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      Pneumococcal Conjugate and Plain Polysaccharide Vaccines Have Divergent Effects on Antigen-Specific B Cells

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          Abstract

          Background.  A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults.

          Methods.  We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved.

          Results.  A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans.

          Conclusions.  This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP.

          Clinical Trials Registration. ISRCTN: 78768849.

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          Most cited references20

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          Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.

          Techniques which identify hapten-specific B cells in tissues have been used to determine the sites of B cell activation in rat spleens in response to T cell-dependent (TD) antigens and T cell-independent type-1 (TI-1) antigens. Surface-associated hapten binding by specific memory B cells and B blasts was distinguished from the strong cytoplasmic hapten binding by specific plasma cells and plasmablasts. Blast cells in S phase were identified in tissue sections by staining cells which had been pulse labeled in vivo with 5-bromo-2'-deoxyuridine. Hapten-specific B blast cells are found in three sites: (a) around interdigitating cells in the T cell-rich zones; (b) in the follicular dendritic cell network and (c) in association with macrophages in the red pulp. Hapten-binding memory B cells, which are not in cell cycle, accumulate in the marginal zones and to a lesser extent the follicular mantles in response to TD and TI-1 antigens. The hapten-specific blast response in T zones is confined to the first few days after antigen is given and is low for primary responses to TD antigens, but massive on secondary challenge, when marginal zone memory B cells migrate to the T zones. Both the primary and secondary T zone responses to TI-1 antigens are impressive and in these responses hapten-specific B blasts are also found in the splenic red pulp. The follicular response to TD antigens starts with a small number of B blasts (fewer than five) entering each follicle. These increase in number exponentially so that by the 4th day after immunization they fill the follicle. The oligoclonality of the response is shown in simultaneous responses to two haptens where 6%-31% of the follicles on day 3 after immunization contain blasts specific for only one of the two haptens. During the 4th day classical zonal pattern of germinal centers develops. The surface immunoglobulin-positive B blasts are lost from the follicle center, while one pole of the follicular dendritic cell network fills with surface immunoglobulin-negative centroblasts. Centroblasts do not increase in numbers but divide to give rise to centrocytes, which re-express sIg and migrate into the follicular dendritic cell network. Cell kinetic studies indicate that the centrocyte population is renewed from centroblasts every 7 h. Centrocytes either leave the germinal center within this time or die in situ.(ABSTRACT TRUNCATED AT 400 WORDS)
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            The protective efficacy of polyvalent pneumococcal polysaccharide vaccine.

            Although the protective efficacy of pneumococcal polysaccharide vaccine has been demonstrated in randomized trials in young African gold miners, there has been controversy about its efficacy in older Americans at risk for serious pneumococcal infections. To assess the vaccine's protective efficacy against invasive pneumococcal infections, we conducted a hospital-based case-control study of the efficacy of pneumococcal vaccine in adults with a condition recognized to be an indication for receiving the vaccine. From 1984 to 1990, adults in whom Streptococcus pneumoniae was isolated from any normally sterile site were identified by prospective surveillance in the microbiology laboratories of 11 large hospitals; those with an indication for pneumococcal vaccine were enrolled as case patients. For each case patient, one control was matched according to age, underlying illness, and site of hospitalization. We contacted all providers of medical care to ascertain each subject's history of immunization with pneumococcal vaccine. Isolates of S. pneumoniae were serotyped by an investigator unaware of the subject's vaccination history. Thirteen percent of the 1,054 case patients and 20 percent of the 1,054 matched controls had received pneumococcal vaccine (P less than 0.001). When vaccine was given in either its 14-valent or its 23-valent form, its aggregate protective efficacy (calculated as a percentage: 1 minus the odds ratio of having been vaccinated times 100) against infections caused by the serotypes represented in the vaccine was 56 percent (95 percent confidence interval, 42 percent to 67 percent; P less than 0.00001) for all 983 patients infected with a serotype represented in the vaccine, 61 percent for a subgroup of 808 immunocompetent patients (95 percent confidence interval, 47 percent to 72 percent; P less than 0.00001), and 21 percent for a subgroup of 175 immunocompromised patients (95 percent confidence interval, -55 percent to 60 percent; P = 0.48). The vaccine was not efficacious against infections caused by serotypes not represented in the vaccine (protective efficacy, -73 percent; 95 percent confidence interval, -263 percent to 18 percent; P = 0.15). Polyvalent pneumococcal vaccine is efficacious in preventing invasive pneumococcal infections in immunocompetent patients with indications for its administration. This vaccine should be used more widely.
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              Identification of a B-1 B cell-specified progenitor.

              The B-1 subpopulation of B lymphocytes differs phenotypically and functionally from conventional B-2 B cells. B-1 B cells are proposed to derive from a distinct progenitor, but such a population has not been isolated. Here we identify and characterize a B-1 B cell progenitor whose numbers peaked in fetal bone marrow but were less abundant in postnatal bone marrow. These Lin(-)CD45R(lo-neg)CD19(+) cells responded to thymic stromal lymphopoietin and 'preferentially' reconstituted functional sIgM(hi)CD11b(+)CD5(lo-neg) B-1 B cells, but not sIgM(+)CD11b(-) B-2 B cells, in vivo. These data indicate that the CD45R(lo-neg)CD19(+) population includes B-1 B cell-specified progenitors and support models proposing distinct developmental pathways for B-1 B cells.
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                Author and article information

                Journal
                J Infect Dis
                J. Infect. Dis
                jinfdis
                jinfdis
                The Journal of Infectious Diseases
                Oxford University Press
                0022-1899
                1537-6613
                01 May 2012
                28 March 2012
                28 March 2012
                : 205
                : 9
                : 1408-1416
                Affiliations
                [1 ]Oxford Vaccine Group, Department of Paediatrics, University of Oxford
                [2 ]The Centre for Statistics in Medicine, Oxford
                [3 ]Nuffield Department of Clinical Medicine
                [4 ]The Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine
                [5 ]Department of Primary Health Care, University of Oxford, United Kingdom
                Author notes
                Correspondence: Rajeka Lazarus, MB BCh, Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, OX3 7LR, UK ( rajeka@ 123456doctors.org.uk ).
                [a]

                E. A. C. and R. L. contributed equally to this work.

                [b]

                Present affiliations: Department of Immunology, Oxford Radcliffe NHS Trust

                [c]

                State of Jersey Public Health Department.

                Article
                10.1093/infdis/jis212
                3324398
                22457293
                be9ec491-ffc0-40ef-be51-bdf976120954
                © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 August 2011
                : 16 November 2011
                Page count
                Pages: 9
                Categories
                Major Articles and Brief Reports
                Bacteria

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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