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      Antibody to Poly- N-acetyl glucosamine provides protection against intracellular pathogens: Mechanism of action and validation in horse foals challenged with Rhodococcus equi

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          Abstract

          Immune correlates of protection against intracellular bacterial pathogens are largely thought to be cell-mediated, although a reasonable amount of data supports a role for antibody-mediated protection. To define a role for antibody-mediated immunity against an intracellular pathogen, Rhodococcus equi, that causes granulomatous pneumonia in horse foals, we devised and tested an experimental system relying solely on antibody-mediated protection against this host-specific etiologic agent. Immunity was induced by vaccinating pregnant mares 6 and 3 weeks prior to predicted parturition with a conjugate vaccine targeting the highly conserved microbial surface polysaccharide, poly- N-acetyl glucosamine (PNAG). We ascertained antibody was transferred to foals via colostrum, the only means for foals to acquire maternal antibody. Horses lack transplacental antibody transfer. Next, a randomized, controlled, blinded challenge was conducted by inoculating at ~4 weeks of age ~10 6 cfu of R. equi via intrabronchial challenge. Eleven of 12 (91%) foals born to immune mares did not develop clinical R. equi pneumonia, whereas 6 of 7 (86%) foals born to unvaccinated controls developed pneumonia (P = 0.0017). In a confirmatory passive immunization study, infusion of PNAG-hyperimmune plasma protected 100% of 5 foals against R. equi pneumonia whereas all 4 recipients of normal horse plasma developed clinical disease (P = 0.0079). Antibodies to PNAG mediated killing of extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms depended on antibody recognition of surface expression of PNAG on infected cells, along with complement deposition and PMN-assisted lysis of infected macrophages. Peripheral blood mononuclear cells from immune and protected foals released higher levels of interferon-γ in response to PNAG compared to controls, indicating vaccination also induced an antibody-dependent cellular release of this critical immune cytokine. Overall, antibody-mediated opsonic killing and interferon-γ release in response to PNAG may protect against diseases caused by intracellular bacterial pathogens.

          Author summary

          Development of effective vaccines for diseases such as tuberculosis, brucellosis and others caused by intracellular pathogens has proved challenging, as data exist supporting both antibody and cellular immune effectors as mediators of protection. To address this problem against an important, and representative, equine intracellular pathogen, we chose to test a vaccine candidate for the ability to protect horse foals challenged at 4 weeks of age with Rhodococcus equi. To make these foals immune, their pregnant mares were immunized with a vaccine targeting the conserved surface antigen found on many microbes, termed PNAG. Antibody in the pregnant mares was transferred to their foals and, after the foals were challenged, 91% of those born to vaccinated mares were protected against R. equi pneumonia. Meanwhile, 86% of the non-vaccinated controls developed pneumonia. We also showed antibody to PNAG could kill various bacteria that produce this antigen when residing inside of human macrophage cells, a new mechanism for antibody-mediated immunity to intracellular bacteria. These results support the development of PNAG as a vaccine for intracellular bacterial pathogens.

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          Most cited references 38

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          Antibody-mediated immunity against tuberculosis: implications for vaccine development.

          There is an urgent need for new and better vaccines against tuberculosis (TB). Current vaccine design strategies are generally focused on the enhancement of cell-mediated immunity. Antibody-based approaches are not being considered, mostly due to the paradigm that humoral immunity plays little role in the protection against intracellular pathogens. Here, we reappraise and update the increasing evidence for antibody-mediated immunity against Mycobacterium tuberculosis, discuss the complexity of antibody responses to mycobacteria, and address mechanism of protection. Based on these findings and discussions, we challenge the common belief that immunity against M. tuberculosis relies solely on cellular defense mechanisms, and posit that induction of antibody-mediated immunity should be included in TB vaccine development strategies. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens.

            Microbial capsular antigens are effective vaccines but are chemically and immunologically diverse, resulting in a major barrier to their use against multiple pathogens. A β-(1→6)-linked poly-N-acetyl-d-glucosamine (PNAG) surface capsule is synthesized by four proteins encoded in genetic loci designated intercellular adhesion in Staphylococcus aureus or polyglucosamine in selected Gram-negative bacterial pathogens. We report that many microbial pathogens lacking an identifiable intercellular adhesion or polyglucosamine locus produce PNAG, including Gram-positive, Gram-negative, and fungal pathogens, as well as protozoa, e.g., Trichomonas vaginalis, Plasmodium berghei, and sporozoites and blood-stage forms of Plasmodium falciparum. Natural antibody to PNAG is common in humans and animals and binds primarily to the highly acetylated glycoform of PNAG but is not protective against infection due to lack of deposition of complement opsonins. Polyclonal animal antibody raised to deacetylated glycoforms of PNAG and a fully human IgG1 monoclonal antibody that both bind to native and deacetylated glycoforms of PNAG mediated complement-dependent opsonic or bactericidal killing and protected mice against local and/or systemic infections by Streptococcus pyogenes, Streptococcus pneumoniae, Listeria monocytogenes, Neisseria meningitidis serogroup B, Candida albicans, and P. berghei ANKA, and against colonic pathology in a model of infectious colitis. PNAG is also a capsular polysaccharide for Neisseria gonorrhoeae and nontypable Hemophilus influenzae, and protects cells from environmental stress. Vaccination targeting PNAG could contribute to immunity against serious and diverse prokaryotic and eukaryotic pathogens, and the conserved production of PNAG suggests that it is a critical factor in microbial biology.
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              Comparative opsonic and protective activities of Staphylococcus aureus conjugate vaccines containing native or deacetylated Staphylococcal Poly-N-acetyl-beta-(1-6)-glucosamine.

              Staphylococcus aureus and Staphylococcus epidermidis both synthesize the surface polysaccharide poly-N-acetyl-beta-(1-6)-glucosamine (PNAG), which is produced in vitro with a high level (>90%) of the amino groups substituted by acetate. Here, we examined the role of the acetate substituents of PNAG in generating opsonic and protective antibodies. PNAG and a deacetylated form of the antigen (dPNAG; 15% acetylation) were conjugated to the carrier protein diphtheria toxoid (DT) and used to immunize animals. Mice responded in a dose-dependent fashion to both conjugate vaccines, with maximum antibody titers observed at the highest dose and 4 weeks after the last of three weekly immunizations. PNAG-DT and dPNAG-DT vaccines were also very immunogenic in rabbits. Antibodies raised to the conjugate vaccines in rabbits mediated the opsonic killing of various staphylococcal strains, but the specificity of the opsonic killing was primarily to dPNAG, as this antigen inhibited the killing of S. aureus strains by both PNAG- and dPNAG-specific antibodies. Passive immunization of mice with anti-dPNAG-DT rabbit sera showed significant levels of clearance of S. aureus from the blood (54 to 91%) compared to control mice immunized with normal rabbit sera, whereas PNAG-specific antibodies were ineffective at clearing S. aureus. Passive immunization of mice with a goat antiserum raised to the dPNAG-DT vaccine protected against a lethal dose of three different S. aureus strains. Overall, these data show that immunization of animals with a conjugate vaccine of dPNAG elicit antibodies that mediated opsonic killing and protected against S. aureus infection, including capsular polysaccharide types 5 and 8 and an untypable strain.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Methodology
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Methodology
                Role: Data curationRole: Methodology
                Role: Data curationRole: Methodology
                Role: Data curationRole: Formal analysis
                Role: MethodologyRole: Resources
                Role: Resources
                Role: Resources
                Role: Formal analysisRole: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                19 July 2018
                July 2018
                : 14
                : 7
                Affiliations
                [1 ] Harvard Medical School, Brigham & Women’s Hospital, Boston, MA, United States of America
                [2 ] College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, United States of America
                [3 ] Mg Biologics, Ames, IA, United States of America
                [4 ] ALOPEXX Vaccine LLC, Concord, MA, United States of America
                [5 ] College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America
                University of Washington, UNITED STATES
                Author notes

                Gerald B. Pier is an inventor of intellectual properties [human monoclonal antibody to PNAG and PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Vaccine, LLC, and Alopexx Pharmaceuticals, LLC, entities in which GBP also holds equity. As an inventor of intellectual properties, GBP also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Pharmaceuticals, LLC, and Alopexx Vaccine, LLC. GBP’s interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict of interest policies. Colette Cywes-Bentley is an inventor of intellectual properties [use of human monoclonal antibody to PNAG and use of PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Pharmaceuticals, LLC. As an inventor of intellectual properties, CC-B also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Pharmaceuticals, LLC. Noah D. Cohen has received an unrestricted gift to the EIDL from Alopexx Vaccines, LLC. Daniel Vlock, holds an equity share and potential royalty income from Alopexx Vaccines, LLC for vaccines to PNAG and monoclonal antibody to PNAG from Alopexx Pharmaceuticals, LLC. Mark Meyer holds minority equity shares of Mg Biologics, Inc. Sarah Anthony and McKenzie Lambert are employees of Mg Biologics, Inc.

                ‡ These authors are joint first authors and contributed equally to this work.

                Article
                PPATHOGENS-D-18-00683
                10.1371/journal.ppat.1007160
                6053243
                30024986
                © 2018 Cywes-Bentley 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.

                Page count
                Figures: 6, Tables: 3, Pages: 24
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100001250, Morris Animal Foundation;
                Award ID: D15EQ-035
                Award Recipient :
                Funded by: Link Equine Research Endowment
                Award Recipient :
                Funded by: Alopexx Vaccines, LLC
                Award Recipient :
                This study was funded by a grant from the Morris Animal Foundation (MAF) ( https://www.morrisanimalfoundation.org/grants) and Alopexx Vaccine LLC) http://www.alopexx.com/company/vaccine/). The results have not been reviewed or endorsed by MAF, and the views expressed do not necessarily reflect the views of the MAF, its officers, directors, affiliates or agents. Additional support was provided by the Link Equine Research Endowment, Texas A&M University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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