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      Recombinant BCG Vaccines Reduce Pneumovirus-Caused Airway Pathology by Inducing Protective Humoral Immunity

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          Abstract

          The Human Respiratory Syncytial Virus (hRSV) and the Human Metapneumovirus (hMPV) are two pneumoviruses that are leading agents causing acute lower respiratory tract infections (ALRTIs) affecting young infants, the elderly, and immunocompromised patients worldwide. Since these pathogens were first discovered, many approaches for the licensing of safe and effective vaccines have been explored being unsuccessful to date. We have previously described that immunization with recombinant strains of Mycobacterium bovis Bacillus Calmette-Guérin (rBCG) expressing the hRSV nucleoprotein (rBCG-N) or the hMPV phosphoprotein (rBCG-P) induced immune protection against each respective virus. These vaccines efficiently promoted viral clearance without significant lung damage, mainly through the induction of a T helper 1 cellular immunity. Here we show that upon viral challenge, rBCG-immunized mice developed a protective humoral immunity, characterized by production of antibodies specific for most hRSV and hMPV proteins. Further, isotype switching from IgG1 to IgG2a was observed in mice immunized with rBCG vaccines and correlated with an increased viral clearance, as compared to unimmunized animals. Finally, sera obtained from animals immunized with rBCG vaccines and infected with their respective viruses exhibited virus neutralizing capacity and protected naïve mice from viral replication and pulmonary disease. These results support the notion that the use of rBCG strains could be considered as an effective vaccination approach against other respiratory viruses with similar biology as hRSV and hMPV.

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          Most cited references 44

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          Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children.

          We sought to determine the role of human metapneumovirus in lower respiratory tract illness in previously healthy infants and children. We tested nasal-wash specimens, obtained over a 25-year period from otherwise healthy children presenting with acute respiratory tract illness, for human metapneumovirus. 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. 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. Copyright 2004 Massachusetts Medical Society
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            Taxonomy of the order Mononegavirales: update 2016.

            In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
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              Lymphokine control of in vivo immunoglobulin isotype selection.

              Several specific conclusions can be drawn from these studies: 1. IL-4 is required for the generation of both primary polyclonal and secondary antigen-specific IgE responses in vivo. 2. IL-4 is required to maintain established, ongoing, antigen-specific and polyclonal IgE responses. 3. Most, but not all, polyclonal IgE production during a secondary immune response is IL-4-dependent. Memory B cells that have already switched to IgE at the DNA level may no longer require stimulation with IL-4 to be induced to secrete IgE. 4. The generation of a secondary IgE response is not dependent upon the presence of IL-4 during primary immunization. However, if IL-4 is not present during primary immunization, it is required during secondary immunization for the generation of an IgE response. 5. IL-4 does not appear to be required for the generation of in vivo IgG1 responses, and in at least some instances, does not contribute significantly to the generation of IgG1 responses in vivo. 6. A late-acting form of T-cell help other than IL-4 appears to be required for the generation of an IgE, but not an IgG1 response. 7. An antibody that inhibits IL-4 binding to IL-4 receptors affects Ig isotype selection in the same way as an antibody that neutralizes IL-4. 8. IFN-gamma can act in both spontaneous and induced immune responses to suppress IgE production. 9. IFN-gamma can also suppress IgG1 production and stimulate IgG2a production. However, IFN-gamma appears to suppress polyclonal IgG1 responses more than antigen-specific IgG1 responses, and it enhances, but is not required for, the generation of IgG2a responses. 10. IFN-alpha appears to resemble IFN-gamma in its ability to inhibit IgE and enhance IgG2a responses in GaM delta-injected mice, but it requires the presence of IFN-gamma to suppress IgG1 production in these mice. 11. Both IFN-alpha and IFN-gamma appear to be able to decrease IgE production in some human patients. 12. There is no direct evidence that IL-5 contributes to the generation of in vivo antibody responses. Two general conclusions may also be drawn.(ABSTRACT TRUNCATED AT 400 WORDS)
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                06 December 2018
                2018
                : 9
                Affiliations
                1Departamento de Genética Moleculary Microbiología, Facultad de Ciencias Biológicas, Millennium Institute of Immunology and Immunotherapy, Pontificia Universidad Católica de Chile , Santiago, Chile
                2Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
                Author notes

                Edited by: Christophe Chevalier, Institut National de la Recherche Agronomique (INRA), France

                Reviewed by: Michael Schotsaert, Icahn School of Medicine at Mount Sinai, United States; Aude Remot, Institut National de la Recherche Agronomique (INRA), France

                *Correspondence: Alexis M. Kalergis akalergis@ 123456bio.puc.cl

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                †These authors have contributed equally in this work

                Article
                10.3389/fimmu.2018.02875
                6293239
                Copyright © 2018 Soto, Gálvez, Rivera, Palavecino, Céspedes, Rey-Jurado, Bueno and Kalergis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 56, Pages: 16, Words: 11505
                Categories
                Immunology
                Original Research

                Immunology

                hrsv, hmpv, antibodies, humoral immune response, vaccine, respiratory virus, bcg

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