CpG Oligodeoxynucleotides Act as Adjuvants for Pneumococcal Polysaccharide-Protein Conjugate Vaccines and Enhance Antipolysaccharide Immunoglobulin G2a (IgG2a) and IgG3 Antibodies

Chu, Rose S.; McCool, Tera L.; Greenspan, Neil S.; Schreiber, John R.; Harding, Clifford V.

doi:10.1128/iai.68.3.1450-1456.2000

Cited by 78 publications

(42 citation statements)

References 32 publications

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“…Indeed, CpG ODN has been shown to enhance Ab responses against S. pneumoniae polysaccharide types 19F and 6B (33). Our previous study showed that mice given nasal recombinant protective Ag of anthrax toxin plus CpG ODN exhibited high levels of protective Ag- Mice were nasally immunized weekly for four consecutive weeks with 1 mg PspA, 50 mg pFL, and 10 mg CpG ODN and for 3 consecutive wk with 5 mg PspA, 50 mg pFL, and 10 mg CpG ODN in young adult and aged mice, respectively.…”

Section: Discussionmentioning

confidence: 99%

A Combination of Flt3 Ligand cDNA and CpG Oligodeoxynucleotide as Nasal Adjuvant Elicits Protective Secretory-IgA Immunity to Streptococcus pneumoniae in Aged Mice

Fukuyama

King

Kataoka

et al. 2011

The Journal of Immunology

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Our previous study showed that a combination of a plasmid-expressing Flt3 ligand (pFL) and CpG oligodeoxynucleotides (CpG ODN) as a combined nasal adjuvant elicited mucosal immune responses in aged (2-y-old) mice. In this study, we investigated whether a combination of pFL and CpG ODN as a nasal adjuvant for a pneumococcal surface protein A (PspA) would enhance PspA-specific secretory-IgA Ab responses, which could provide protective mucosal immunity against Streptococcus pneumoniae infection in aged mice. Nasal immunization with PspA plus a combination of pFL and CpG ODN elicited elevated levels of PspA-specific secretory-IgA Ab responses in external secretions and plasma in both young adult and aged mice. Significant levels of PspA-specific CD4+ T cell proliferative and PspA-induced Th1- and Th2- type cytokine responses were noted in nasopharyngeal-associated lymphoreticular tissue, cervical lymph nodes, and spleen of aged mice, which were equivalent to those in young adult mice. Additionally, increased numbers of mature-type CD8, CD11b-expressing dendritic cells were detected in mucosal inductive and effector lymphoid tissues of aged mice. Importantly, aged mice given PspA plus a combination of pFL and CpG ODN showed protective immunity against nasal S. pneumoniae colonization. These results demonstrate that nasal delivery of a combined DNA adjuvant offers an attractive possibility for protection against S. pneumoniae in the elderly.

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Section: Discussionmentioning

confidence: 99%

A Combination of Flt3 Ligand cDNA and CpG Oligodeoxynucleotide as Nasal Adjuvant Elicits Protective Secretory-IgA Immunity to Streptococcus pneumoniae in Aged Mice

Fukuyama

King

Kataoka

et al. 2011

The Journal of Immunology

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“…17,18 We thus explored whether the use of a TLR9 agonist (CpG ODNs) expected to mimic some of the cosignals provided by whole bacteria could modulate the amplitude and duration of the Ab response to PS3. In a coadministration protocol, CpG ODNs have been reported to amplify the Ab response to PS-protein conjugates 19,20 or to NP-Ficoll but not to a plain PS vaccine. 21 To reconsider the effect of TLR agonists on TI B-cell responses, we conducted experiments in which CpG1668 was administrated subcutaneously before immunization, at the time of immunization, or after immunization with PS3.…”

Section: Cpg1668 Enhances the Ab Response To Ps3 In A T Cell-independmentioning

confidence: 99%

The thymus-independent immunity conferred by a pneumococcal polysaccharide is mediated by long-lived plasma cells

Taillardet

Haffar

Mondière

et al. 2009

Blood

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It was recently shown that bacterial thymus-independent (TI) antigens confer long-lasting immunity and generate memory B lymphocytes. However, reactivation of TI memory B cells is repressed in immunocompetent mice, thus raising the issue of the mechanism whereby TI vaccines confer immune protection. Here, we propose an explanation to this apparent paradox by showing that a Streptococcus pneumoniae capsular polysaccharide (PS) generates long-lived bone marrow (BM) plasma cells which frequency can be increased by CpG oligodeoxynucleotides (ODNs). The adjuvant effect of CpG ODNs on the PS3 Ab response is directly targeted to B cells and does not involve B-1a cells. We also demonstrated that BM plasma cells generated in response to the thymus-dependent (TD) form of the PS vaccine have a higher secretion capacity than those produced after immunization with the CpGadjuvanted PS vaccine. Finally, we show that the PS-specific BM plasma cell compartment is sufficient to confer full protection of vaccinated mice against S pneumoniae infection. Altogether, our results show that TI antigens like their TD counterparts can generate both the lymphoid and the plasma cell component of B-cell memory. They also provide a framework for the improvement and widespread usage of TI vaccines. IntroductionDespite advances in antimicrobial therapy, infections with extracellular polysaccharide (PS)-encapsulated bacteria remain an important clinical problem and a primary source of death worldwide. Pathogenic bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae express capsular PSs that behave as prototypic thymus-independent (TI) antigens (Ags). These Ags have initially been defined on the basis of their ability to elicit an antibody (Ab) response in T cell-deficient or athymic mice by a mechanism that requires expression of a functional Bruton tyrosine kinase. 1 They are mostly nonpeptidic molecules, which in their great majority, are unable to follow the conventional Agprocessing pathway leading to presentation by MHC class I and II molecules. 2 To overcome systemic infections by encapsulated extracellular bacteria such as S pneumoniae, B cells rapidly generate a protective Ab response against capsular PS. B-1 and marginal zone B cells have been envisioned as key players in the humoral response against TI Ags. 3 More recently, 2 studies, using Borrelia hermsii or capsular PSs from S pneumoniae as immunogens, have shown that B-1b cells are critically involved in bacterial clearance in vaccinated mice. 4,5 It has long been thought that the generation of memory B cells is restricted to thymus-dependent (TD) responses. However, the recent observation that adoptive transfer of B-1b cells from donor mice immunized with whole bacteria can confer long-lasting TI immunity to immunodeficient mice shows that TI Ags generate B-cell memory and that this function can be assigned to the B-1b-cell subset. 5 Nonetheless, the concept of TI B-cell memory is at odds with the fact that, unlike TD Ags, TI Ags fail to...

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“…We thus wished to determine whether the IgG anti-PspA and IgG anti-PPS14 responses to conjugate, in the absence or presence of adjuvant, were also dependent on IL-1R1 Ϫ/Ϫ signaling. Coinjection of conjugate with a TLR ligand can markedly enhance the subsequent humoral immune response (45,50,51), which could, in theory, influence its relative dependence on costimulation with endogenous IL-1.…”

Section: Cd4 ϩ T Cells From Pn14-immunized Il-1r1mentioning

confidence: 99%

Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to IntactStreptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine

Chen

Sen

Snapper

2006

The Journal of Immunology

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MyD88−/− mice exhibit defective innate, diminished CD4+ T cell-dependent (TD) type 1, but enhanced type 2, humoral immunity in response to intact Streptococcus pneumoniae (Pn). Because type 1 IL-1R (IL-1R1) signaling is MyD88 dependent, a role for endogenous IL-1 was determined. IL-1R1−/−, in contrast to MyD88−/−, mice exhibited relatively intact innate splenic cytokine expression in response to Pn. Nevertheless, IL-1R1−/−, like MyD88−/−, mice were more sensitive to killing with live Pn relative to wild-type controls. Although IL-1R1−/− mice elicited a normal T cell-independent IgM antipolysaccharide (PS) response to heat-killed Pn, the induction of PS- and protein-specific cognate, but not noncognate, TD type 1 and type 2 IgG isotypes were markedly reduced. Additionally, CD4+ T cells from Pn-primed IL-1R1−/− mice failed to elicit IFN-γ, IL-5, or IL-13 secretion upon restimulation with Pn in vitro, whereas MyD88−/− mice secreted normal levels of IFN-γ and enhanced levels of IL-5 and IL-13. In contrast, IgG responses to a soluble, pneumococcal protein-PS conjugate, with or without adjuvant, showed little dependence on IL-1R1 and normal CD4+ T cell priming. These data are the first to demonstrate a nonredundant role for endogenous IL-1 in TD induction of humoral immune responses to an intact pathogen, although not a pathogen-derived soluble conjugate, suggesting that antigenic context is a key determinant for IL-1 dependence. These data further suggest that IL-1 may be critical for preserving CD4+ Th2 function in the presence, but not absence, of MyD88-dependent signaling via TLRs.

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CpG Oligodeoxynucleotides Act as Adjuvants for Pneumococcal Polysaccharide-Protein Conjugate Vaccines and Enhance Antipolysaccharide Immunoglobulin G2a (IgG2a) and IgG3 Antibodies

Cited by 78 publications

References 32 publications

A Combination of Flt3 Ligand cDNA and CpG Oligodeoxynucleotide as Nasal Adjuvant Elicits Protective Secretory-IgA Immunity to Streptococcus pneumoniae in Aged Mice

A Combination of Flt3 Ligand cDNA and CpG Oligodeoxynucleotide as Nasal Adjuvant Elicits Protective Secretory-IgA Immunity to Streptococcus pneumoniae in Aged Mice

The thymus-independent immunity conferred by a pneumococcal polysaccharide is mediated by long-lived plasma cells

Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to IntactStreptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine

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