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Broadly neutralizing antibody

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https://www.readbyqxmd.com/read/28816583/mammalian-cell-surface-display-for-monoclonal-antibody-based-facs-selection-of-viral-envelope-proteins
#1
Tim-Henrik Bruun, Veronika Grassmann, Benjamin Zimmer, Benedikt Asbach, David Peterhoff, Alexander Kliche, Ralf Wagner
The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation...
August 17, 2017: MAbs
https://www.readbyqxmd.com/read/28807912/safety-and-efficacy-of-mhaa4549a-a-broadly-neutralizing-monoclonal-antibody-in-a-human-influenza-a-challenge-model-a-phase-2-randomized-trial
#2
Jacqueline M McBride, Jeremy J Lim, Tracy Burgess, Rong Deng, Michael A Derby, Mauricio Maia, Priscilla Horn, Omer Siddiqui, Daniel Sheinson, Haiyin Chen-Harris, Elizabeth M Newton, Dimitri Fillos, Denise Nazzal, Carrie M Rosenberger, Maikke B Ohlson, Rob Lambkin-Williams, Hosnieh Fathi, Jeffrey M Harris, Jorge A Tavel
BACKGROUND: MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. Safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV-challenge model. METHODS: One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24-36 hours later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1200, or 3600 mg) or a standard oral dose of oseltamivir...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28799906/of-mice-macaques-and-men-broadly-neutralizing-antibody-immunotherapy-for-hiv-1
#3
REVIEW
Yoshiaki Nishimura, Malcolm A Martin
The neutralizing antibodies targeting the HIV-1 envelope protein have been a major focus for HIV therapy. Early studies with anti-HIV-1 neutralizing monoclonal antibodies (mAbs) administered to infected individuals showed some promise, as they resulted in transient reductions in plasma viremia in some recipients. However, resistant viral variants rapidly emerged. A major development during the past 6 to 7 years has been the isolation and characterization of highly potent and broadly neutralizing mAbs (bNAbs) from infected individuals known as "elite neutralizers...
August 9, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28796912/nanobody-mediated-resistance-to-grapevine-fanleaf-virus-in-plants
#4
Caroline Hemmer, Samia Djennane, Léa Ackerer, Kamal Hleibieh, Aurélie Marmonier, Sophie Gersch, Shahinez Garcia, Emmanuelle Vigne, Véronique Komar, Mireille Perrin, Claude Gertz, Lorène Belval, François Berthold, Baptiste Monsion, Corinne Schmitt-Keichinger, Olivier Lemaire, Bernard Lorber, Carlos Gutiérrez, Serge Muyldermans, Gérard Demangeat, Christophe Ritzenthaler
Since their discovery, single-domain antigen-binding fragments of camelid-derived heavy chain-only antibodies, also known as Nanobodies (Nbs), have proven to be of outstanding interest as therapeutics against human diseases and pathogens including viruses, but their use against phytopathogens remains limited. Many plant viruses including Grapevine fanleaf virus (GFLV), a nematode-transmitted icosahedral virus and causal agent of fanleaf degenerative disease, have worldwide distribution and huge burden on crop yields representing billions of US dollars of losses annually, yet solutions to combat these viruses are often limited or inefficient...
August 10, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28794282/partial-efficacy-of-a-broadly-neutralizing-antibody-against-cell-associated-shiv-infection
#5
Matthew S Parsons, Sarah B Lloyd, Wen Shi Lee, Anne B Kristensen, Thakshila Amarasena, Rob J Center, Brandon F Keele, Jeffrey D Lifson, Celia C LaBranche, David Montefiori, Bruce D Wines, P Mark Hogarth, Kristine M Swiderek, Vanessa Venturi, Miles P Davenport, Stephen J Kent
Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794022/potent-in-vivo-nk-cell-mediated-elimination-of-hiv-1-infected-cells-mobilized-by-a-gp120-bispecific-and-hexavalent-broadly-neutralizing-fusion-protein
#6
Ariola Bardhi, Yanling Wu, Weizao Chen, Zhongyu Zhu, Jian Hua Zheng, Hing Wong, Emily Jeng, Jennifer Jones, Christina Ochsenbauer, John C Kappes, Dimiter S Dimitrov, Tianlei Ying, Harris Goldstein
Antibodies bound to HIV-1 envelope protein expressed by infected cells mobilize antibody dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to functional HIV-1 cure...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28794021/structure-based-design-of-hepatitis-c-virus-vaccines-that-elicit-neutralizing-antibody-responses-to-a-conserved-epitope
#7
Brian G Pierce, Elisabeth N Boucher, Kurt H Piepenbrink, Monir Ejemel, Chelsea A Rapp, William D Thomas, Eric J Sundberg, Zhiping Weng, Yang Wang
Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response, thus an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412-423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28790432/conformational-modulation-of-influenza-virus-hemagglutinin-characterization-and-in-vivo-efficacy-of-monomeric-form
#8
Jong Hyeon Seok, Jeongwon Kim, Dan Bi Lee, Ki Joon Cho, Ji-Hye Lee, Garam Bae, Mi Sook Chung, Kyung Hyun Kim
Mutational changes that mostly occur at the head region of hemagglutinin (HA) lead to the emergence of new epidemic influenza viruses, whereas HA antigens have been modified to generate broadly neutralizing antibodies toward highly conserved epitopes in the HA stem. Interestingly, a recent analysis of serum antibody repertoires showed that broadly neutralizing antibodies bind to HA monomer at a conserved region occluded at the intermonomer interface of HA trimer and confer protection in animal models. We showed previously that the recombinant HA ectodomain from a pandemic strain A/Korea/01/2009 was monomeric in solution and crystal structure...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28783671/potent-and-broad-hiv-neutralizing-antibodies-in-memory-b-cells-and-plasma
#9
LaTonya D Williams, Gilad Ofek, Sebastian Schätzle, Jonathan R McDaniel, Xiaozhi Lu, Nathan I Nicely, Liming Wu, Caleb S Lougheed, Todd Bradley, Mark K Louder, Krisha McKee, Robert T Bailer, Sijy O'Dell, Ivelin S Georgiev, Michael S Seaman, Robert J Parks, Dawn J Marshall, Kara Anasti, Guang Yang, Xiaoyan Nie, Nancy L Tumba, Kevin Wiehe, Kshitij Wagh, Bette Korber, Thomas B Kepler, S Munir Alam, Lynn Morris, Gift Kamanga, Myron S Cohen, Mattia Bonsignori, Shi-Mao Xia, David C Montefiori, Garnett Kelsoe, Feng Gao, John R Mascola, M Anthony Moody, Kevin O Saunders, Hua-Xin Liao, Georgia D Tomaras, George Georgiou, Barton F Haynes
Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1-specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1-infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage...
January 27, 2017: Science Immunology
https://www.readbyqxmd.com/read/28771513/a-modified-vaccinia-ankara-vaccine-vector-expressing-a-mosaic-h5-hemagglutinin-reduces-viral-shedding-in-rhesus-macaques
#10
Nicholas W Florek, Attapon Kamlangdee, James P Mutschler, Brock Kingstad-Bakke, Nancy Schultz-Darken, Karl W Broman, Jorge E Osorio, Thomas C Friedrich
The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a "mosaic" hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus...
2017: PloS One
https://www.readbyqxmd.com/read/28768869/protective-efficacy-of-broadly-neutralizing-antibodies-with-incomplete-neutralization-activity-against-shiv-in-rhesus-monkeys
#11
Boris Julg, Devin Sok, Stephen D Schmidt, Peter Abbink, Ruchi M Newman, Thomas Broge, Caitlyn Linde, Joseph Nkolola, Khoa Le, David Su, Julia Torabi, Melissa Pack, Amarendra Pegu, Todd M Allen, John R Mascola, Dennis R Burton, Dan H Barouch
HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with non-sigmoidal slopes and plateaus at <100% neutralization against a variety of viruses. The significance of incomplete neutralization for the ability of bnAbs to mediate protective effects in vivo however is undetermined. In the current study, we selected two bnAbs, PGT121 and 3BNC117, as they incompletely neutralize the clade C SHIV stock (SHIV-327c) at 85% and 70%, respectively, and performed a protection study in rhesus macaques...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28768724/pd-l2-regulates-b-1-cell-antibody-production-against-phosphorylcholine-through-an-il-5-dependent-mechanism
#12
Jerome T McKay, Marcela A Haro, Christina A Daly, Rama D Yammani, Bing Pang, W Edward Swords, Karen M Haas
B-1 cells produce natural Abs which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate that programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural Abs against phosphorylcholine (PC). Naive PD-L2-deficient (PD-L2(-/-)) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2(-/-) mice with selectively enhanced protection against PC-expressing nontypeable Haemophilus influenzae, but not PC-negative nontypeable Haemophilus influenzae, relative to wild-type mice...
August 2, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28767426/human-papillomavirus-16l1-58l2-chimeric-virus-like-particles-elicit-durable-neutralizing-antibody-responses-against-a-broad-spectrum-of-human-papillomavirus-types
#13
Xue Chen, Hongyang Liu, Zhirong Wang, Shuo Wang, Ting Zhang, Meili Hu, Liang Qiao, Xuemei Xu
The neutralizing antibodies elicited by human papillomavirus (HPV) major capsid protein L1 virus-like particle (VLP)-based vaccines are largely type-specific. An HPV vaccine inducing cross-neutralizing antibodies broadly will be cost-effective and of great value. To this end, we constructed HPV16L1-58L2 chimeric VLP (cVLP) by displaying HPV58 L2 aa.16-37 on the DE surface region of HPV16 L1. We found that vaccination with the HPV16L1-58L2 cVLP formulated with alum plus monophosphoryl lipid A (Alum-MPL) adjuvant elicited robust neutralizing antibodies in both mice and rabbits against all tested HPV types including HPV16/31/33/35/52/58 (genus α9), HPV18/39/45/59/68 (genus α7), HPV6/11 (genus α10), HPV2/27/57 (genus α4), and HPV5 (genus β1)...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28762497/t-cell-dependent-antigen-adjuvanted-with-dotap-cpg-b-but-not-dotap-cpg-a-induces-robust-germinal-center-responses-and-high-affinity-antibodies-in-mice
#14
Munir Akkaya, Billur Akkaya, Patrick W Sheehan, Pietro Miozzo, Mirna Pena, Chen-Feng Qi, Javier Manzella-Lapeira, Silvia Bolland, Susan K Pierce
The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T-cell dependent antigen, NP-conjugated to chicken gamma globulin (NP-CGG) adjuvanted with the toll-like receptor 9 (TLR9) ligands, CpG-A or CpG-B, alone or conjugated with the cationic lipid carrier, DOTAP...
August 1, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28758637/dna-prime-protein-boost-vaccination-elicits-robust-humoral-response-in-rhesus-macaques-using-oligomeric-simian-immunodeficiency-virus-envelope-and-advax-delta-inulin-adjuvant
#15
Veena Menon, Victor I Ayala, Sneha P Rangaswamy, Irene Kalisz, Stephen Whitney, Lindsey Galmin, Asma Ashraf, Celia LaBranche, David Montefiori, Nikolai Petrovsky, Vaniambadi S Kalyanaraman, Ranajit Pal
The partial success of the RV144 trial underscores the importance of envelope-specific antibody responses for an effective HIV-1 vaccine. Oligomeric HIV-1 envelope proteins delivered with a potent adjuvant are expected to elicit strong antibody responses with broad neutralization specificity. To test this hypothesis, two SIV envelope proteins were formulated with delta inulin-based adjuvant (Advax) and used to immunize nonhuman primates. Oligomeric gp140-gp145 from SIVmac251 and SIVsmE660 was purified to homogeneity...
July 31, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28757252/non-neutralizing-antibodies-alter-the-course-of-hiv-1-infection-in%C3%A2-vivo
#16
Joshua A Horwitz, Yotam Bar-On, Ching-Lan Lu, Daniela Fera, Ainsley A K Lockhart, Julio C C Lorenzi, Lilian Nogueira, Jovana Golijanin, Johannes F Scheid, Michael S Seaman, Anna Gazumyan, Susan Zolla-Pazner, Michel C Nussenzweig
Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize, the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28756236/accuracy-estimation-of-an-indirect-elisa-for-the-detection-of-west-nile-virus-antibodies-in-wild-birds-using-a-latent-class-model
#17
Marco Tamba, Antonino Caminiti, Alice Prosperi, Philippe Desprès, Davide Lelli, Giorgio Galletti, Ana Moreno, Giulia Paternoster, Annalisa Santi, Elio Licata, Sylvie Lecollinet, Luca Gelmini, Gianluca Rugna, Anna Procopio, Antonio Lavazza
West Nile virus (WNV) and Usutu virus (USUV), genus Flavivirus, are members of the Japanese encephalitis virus antigenic complex, and are maintained primarily in an enzootic cycle between mosquitoes and birds. WNV is zoonotic, and poses a threat to public health, especially in relation to blood transfusion. Serosurveillance of wild birds is suitable for early detection of WNV circulation, although concerns remain to be addressed as regards i) the type of test used, whether ELISA, virus neutralization test (VNT), plaque reduction neutralization test (PRNT), ii) the reagents (antigens, revealing antibodies), iii) the different bird species involved, and iv) potential cross-reactions with other Flaviviruses, such as USUV...
July 27, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28756066/prospects-and-challenges-in-the-development-of-a-norovirus-vaccine
#18
REVIEW
Nicolas W Cortes-Penfield, Sasirekha Ramani, Mary K Estes, Robert L Atmar
PURPOSE: Norovirus is the leading cause of acute epidemic gastroenteritis among children under the age of 5 years and adults in the United States and in adults worldwide, accounting for an estimated 20% of episodes of acute gastroenteritis across all ages. No effective vaccine is presently available. This article provides an overview of the current state of norovirus vaccine development, emphasizing barriers and challenges in the development of an effective vaccine, correlates of protection used to assess vaccine efficacy, and the results of clinical trials of the major candidate vaccines...
July 26, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28752105/an-entry-competent-intermediate-state-of-the-hiv-1-envelope-glycoproteins
#19
Alon Herschhorn, Joseph Sodroski
The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) mediate viral entry and are the sole target of neutralizing antibodies. Recent studies show that the metastable HIV-1 Env trimer can transit among three conformational states: State 1, State 3, and State 2, corresponding to the "closed", "open" and intermediate conformations, respectively. During virus entry, binding to the CD4 receptor drives Env from state 1 to state 3. In the unliganded Env, transitions from the closed (State 1) conformation are restrained by intramolecular interactions among different Env residues, which regulate HIV-1 Env conformation...
2017: Receptors & Clinical Investigation
https://www.readbyqxmd.com/read/28747530/sequence-intrinsic-somatic-mutation-mechanisms-contribute-to-affinity-maturation-of-vrc01-class-hiv-1-broadly-neutralizing-antibodies
#20
Joyce K Hwang, Chong Wang, Zhou Du, Robin M Meyers, Thomas B Kepler, Donna Neuberg, Peter D Kwong, John R Mascola, M Gordon Joyce, Mattia Bonsignori, Barton F Haynes, Leng-Siew Yeap, Frederick W Alt
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity...
July 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
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