodies, Neutralizing blood, Antibodies, Viral immunology, Antibodies, Viral blood, COVID-19 immunology, COVID-19 prevention & control, COVID-19 virology, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines genetics, COVID-19 Vaccines immunology, Immunization, Secondary, mRNA Vaccines administration & dosage, mRNA Vaccines genetics, mRNA Vaccines immunology, SARS-CoV-2 classification, SARS-CoV-2 genetics, SARS-CoV-2 immunology
- Abstract
Immune imprinting is a phenomenon in which prior antigenic experiences influence responses to subsequent infection or vaccination
1,2 . The effects of immune imprinting on serum antibody responses after boosting with variant-matched SARS-CoV-2 vaccines remain uncertain. Here we characterized the serum antibody responses after mRNA vaccine boosting of mice and human clinical trial participants. In mice, a single dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike protein minimally imprinted serum responses elicited by Omicron boosters, enabling generation of type-specific antibodies. However, imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron vaccine. In both SARS-CoV-2-infected and uninfected humans who received two Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with Omicron variants as well as more distantly related sarbecoviruses. Because serum neutralizing responses against Omicron strains and other sarbecoviruses were abrogated after pre-clearing with Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes targeted by the antecedent mRNA-1273 primary series. Thus, the antibody response to Omicron-based boosters in humans is imprinted by immunizations with historical mRNA-1273 vaccines, but this outcome may be beneficial as it drives expansion of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and distantly related sarbecoviruses., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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19. Potent HPIV3-neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity.
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Abu-Shmais AA, Miller RJ, Janke AK, Wolters RM, Holt CM, Raju N, Carnahan RH, Crowe JE Jr, Mousa JJ, and Georgiev IS
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- Humans, Viral Fusion Proteins genetics, Epitopes, Antibodies, Viral, Antibodies, Neutralizing, Parainfluenza Virus 3, Human
- Abstract
Human parainfluenza virus 3 (HPIV3) is a widespread pathogen causing severe and lethal respiratory illness in at-risk populations. Effective countermeasures are in various stages of development; however, licensed therapeutic and prophylactic options are not available. The fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing Abs that inhibit infection. Although several neutralizing Abs against a small number of HPIV3 F epitopes have been identified to date, relatively little is known about the Ab response to HPIV3 compared with other pathogens, such as influenza virus and SARS-CoV-2. In this study, we aimed to characterize a set of HPIV3-specific Abs identified in multiple individuals for genetic signatures, epitope specificity, neutralization potential, and publicness. We identified 12 potently neutralizing Abs targeting three nonoverlapping epitopes on HPIV3 F. Among these, six Abs identified from two different individuals used Ig heavy variable gene IGHV 5-51, with five of the six Abs targeting the same epitope. However, despite the use of the same H chain variable (VH) gene, these Abs used multiple different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. Together, these results provide further information about the genetic and functional characteristics of HPIV3-neutralizing Abs and suggest the existence of a reproducible VH-dependent Ab response associated with VL and CDRH3 promiscuity. Understanding sites of HPIV3 F vulnerability and the genetic and molecular characteristics of Abs targeting these sites will help guide efforts for effective vaccine and therapeutic development., (Copyright © 2024 by The American Association of Immunologists, Inc.)
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- 2024
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20. Computationally restoring the potency of a clinical antibody against Omicron.
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Desautels TA, Arrildt KT, Zemla AT, Lau EY, Zhu F, Ricci D, Cronin S, Zost SJ, Binshtein E, Scheaffer SM, Dadonaite B, Petersen BK, Engdahl TB, Chen E, Handal LS, Hall L, Goforth JW, Vashchenko D, Nguyen S, Weilhammer DR, Lo JK, Rubinfeld B, Saada EA, Weisenberger T, Lee TH, Whitener B, Case JB, Ladd A, Silva MS, Haluska RM, Grzesiak EA, Earnhart CG, Hopkins S, Bates TW, Thackray LB, Segelke BW, Lillo AM, Sundaram S, Bloom JD, Diamond MS, Crowe JE Jr, Carnahan RH, and Faissol DM
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- Animals, Female, Humans, Mice, COVID-19 immunology, COVID-19 virology, Mutation, Neutralization Tests, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, DNA Mutational Analysis, Antigenic Drift and Shift genetics, Antigenic Drift and Shift immunology, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing immunology, Antibodies, Viral chemistry, Antibodies, Viral immunology, SARS-CoV-2 classification, SARS-CoV-2 genetics, SARS-CoV-2 immunology, Drug Design methods, Computer Simulation
- Abstract
The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs
1-3 and revealed how quickly viral escape can curtail effective options4,5 . When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6 . Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities., (© 2024. The Author(s).)- Published
- 2024
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21. Functional and antigenic landscape of the Nipah virus receptor binding protein.
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Larsen BB, McMahon T, Brown JT, Wang Z, Radford CE, Crowe JE Jr, Veesler D, and Bloom JD
- Abstract
Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies, and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.
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- 2024
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22. Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates.
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Zeitlin L, Cross RW, Woolsey C, West BR, Borisevich V, Agans KN, Prasad AN, Deer DJ, Stuart L, McCavitt-Malvido M, Kim DH, Pettitt J, Crowe JE Jr, Whaley KJ, Veesler D, Dimitrov A, Abelson DM, Geisbert TW, and Broder CC
- Subjects
- Animals, Antibodies, Monoclonal, Bangladesh, Chlorocebus aethiops, Glycoproteins metabolism, Primates, Clinical Trials, Phase I as Topic, Henipavirus Infections prevention & control, Nipah Virus
- Abstract
No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra virus (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial and has been provided under compassionate use for both HeV and NiV exposures. NiV is a highly pathogenic zoonotic paramyxovirus causing regular outbreaks in humans and animals in South and Southeast Asia. The mortality rate of NiV infection in humans ranges from 40% to more than 90%, making it a substantial public health concern. The NiV G glycoprotein mediates host cell attachment, and the F glycoprotein facilitates membrane fusion and infection. We hypothesized that a mAb against the prefusion conformation of the F glycoprotein may confer better protection than m102.4. To test this, two potent neutralizing mAbs against NiV F protein, hu1F5 and hu12B2, were compared in a hamster model. Hu1F5 provided superior protection to hu12B2 and was selected for comparison with m102.4 for the ability to protect African green monkeys (AGMs) from a stringent NiV challenge. AGMs were exposed intranasally to the Bangladesh strain of NiV and treated 5 days after exposure with either mAb (25 milligrams per kilogram). Whereas only one of six AGMs treated with m102.4 survived until the study end point, all six AGMs treated with hu1F5 were protected. Furthermore, a reduced 10 milligrams per kilogram dose of hu1F5 also provided complete protection against NiV challenge, supporting the upcoming clinical advancement of this mAb for postexposure prophylaxis and therapy.
- Published
- 2024
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23. Transient Generalized Osteosclerosis in a Newborn Mimicking Congenital Osteopetrosis with Negative Comprehensive Genetic Workup: A Case Report.
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Hauck J, Gerard A, Crowe JE, Martinez CA, and Machol K
- Abstract
We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs with severe forms of osteopetrosis, familiarity with this condition is crucial for correct diagnosis and management., Competing Interests: The authors have nothing to disclose., (© 2024 The Author(s).)
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- 2024
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24. A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection.
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Adams LJ, VanBlargan LA, Liu Z, Gilchuk P, Zhao H, Chen RE, Raju S, Chong Z, Whitener BM, Shrihari S, Jethva PN, Gross ML, Crowe JE Jr, Whelan SPJ, Diamond MS, and Fremont DH
- Subjects
- Animals, Mice, SARS-CoV-2, Antibodies, Viral, Epitopes genetics, Antibodies, Monoclonal, Antibodies, Neutralizing, COVID-19
- Abstract
Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, Ocugen, Topspin Therapeutics, GlaxoSmithKline, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, and Moderna. Some of the mAbs described in this study have been licensed by Washington University to Bio X Cell. D.H.F. is a founder of Courier Therapeutics and has received funding support in a sponsored research agreement from Emergent BioSolutions. J.E.C. has served as a consultant for Eli Lilly and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is the founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from AstraZeneca and IDBiologics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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25. SARS-CoV-2 antibodies from children exhibit broad neutralization and belong to adult public clonotypes.
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Wall SC, Suryadevara N, Kim C, Shiakolas AR, Holt CM, Irbe EB, Wasdin PT, Suresh YP, Binshtein E, Chen EC, Zost SJ, Canfield E, Crowe JE Jr, Thompson-Arildsen MA, Sheward DJ, Carnahan RH, and Georgiev IS
- Subjects
- Humans, Adult, Child, SARS-CoV-2 genetics, Antibodies, Viral, Antibodies, Neutralizing therapeutic use, Pandemics, COVID-19
- Abstract
From the beginning of the COVID-19 pandemic, children have exhibited different susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, reinfection, and disease compared with adults. Motivated by the established significance of SARS-CoV-2-neutralizing antibodies in adults, here we characterize SARS-CoV-2-specific antibody repertoires in a young cohort of individuals aged from 5 months to 18 years old. Our results show that neutralizing antibodies in children possess similar genetic features compared to antibodies identified in adults, with multiple antibodies from children belonging to previously established public antibody clonotypes in adults. Notably, antibodies from children show potent neutralization of circulating SARS-CoV-2 variants that have cumulatively resulted in resistance to virtually all approved monoclonal antibody therapeutics. Our results show that children can rely on similar SARS-CoV-2 antibody neutralization mechanisms compared to adults and are an underutilized source for the discovery of effective antibody therapeutics to counteract the ever-evolving pandemic., Competing Interests: Declaration of interests S.C.W. and I.S.G. are listed as inventors on antibodies described here. A.R.S. and I.S.G. are co-founders of AbSeek Bio. I.S.G. and A.R.S. are listed as inventors on patent applications for the LIBRA-seq technology. D.J.S. has served as a consultant for AstraZeneca AB. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory has received funding support in sponsored research agreements from AstraZeneca, IDBiologics, and Takeda. The Georgiev laboratory at VUMC has received unrelated funding from Takeda Pharmaceuticals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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26. Homotypic antibodies target novel E glycoprotein domains after natural DENV 3 infection/vaccination.
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Munt JE, Henein S, Adams C, Young E, Hou YJ, Conrad H, Zhu D, Dong S, Kose N, Yount B, Meganck RM, Tse LPV, Kuan G, Balmaseda A, Ricciardi MJ, Watkins DI, Crowe JE Jr, Harris E, DeSilva AM, and Baric RS
- Subjects
- Humans, Antibodies, Viral, Antibodies, Neutralizing, Viral Envelope Proteins genetics, Glycoproteins, Vaccination, Dengue Virus, Dengue Vaccines, Dengue
- Abstract
The envelope (E) glycoprotein is the primary target of type-specific (TS) neutralizing antibodies (nAbs) after infection with any of the four distinct dengue virus serotypes (DENV1-4). nAbs can be elicited to distinct structural E domains (EDs) I, II, or III. However, the relative contribution of these domain-specific antibodies is unclear. To identify the primary DENV3 nAb targets in sera after natural infection or vaccination, chimeric DENV1 recombinant encoding DENV3 EDI, EDII, or EDIII were generated. DENV3 EDII is the principal target of TS polyclonal nAb responses and encodes two or more neutralizing epitopes. In contrast, some were individuals vaccinated with a DENV3 monovalent vaccine-elicited serum TS nAbs targeting each ED in a subject-dependent fashion, with an emphasis on EDI and EDIII. Vaccine responses were also sensitive to DENV3 genotypic variation. This DENV1/3 panel allows the measurement of serum ED TS nAbs, revealing differences in TS nAb immunity after natural infection or vaccination., Competing Interests: Declaration of interests R.S.B. and E.H. have served on the Scientific Advisory Boards for Takeda vaccines, VaxArt, and Invivyd Therapeutics and has collaborations with Gilead, Janssen Pharmaceuticals, Pardas Biosciences, and Chimerix. A.M.D. has served as an unpaid consultant for Moderna and Takeda vaccines and is an unpaid member of Merck’s dengue vaccine Scientific Advisory Board, and R.S.B. and A.M.D. are inventors on pending and approved flavivirus vaccine and diagnostic patents filed by the University of North Carolina at Chapel Hill. A.M.D. is co-directing a partnership program between UNC and Moderna to develop flavivirus vaccines. UNC has applied for a patent related to the chimeric viruses. J.E.C. has served as a consultant for Takeda vaccines, Sanofi Pasteur, Pfizer, and Novavax; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is a Founder of IDBiologics, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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27. Aerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology.
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Streblow DN, Hirsch AJ, Stanton JJ, Lewis AD, Colgin L, Hessell AJ, Kreklywich CN, Smith JL, Sutton WF, Chauvin D, Woo J, Bimber BN, LeBlanc CN, Acharya SN, O'Roak BJ, Sardar H, Sajadi MM, Tehrani ZR, Walter MR, Martinez-Sobrido L, Kobie JJ, Reader RJ, Olstad KJ, Hobbs TR, Saphire EO, Schendel SL, Carnahan RH, Knoch J, Branco LM, Crowe JE Jr, Van Rompay KKA, Lovalenti P, Vu Truong, Forthal DN, and Haigwood NL
- Subjects
- Animals, Humans, Macaca mulatta, Respiratory Aerosols and Droplets, Lung pathology, Antibodies, Viral, Virus Replication, Antibodies, Monoclonal, SARS-CoV-2, COVID-19 pathology
- Abstract
Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity., (© 2023. The Author(s).)
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- 2023
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28. Blocking of ebolavirus spread through intercellular connections by an MPER-specific antibody depends on BST2/tetherin.
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Santos RI, Ilinykh PA, Pietzsch CA, Ronk AJ, Huang K, Kuzmina NA, Zhou F, Crowe JE, and Bukreyev A
- Subjects
- Humans, Antigens, CD, GPI-Linked Proteins, Antibodies, Monoclonal, Antibodies, Viral, Bone Marrow Stromal Antigen 2 immunology, Ebolavirus immunology, Hemorrhagic Fever, Ebola virology
- Abstract
Ebola virus (EBOV) and Bundibugyo virus (BDBV) belong to the family Filoviridae and cause a severe disease in humans. We previously isolated a large panel of monoclonal antibodies from B cells of human survivors from the 2007 Uganda BDBV outbreak, 16 survivors from the 2014 EBOV outbreak in the Democratic Republic of the Congo, and one survivor from the West African 2013-2016 EBOV epidemic. Here, we demonstrate that EBOV and BDBV are capable of spreading to neighboring cells through intercellular connections in a process that depends upon actin and T cell immunoglobulin and mucin 1 protein. We quantify spread through intercellular connections by immunofluorescence microscopy and flow cytometry. One of the antibodies, BDBV223, specific to the membrane-proximal external region, induces virus accumulation at the plasma membrane. The inhibiting activity of BDBV223 depends on BST2/tetherin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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29. Developing a Prototype Pathogen Plan and Research Priorities for the Alphaviruses.
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Powers AM, Williamson LE, Carnahan RH, Crowe JE Jr, Hyde JL, Jonsson CB, Nasar F, and Weaver SC
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- Animals, Horses, Humans, Research, Chikungunya virus, Culicidae
- Abstract
The Togaviridae family, genus, Alphavirus, includes several mosquito-borne human pathogens with the potential to spread to near pandemic proportions. Most of these are zoonotic, with spillover infections of humans and domestic animals, but a few such as chikungunya virus (CHIKV) have the ability to use humans as amplification hosts for transmission in urban settings and explosive outbreaks. Most alphaviruses cause nonspecific acute febrile illness, with pathogenesis sometimes leading to either encephalitis or arthralgic manifestations with severe and chronic morbidity and occasional mortality. The development of countermeasures, especially against CHIKV and Venezuelan equine encephalitis virus that are major threats, has included vaccines and antibody-based therapeutics that are likely to also be successful for rapid responses with other members of the family. However, further work with these prototypes and other alphavirus pathogens should target better understanding of human tropism and pathogenesis, more comprehensive identification of cellular receptors and entry, and better understanding of structural mechanisms of neutralization., Competing Interests: Potential conflicts of interest. J. E. C. has served as a consultant for Luna Innovations, Merck, and GlaxoSmithKline, he is a member of the Scientific Advisory Board of Meissa Vaccines, and he is founder of IDBiologics. The laboratory of J. E. C. has received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics. Vanderbilt University has applied for patents for some of the antibodies referenced in this article. F. N. and S. C. W. have patents on multiple alphavirus vaccine and diagnostic technologies. L.E.W. serves as a consultant for BigHat Biosciences. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)
- Published
- 2023
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30. Host range, transmissibility and antigenicity of a pangolin coronavirus.
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Hou YJ, Chiba S, Leist SR, Meganck RM, Martinez DR, Schäfer A, Catanzaro NJ, Sontake V, West A, Edwards CE, Yount B, Lee RE, Gallant SC, Zost SJ, Powers J, Adams L, Kong EF, Mattocks M, Tata A, Randell SH, Tata PR, Halfmann P, Crowe JE Jr, Kawaoka Y, and Baric RS
- Subjects
- Cricetinae, Humans, Animals, Mice, Host Specificity, Pangolins, SARS-CoV-2 genetics, Antibodies, Viral, COVID-19 Vaccines, Mice, Inbred BALB C, COVID-19 prevention & control, Severe acute respiratory syndrome-related coronavirus
- Abstract
The pathogenic and cross-species transmission potential of SARS-CoV-2-related coronaviruses (CoVs) remain poorly characterized. Here we recovered a wild-type pangolin (Pg) CoV GD strain including derivatives encoding reporter genes using reverse genetics. In primary human cells, PgCoV replicated efficiently but with reduced fitness and showed less efficient transmission via airborne route compared with SARS-CoV-2 in hamsters. PgCoV was potently inhibited by US Food and Drug Administration approved drugs, and neutralized by COVID-19 patient sera and SARS-CoV-2 therapeutic antibodies in vitro. A pan-Sarbecovirus antibody and SARS-CoV-2 S2P recombinant protein vaccine protected BALB/c mice from PgCoV infection. In K18-hACE2 mice, PgCoV infection caused severe clinical disease, but mice were protected by a SARS-CoV-2 human antibody. Efficient PgCoV replication in primary human cells and hACE2 mice, coupled with a capacity for airborne spread, highlights an emergence potential. However, low competitive fitness, pre-immune humans and the benefit of COVID-19 countermeasures should impede its ability to spread globally in human populations., (© 2023. The Author(s).)
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- 2023
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31. Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses.
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Chapman NS, Hulswit RJG, Westover JLB, Stass R, Paesen GC, Binshtein E, Reidy JX, Engdahl TB, Handal LS, Flores A, Gowen BB, Bowden TA, and Crowe JE Jr
- Subjects
- Animals, Mice, Humans, Biological Assay, Disease Models, Animal, Low Density Lipoprotein Receptor-Related Protein-1, Antibodies, Monoclonal, Rift Valley fever virus
- Abstract
The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic., (© 2023. Springer Nature Limited.)
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- 2023
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32. Potent cross-neutralization of respiratory syncytial virus and human metapneumovirus through a structurally conserved antibody recognition mode.
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Wen X, Suryadevara N, Kose N, Liu J, Zhan X, Handal LS, Williamson LE, Trivette A, Carnahan RH, Jardetzky TS, and Crowe JE Jr
- Subjects
- Humans, Antibodies, Neutralizing, Antibodies, Viral, Cryoelectron Microscopy, Immunoglobulin Variable Region, Viral Fusion Proteins, Metapneumovirus metabolism, Respiratory Syncytial Virus, Human
- Abstract
Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections pose a significant health burden. Using pre-fusion conformation fusion (F) proteins, we isolated a panel of anti-F antibodies from a human donor. One antibody (RSV-199) potently cross-neutralized 8 RSV and hMPV strains by recognizing antigenic site III, which is partially conserved in RSV and hMPV F. Next, we determined the cryoelectron microscopy (cryo-EM) structures of RSV-199 bound to RSV F trimers, hMPV F monomers, and an unexpected dimeric form of hMPV F. These structures revealed how RSV-199 engages both RSV and hMPV F proteins through conserved interactions of the antibody heavy-chain variable region and how variability within heavy-chain complementarity-determining region 3 (HCDR3) can be accommodated at the F protein interface in site-III-directed antibodies. Furthermore, RSV-199 offered enhanced protection against RSV A and B strains and hMPV in cotton rats. These findings highlight the mechanisms of broad neutralization and therapeutic potential of RSV-199., Competing Interests: Declaration of interests J.E.C. has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, Emergent Biosolutions, GlaxoSmithKline, and BTG International Inc. He is a member of the Scientific Advisory Board of Meissa Vaccines, a former member of the Scientific Advisory Board of Gigagen (Grifols), and founder of IDBiologics. The laboratory of J.E.C. received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. T.S.J. has served as a consultant for Pfizer. Vanderbilt University has applied for patents for some of the antibodies in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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33. A highly potent human neutralizing antibody prevents vertical transmission of Rift Valley fever virus in a rat model.
- Author
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McMillen CM, Chapman NS, Hoehl RM, Skvarca LB, Schwarz MM, Handal LS, Crowe JE Jr, and Hartman AL
- Subjects
- Pregnancy, Animals, Humans, Rats, Female, Antibodies, Neutralizing, Antibodies, Viral, Livestock, Rift Valley fever virus, Rift Valley Fever epidemiology, Abortion, Spontaneous
- Abstract
Rift Valley fever virus (RVFV) is an emerging mosquito-transmitted virus that circulates in livestock and humans in Africa and the Middle East. Outbreaks lead to high rates of miscarriages in domesticated livestock. Women are also at risk of vertical virus transmission and late-term miscarriages. MAb RVFV-268 is a highly potent recombinant neutralizing human monoclonal antibody that targets RVFV. Here we show that mAb RVFV-268 reduces viral replication in rat placenta explant cultures and prevents vertical transmission in a rat model of congenital RVF. Passive transfer of mAb RVFV-268 from mother to fetus occurs as early as 6 h after administration and persists through 24 h. Administering mAb RVFV-268 2 h prior to RVFV challenge or 24 h post-challenge protects the dams and offspring from RVFV infection. These findings support mAb RVFV-268 as a pre- and post-infection treatment to subvert RVFV infection and vertical transmission, thus protecting the mother and offspring., (© 2023. The Author(s).)
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- 2023
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34. Mechanistic basis for potent neutralization of Sin Nombre hantavirus by a human monoclonal antibody.
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Stass R, Engdahl TB, Chapman NS, Wolters RM, Handal LS, Diaz SM, Crowe JE Jr, and Bowden TA
- Subjects
- Humans, Antibodies, Monoclonal, Antibodies, Neutralizing, Glycoproteins, Sin Nombre virus physiology, Hantavirus Infections
- Abstract
Rodent-borne hantaviruses are prevalent worldwide and upon spillover to human populations, cause severe disease for which no specific treatment is available. A potent antibody response is key for recovery from hantavirus infection. Here we study a highly neutralizing human monoclonal antibody, termed SNV-42, which was derived from a memory B cell isolated from an individual with previous Sin Nombre virus (SNV) infection. Crystallographic analysis demonstrates that SNV-42 targets the Gn subcomponent of the tetrameric (Gn-Gc)
4 glycoprotein assembly that is relevant for viral entry. Integration of our 1.8 Å structure with the (Gn-Gc)4 ultrastructure arrangement indicates that SNV-42 targets the membrane-distal region of the virus envelope. Comparison of the SNV-42 paratope encoding variable genes with inferred germline gene segments reveals high sequence conservation, suggesting that germline-encoded antibodies inhibit SNV. Furthermore, mechanistic assays reveal that SNV-42 interferes with both receptor recognition and fusion during host-cell entry. This work provides a molecular-level blueprint for understanding the human neutralizing antibody response to hantavirus infection., (© 2023. The Author(s).)- Published
- 2023
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35. Development of a Kinetic ELISA and Reactive B Cell Frequency Assay to Detect Respiratory Syncytial Virus Pre-Fusion F Protein-Specific Immune Responses in Infants.
- Author
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Rolsma SL, Yoder SM, Nargi RS, Brady E, Jimenez-Truque N, Thomsen I, Kontos M, Carnahan RH, Sutton RE, Armstrong E, Dally L, Crowe JE, Edwards KM, and Creech CB
- Subjects
- Child, Infant, Humans, Child, Preschool, Antibodies, Neutralizing, Antibodies, Viral, Viral Fusion Proteins, Immunity, Enzyme-Linked Immunosorbent Assay, Respiratory Syncytial Virus, Human, Respiratory Syncytial Virus Infections
- Abstract
Background: Respiratory syncytial virus (RSV) is a major cause of respiratory disease in infants, making vaccination an attractive preventive strategy. Due to earlier reports of vaccine-enhanced disease in RSV-naive children, assessing prior RSV infection is critical for determining eligibility for future infant vaccine trials. However, this is complicated by the presence of maternally transferred maternal antibodies. We sought to develop assays that measure immune responses to RSV pre-fusion (F) protein that discriminates between maternal and infant responses., Methods: We measured RSV-specific responses in two groups of children <3 years of age; those with laboratory-confirmed RSV (RSV-infected) and those enrolled prior to their first RSV season (RSV-uninfected). Serial blood samples were obtained and recent infections with RSV and other respiratory viruses were assessed during follow-up. An RSV pre-F-specific kinetic enzyme-linked immunosorbent assay (kELISA) and an F-specific reactive B cell frequency (RBF) assay were developed., Results: One hundred two young children were enrolled between July 2015 and April 2017; 74 were in the RSV-uninfected group and 28 were in the RSV-infected group. Participants were asked to provide sequential blood samples over time, but only 53 participants in the RSV-uninfected group and 22 participants in the RSV-infected groups provided multiple samples. In the RSV-infected group, most had positive kELISA and RBF during the study. In the RSV-uninfected group, two patterns emerged: declining kELISA values without reactive B cells, due to maternal transplacental antibody transfer, and persistently positive kELISA with reactive B cells, due to asymptomatic undiagnosed RSV infection., Conclusions: A kELISA targeting RSV pre-F epitopes and an RBF assay targeting RSV F-specific B cells generally allow discrimination between maternally and infant-derived antibodies., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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36. A chikungunya virus-like particle vaccine induces broadly neutralizing and protective antibodies against alphaviruses in humans.
- Author
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Raju S, Adams LJ, Earnest JT, Warfield K, Vang L, Crowe JE Jr, Fremont DH, and Diamond MS
- Subjects
- Animals, Humans, Cryoelectron Microscopy, Antibodies, Viral, Antibodies, Neutralizing, Antibodies, Monoclonal therapeutic use, Chikungunya virus physiology, Chikungunya Fever prevention & control, Vaccines, Virus-Like Particle
- Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes epidemics of acute and chronic musculoskeletal disease. Here, we analyzed the human B cell response to a CHIKV-like particle-adjuvanted vaccine (PXVX0317) from samples obtained from a phase 2 clinical trial in humans (NCT03483961). Immunization with PXVX0317 induced high levels of neutralizing antibody in serum against CHIKV and circulating antigen-specific B cells up to 6 months after immunization. Monoclonal antibodies (mAbs) generated from peripheral blood B cells of three PXVX0317-vaccinated individuals on day 57 after immunization potently neutralized CHIKV infection, and a subset of these inhibited multiple related arthritogenic alphaviruses. Epitope mapping and cryo-electron microscopy defined two broadly neutralizing mAbs that uniquely bind to the apex of the B domain of the E2 glycoprotein. These results demonstrate the inhibitory breadth and activity of the human B cell response induced by the PXVX0317 vaccine against CHIKV and potentially other related alphaviruses.
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- 2023
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37. Systematic analysis of human antibody response to ebolavirus glycoprotein shows high prevalence of neutralizing public clonotypes.
- Author
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Chen EC, Gilchuk P, Zost SJ, Ilinykh PA, Binshtein E, Huang K, Myers L, Bonissone S, Day S, Kona CR, Trivette A, Reidy JX, Sutton RE, Gainza C, Diaz S, Williams JK, Selverian CN, Davidson E, Saphire EO, Doranz BJ, Castellana N, Bukreyev A, Carnahan RH, and Crowe JE Jr
- Subjects
- Humans, Animals, Mice, Antibodies, Neutralizing, Antibodies, Viral, Antibody Formation, Prevalence, Glycoproteins genetics, Ebolavirus, Hemorrhagic Fever, Ebola
- Abstract
Understanding the human antibody response to emerging viral pathogens is key to epidemic preparedness. As the size of the B cell response to a pathogenic-virus-protective antigen is poorly defined, we perform deep paired heavy- and light-chain sequencing in Ebola virus glycoprotein (EBOV-GP)-specific memory B cells, allowing analysis of the ebolavirus-specific antibody repertoire both genetically and functionally. This approach facilitates investigation of the molecular and genetic basis for the evolution of cross-reactive antibodies by elucidating germline-encoded properties of antibodies to EBOV and identification of the overlap between antibodies in the memory B cell and serum repertoire. We identify 73 public clonotypes of EBOV, 20% of which encode antibodies with neutralization activity and capacity to protect mice in vivo. This comprehensive analysis of the public and private antibody repertoire provides insight into the molecular basis of the humoral immune response to EBOV GP, which informs the design of vaccines and improved therapeutics., Competing Interests: Declaration of interests E.D. and B.J.D. are employees of Integral Molecular, and B.J.D.is a shareholder in that company. J.E.C. has served as a consultant for Luna Labs USA, Merck Sharp & Dohme, Emergent Biosolutions, and GlaxoSmithKline; is a member of the scientific advisory board of Meissa Vaccines; is a former member of the scientific advisory board of Gigagen (Grifols); and is the founder of IDBiologics. The laboratory of J.E.C. received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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38. Corrigendum: Convergent antibody responses are associated with broad neutralization of hepatitis C virus.
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Skinner NE, Ogega CO, Frumento N, Clark KE, Paul H, Yegnasubramanian S, Schuebel K, Meyers J, Gupta A, Wheelan S, Cox AL, Crowe JE Jr, Ray SC, and Bailey JR
- Abstract
[This corrects the article DOI: 10.3389/fimmu.2023.1135841.]., (Copyright © 2023 Skinner, Ogega, Frumento, Clark, Paul, Yegnasubramanian, Schuebel, Meyers, Gupta, Wheelan, Cox, Crowe, Ray and Bailey.)
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- 2023
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39. Potently neutralizing human mAbs against the zoonotic pararubulavirus Sosuga virus.
- Author
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Parrington HM, Kose N, Armstrong E, Handal L, Diaz S, Reidy J, Dong J, Stewart-Jones GB, Shrivastava-Ranjan P, Jain S, Albariño CG, Carnahan RH, and Crowe JE Jr
- Subjects
- Humans, Viral Proteins, Paramyxoviridae, Antibodies, Monoclonal
- Abstract
Sosuga virus (SOSV) is a recently discovered paramyxovirus with a single known human case of disease. There has been little laboratory research on SOSV pathogenesis or immunity, and no approved therapeutics or vaccines are available. Here, we report the discovery of human mAbs from the circulating memory B cells of the only known human case and survivor of SOSV infection. We isolated 6 mAbs recognizing the functional attachment protein hemagglutinin-neuraminidase (HN) and 18 mAbs against the fusion (F) protein. The anti-HN mAbs all targeted the globular head of the HN protein and could be organized into 4 competition-binding groups that exhibited epitope diversity. The anti-F mAbs can be divided into pre- or postfusion conformation-specific categories and further into 8 competition-binding groups. The only Ab in the panel that did not display neutralization activity was the single postfusion-specific anti-F mAb. Most of the anti-HN mAbs were more potently neutralizing than the anti-F mAbs, with mAbs in 1 of the HN competition-binding groups possessing ultrapotent (<1 ng/mL) half-maximal inhibitory virus neutralization values. These findings provide insight into the molecular basis for human Ab recognition of paramyxovirus surface proteins and the mechanisms of SOSV neutralization.
- Published
- 2023
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40. Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants.
- Author
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Desautels TA, Arrildt KT, Zemla AT, Lau EY, Zhu F, Ricci D, Cronin S, Zost SJ, Binshtein E, Scheaffer SM, Dadonaite B, Petersen BK, Engdahl TB, Chen E, Handal LS, Hall L, Goforth JW, Vashchenko D, Nguyen S, Weilhammer DR, Lo JK, Rubinfeld B, Saada EA, Weisenberger T, Lee TH, Whitener B, Case JB, Ladd A, Silva MS, Haluska RM, Grzesiak EA, Earnhart CG, Hopkins S, Bates TW, Thackray LB, Segelke BW, Lillo AM, Sundaram S, Bloom J, Diamond MS, Crowe JE Jr, Carnahan RH, and Faissol DM
- Abstract
The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs
1-3 , but also revealed how quickly viral escape can curtail effective options4,5 . With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld™ and its constituent, cilgavimab4,6 . Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies with a known clinical profile to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign COV2-2130 to rescue in vivo efficacy against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the contemporaneously dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and many variants of concern that subsequently emerged, and provides protection in vivo against the strains tested, WA1/2020, BA.1.1, and BA.5. Deep mutational scanning of tens of thousands pseudovirus variants reveals 2130-1-0114-112 improves broad potency without incurring additional escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Because our approach is computationally driven, not requiring experimental iterations or pre-existing binding data, it could enable rapid response strategies to address escape variants or pre-emptively mitigate escape vulnerabilities., Competing Interests: COMPETING FINANCIAL INTERESTS M.S.D. is a consultant for Inbios, Vir Biotechnology, Ocugen, Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. J.E.C. has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, Emergent Biosolutions, and GlaxoSmithKline, is a member of the Scientific Advisory Board of Meissa Vaccines, a former member of the Scientific Advisory Board of Gigagen (Grifols) and is founder of IDBiologics. The laboratory of J.E.C. received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. J. D. B. is on the scientific advisory boards of Apriori Bio, Aerium Therapuetics, Invivyd, and the Vaccine Company. Lawrence Livermore National Laboratory, Los Alamos National Laboratory, and Vanderbilt University have applied for patents for some of the antibodies in this paper, for which T.A.D, K.T.A, A.T.Z., E.Y.L., F.Z., A.M.L., R.H.C., J.E.C., and D.M.F. are inventors. Vanderbilt University has licensed certain rights to antibodies in this paper to Astra Zeneca. J. D. B. and B.D. are inventors on Fred Hutch licensed patents related to the deep mutational scanning of viral proteins.- Published
- 2023
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41. Structural constraints link differences in neutralization potency of human anti-Eastern equine encephalitis virus monoclonal antibodies.
- Author
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Williamson LE, Bandyopadhyay A, Bailey K, Sirohi D, Klose T, Julander JG, Kuhn RJ, and Crowe JE Jr
- Subjects
- Humans, Horses, Animals, Antibodies, Neutralizing, Antibodies, Viral, Cryoelectron Microscopy, Epitopes, Antibodies, Monoclonal, Neutralization Tests, Encephalitis Virus, Eastern Equine, Encephalomyelitis, Equine
- Abstract
Selection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory concentration (IC
50 ) values, is an important characteristic of candidate therapeutic antibodies. Structural insights into the bases of neutralization potency differences between antiviral neutralizing mAbs are lacking. In this report, we present cryo-electron microscopy (EM) reconstructions of three anti-Eastern equine encephalitis virus (EEEV) neutralizing human mAbs targeting overlapping epitopes on the E2 protein, with greater than 20-fold differences in their respective IC50 values. From our structural and biophysical analyses, we identify several constraints that contribute to the observed differences in the neutralization potencies. Cryo-EM reconstructions of EEEV in complex with these Fab fragments reveal structural constraints that dictate intravirion or intervirion cross-linking of glycoprotein spikes by their IgG counterparts as a mechanism of neutralization. Additionally, we describe critical features for the recognition of EEEV by these mAbs including the epitope-paratope interaction surface, occupancy, and kinetic differences in on-rate for binding to the E2 protein. Each constraint contributes to the extent of EEEV inhibition for blockade of virus entry, fusion, and/or egress. These findings provide structural and biophysical insights into the differences in mechanism and neutralization potencies of these antibodies, which help inform rational design principles for candidate vaccines and therapeutic antibodies for all icosahedral viruses.- Published
- 2023
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42. Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies.
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Engdahl TB, Binshtein E, Brocato RL, Kuzmina NA, Principe LM, Kwilas SA, Kim RK, Chapman NS, Porter MS, Guardado-Calvo P, Rey FA, Handal LS, Diaz SM, Zagol-Ikapitte IA, Tran MH, McDonald WH, Meiler J, Reidy JX, Trivette A, Bukreyev A, Hooper JW, and Crowe JE
- Subjects
- Animals, Humans, Antibodies, Neutralizing, Antibodies, Viral, Rodentia, Orthohantavirus, Hantavirus Infections prevention & control, Hantaan virus, Communicable Diseases
- Abstract
Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While infections in humans are relatively rare, mortality rates range from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the human humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity to authentic hantaviruses. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines., Competing Interests: TE, EB, RB, NK, LP, SK, RK, NC, MP, PG, FR, LH, SD, IZ, MT, WM, JM, JR, AT, AB, JH No competing interests declared, JC has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, Emergent Biosolutions, GlaxoSmithKline and BTG International Inc, is a member of the Scientific Advisory Board of Meissa Vaccines, a former member of the Scientific Advisory Board of Gigagen (Grifols) and is founder of IDBiologics. The laboratory of J.E.C. received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study
- Published
- 2023
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43. Convergent antibody responses are associated with broad neutralization of hepatitis C virus.
- Author
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Skinner NE, Ogega CO, Frumento N, Clark KE, Yegnasubramanian S, Schuebel K, Meyers J, Gupta A, Wheelan S, Cox AL, Crowe JE Jr, Ray SC, and Bailey JR
- Subjects
- Humans, Broadly Neutralizing Antibodies, Antibody Formation, Antibodies, Neutralizing, Antibodies, Monoclonal, Complementarity Determining Regions genetics, Hepacivirus, Hepatitis C
- Abstract
Introduction: Early development of broadly neutralizing antibodies (bNAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein E2 is associated with spontaneous clearance of infection, so induction of bNAbs is a major goal of HCV vaccine development. However, the molecular antibody features important for broad neutralization are not known., Methods: To identify B cell repertoire features associated with broad neutralization, we performed RNA sequencing of the B cell receptors (BCRs) of HCV E2-reactive B cells of HCV-infected individuals with either high or low plasma neutralizing breadth. We then produced a monoclonal antibody (mAb) expressed by pairing the most abundant heavy and light chains from public clonotypes identified among clearance, high neutralization subjects., Results: We found distinctive BCR features associated with broad neutralization of HCV, including long heavy chain complementarity determining region 3 (CDRH3) regions, specific VH gene usage, increased frequencies of somatic hypermutation, and particular VH gene mutations. Most intriguing, we identified many E2-reactive public BCR clonotypes (heavy and light chain clones with the same V and J-genes and identical CDR3 sequences) present only in subjects who produced highly neutralizing plasma. The majority of these public clonotypes were shared by two subjects who cleared infection. A mAb expressing the most abundant public heavy and light chains from these clearance, high neutralization subjects had features enriched in high neutralization clonotypes, such as increased somatic hypermutation frequency and usage of IGHV1-69 , and was cross-neutralizing., Discussion: Together, these results demonstrate distinct BCR repertoires associated with high plasma neutralizing capacity. Further characterization of the molecular features and function of these antibodies can inform HCV vaccine development., Competing Interests: JC has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, Emergent Biosolutions, GlaxoSmithKline and BTG International Inc, is a member of the Scientific Advisory Board of Meissa Vaccines, a former member of the Scientific Advisory Board of Gigagen Grifols and is founder of IDBiologics. The laboratory of JC received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Skinner, Ogega, Frumento, Clark, Yegnasubramanian, Schuebel, Meyers, Gupta, Wheelan, Cox, Crowe, Ray and Bailey.)
- Published
- 2023
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44. Glycan masking in vaccine design: Targets, immunogens and applications.
- Author
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Martina CE, Crowe JE Jr, and Meiler J
- Subjects
- Antibodies, Neutralizing, Epitopes, Polysaccharides, HIV Antibodies, HIV-1
- Abstract
Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low interest and thus focus the immune system on highly therapeutic epitopes. This shielding strategy is inspired by viruses such as influenza and HIV, which are able to escape the immune system by incorporating additional glycosylation and preventing the binding of therapeutic antibodies. Interestingly, the glycan masking technique is mainly used in vaccine design to fight the same viruses that naturally use glycans to evade the immune system. In this review we report the major successes obtained with the glycan masking technique in epitope-focused vaccine design. We focus on the choice of the target antigen, the strategy for immunogen design and the relevance of the carrier vector to induce a strong immune response. Moreover, we will elucidate the different applications that can be accomplished with glycan masking, such as shifting the immune response from hyper-variable epitopes to more conserved ones, focusing the response on known therapeutic epitopes, broadening the response to different viral strains/sub-types and altering the antigen immunogenicity to elicit higher or lower immune response, as desired., Competing Interests: JC has served as a consultant for Luna Labs USA, Merck Sharp & Dohme Corporation, Emergent Biosolutions, GlaxoSmithKline and BTG International Inc, is a member of the Scientific Advisory Board of Meissa Vaccines, a former member of the Scientific Advisory Board of Gigagen (Grifols) and is founder of IDBiologics. The laboratory of JC received unrelated sponsored research agreements from AstraZeneca, Takeda, and IDBiologics. The remaining authors declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martina, Crowe and Meiler.)
- Published
- 2023
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45. Functional HIV-1/HCV cross-reactive antibodies isolated from a chronically co-infected donor.
- Author
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Pilewski KA, Wall S, Richardson SI, Manamela NP, Clark K, Hermanus T, Binshtein E, Venkat R, Sautto GA, Kramer KJ, Shiakolas AR, Setliff I, Salas J, Mapengo RE, Suryadevara N, Brannon JR, Beebout CJ, Parks R, Raju N, Frumento N, Walker LM, Fechter EF, Qin JS, Murji AA, Janowska K, Thakur B, Lindenberger J, May AJ, Huang X, Sammour S, Acharya P, Carnahan RH, Ross TM, Haynes BF, Hadjifrangiskou M, Crowe JE Jr, Bailey JR, Kalams S, Morris L, and Georgiev IS
- Subjects
- Humans, Hepacivirus, Antibodies, Neutralizing, SARS-CoV-2, HIV Antibodies, HIV-1, Coinfection, HIV Infections, COVID-19, Hepatitis C
- Abstract
Despite prolific efforts to characterize the antibody response to human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) mono-infections, the response to chronic co-infection with these two ever-evolving viruses is poorly understood. Here, we investigate the antibody repertoire of a chronically HIV-1/HCV co-infected individual using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq). We identify five HIV-1/HCV cross-reactive antibodies demonstrating binding and functional cross-reactivity between HIV-1 and HCV envelope glycoproteins. All five antibodies show exceptional HCV neutralization breadth and effector functions against both HIV-1 and HCV. One antibody, mAb688, also cross-reacts with influenza and coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examine the development of these antibodies using next-generation sequencing analysis and lineage tracing and find that somatic hypermutation established and enhanced this reactivity. These antibodies provide a potential future direction for therapeutic and vaccine development against current and emerging infectious diseases. More broadly, chronic co-infection represents a complex immunological challenge that can provide insights into the fundamental rules that underly antibody-antigen specificity., Competing Interests: Declaration of interests K.A.P. and I.S.G. are listed as inventors on patents filed describing the antibodies discovered here. A.R.S. and I.S.G. are co-founders of AbSeek Bio. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda Vaccines, IDBiologics, and AstraZeneca. The Georgiev laboratory at Vanderbilt University Medical Center has received unrelated funding from Takeda Pharmaceuticals., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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46. Antibody-based protection against respiratory syncytial virus in mice and their offspring through vectored immunoprophylaxis.
- Author
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Rghei AD, Yates JGE, Lopes JA, Zhan X, Guilleman MM, Pei Y, van Lieshout LP, Santry LA, Bridle BW, Karimi K, Thompson B, Susta L, Crowe JE Jr, and Wootton SK
- Abstract
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections, with potential lower respiratory tract infections, which can be particularly problematic in infants and the elderly. There are no approved vaccines for RSV. The current standard of care for high-risk individuals is monthly administration of palivizumab, a humanized murine monoclonal antibody (mAb) targeting the RSV fusion protein. Adeno-associated virus (AAV)-mediated expression of mAbs has previously led to sustained expression of therapeutic concentrations of mAbs in several animal models, representing an alternative to repetitive passive administration. Intramuscular (IM) administration of AAV6.2FF expressing RSV antibodies, palivizumab or hRSV90, resulted in high concentrations of human (h)IgG1 mAbs in the serum and at various mucosal surfaces, while intranasal administration limited hIgG expression to the respiratory tract. IM administration of AAV6.2FF-hRSV90 or AAV6.2FF-palivizumab in a murine model provided sterilizing immunity against challenge with RSV A2. Evidence of maternal passive transfer of vectorized hRSV90 was detected in both murine and ovine models, with circulating mAbs providing sterilizing immunity in mouse progeny. Finally, addition of a "kill switch" comprised of LoxP sites flanking the mAb genes resulted in diminished serum hIgG after AAV-DJ-mediated delivery of Cre recombinase to the same muscle group that was originally transduced with the AAV-mAb vector. The ability of this AAV-mAb system to mediate robust, sustained mAb expression for maternal transfer to progeny in murine and ovine models emphasizes the potential of this platform for use as an alternative prophylactic vaccine for protection against neonatal infections, particularly in high-risk infants., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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47. Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape.
- Author
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Mazur NI, Terstappen J, Baral R, Bardají A, Beutels P, Buchholz UJ, Cohen C, Crowe JE Jr, Cutland CL, Eckert L, Feikin D, Fitzpatrick T, Fong Y, Graham BS, Heikkinen T, Higgins D, Hirve S, Klugman KP, Kragten-Tabatabaie L, Lemey P, Libster R, Löwensteyn Y, Mejias A, Munoz FM, Munywoki PK, Mwananyanda L, Nair H, Nunes MC, Ramilo O, Richmond P, Ruckwardt TJ, Sande C, Srikantiah P, Thacker N, Waldstein KA, Weinberger D, Wildenbeest J, Wiseman D, Zar HJ, Zambon M, and Bont L
- Subjects
- Infant, Female, Humans, Pregnancy, Aged, Antibodies, Monoclonal therapeutic use, Immunization, Antibodies, Viral, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus, Human
- Abstract
Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results., Competing Interests: Declaration of interests UMCU received minor funding from The Bill & Melinda Gates Medical Research Institute. DMW has received consulting fees from Pfizer, Merck, Affinivax, and Matrivax, unrelated to this manuscript; and is a principal investigator with grant support from Pfizer and Merck to Yale University, unrelated to this manuscript. NIM has regular interaction with pharameutical and other industrial partners: UMC Utrecht has received fees for invited lectures by Abbvie, Merck, and Sanofi. LB has regular interaction with pharmaceutical and other industrial partners. BSG is an inventor of patents for RSV vaccines using the stabilised prefusion F protein. AM has received research grants from National Institutes of Health, Janssen, and Merck institution; fees for participation in advisory boards from Janssen, Sanofi-Pasteur, and Merck; and fees for educational lectures from Sanofi-Pasteur and AstraZeneca. TJR was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. BSG was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UJB was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UMCU has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, Pfizer, the Bill & Melinda Gates Foundation, and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public private partnership IMI-funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015-17 (total annual estimate less than €20 000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, and Janssen (total annual estimate less than €20 000). Dr. Bont is the founding chairman of the ReSViNET Foundation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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48. Neutralization fingerprinting technology for characterizing polyclonal antibody responses to dengue vaccines.
- Author
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Raju N, Zhan X, Das S, Karwal L, Dean HJ, Crowe JE Jr, Carnahan RH, and Georgiev IS
- Subjects
- Humans, Antibody Formation, Antibodies, Viral, Antibodies, Neutralizing, Technology, Dengue Vaccines, Dengue Virus, Dengue
- Abstract
Dengue is a major public health threat. There are four dengue virus (DENV) serotypes; therefore, efforts are focused on developing safe and effective tetravalent DENV vaccines. While neutralizing antibodies contribute to protective immunity, there are still important gaps in understanding of immune responses elicited by dengue infection and vaccination. To that end, here, we develop a computational modeling framework based on the concept of antibody-virus neutralization fingerprints in order to characterize samples from clinical studies of TAK-003, a tetravalent vaccine candidate currently in phase 3 trials. Our results suggest a similarity of neutralizing antibody specificities in baseline-seronegative individuals. In contrast, amplification of pre-existing neutralizing antibody specificities is predicted for baseline-seropositive individuals, thus quantifying the role of immunologic imprinting in driving antibody responses to DENV vaccines. The neutralization fingerprinting analysis framework presented here can contribute to understanding dengue immune correlates of protection and help guide further vaccine development and optimization., Competing Interests: Declaration of interests This research was supported by Takeda. Serum from DEN-205 trial (30 samples from 20 donors) and funding were provided by Takeda to support Vanderbilt University Medical Center’s evaluation of the NFP algorithm. I.S.G. is a co-founder of AbSeek Bio. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. L.K. is an employee of Takeda Vaccines, Inc. S.D. and H.J.D. were employees of Takeda Vaccines, Inc., at the time these studies were performed. H.J.D. is a consultant for Takeda Vaccines, Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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49. Computational epitope mapping of class I fusion proteins using low complexity supervised learning methods.
- Author
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Fischer MFS, Crowe JE, and Meiler J
- Subjects
- Epitope Mapping methods, Cryoelectron Microscopy, Epitopes, Supervised Machine Learning, Antibodies, Viral, Antibodies, Monoclonal, Antibodies, Neutralizing
- Abstract
Antibody epitope mapping of viral proteins plays a vital role in understanding immune system mechanisms of protection. In the case of class I viral fusion proteins, recent advances in cryo-electron microscopy and protein stabilization techniques have highlighted the importance of cryptic or 'alternative' conformations that expose epitopes targeted by potent neutralizing antibodies. Thorough epitope mapping of such metastable conformations is difficult but is critical for understanding sites of vulnerability in class I fusion proteins that occur as transient conformational states during viral attachment and fusion. We introduce a novel method Accelerated class I fusion protein Epitope Mapping (AxIEM) that accounts for fusion protein flexibility to improve out-of-sample prediction of discontinuous antibody epitopes. Harnessing data from previous experimental epitope mapping efforts of several class I fusion proteins, we demonstrate that accuracy of epitope prediction depends on residue environment and allows for the prediction of conformation-dependent antibody target residues. We also show that AxIEM can identify common epitopes and provide structural insights for the development and rational design of vaccines., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Fischer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2022
- Full Text
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50. Nebulized mRNA-Encoded Antibodies Protect Hamsters from SARS-CoV-2 Infection.
- Author
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Vanover D, Zurla C, Peck HE, Orr-Burks N, Joo JY, Murray J, Holladay N, Hobbs RA, Jung Y, Chaves LCS, Rotolo L, Lifland AW, Olivier AK, Li D, Saunders KO, Sempowski GD, Crowe JE Jr, Haynes BF, Lafontaine ER, Hogan RJ, and Santangelo PJ
- Subjects
- Humans, SARS-CoV-2, RNA, Messenger genetics, Antibodies, Neutralizing therapeutic use, COVID-19
- Abstract
Despite the success of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines, there remains a clear need for new classes of preventatives for respiratory viral infections due to vaccine hesitancy, lack of sterilizing immunity, and for at-risk patient populations, including the immunocompromised. While many neutralizing antibodies have been identified, and several approved, to treat COVID-19, systemic delivery, large doses, and high costs have the potential to limit their widespread use, especially in low- and middle-income countries. To use these antibodies more efficiently, an inhalable formulation is developed that allows for the expression of mRNA-encoded, membrane-anchored neutralizing antibodies in the lung to mitigate SARS-CoV-2 infections. First, the ability of mRNA-encoded, membrane-anchored, anti-SARS-CoV-2 antibodies to prevent infections in vitro is demonstrated. Next, it is demonstrated that nebulizer-based delivery of these mRNA-expressed neutralizing antibodies potently abrogates disease in the hamster model. Overall, these results support the use of nebulizer-based mRNA expression of neutralizing antibodies as a new paradigm for mitigating respiratory virus infections., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)
- Published
- 2022
- Full Text
- View/download PDF
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