Thymus-Independent and Thymus-Dependent Responses to Polysaccharide Antigens

Stein, Kathryn E.

doi:10.1093/infdis/165-supplement_1-s49

Cited by 335 publications

(225 citation statements)

References 33 publications

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“…Polysaccharides and organic polymers, such as PGA, are classic T-independent antigens (3,10). These antigens typically elicit low-affinity IgM-dominated humoral immune responses and no memory.…”

Section: Discussionmentioning

confidence: 99%

Conjugate-like immunogens produced as protein capsular matrix vaccines

Thanawastien¹,

Cartee²,

Griffin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Capsular polysaccharides are the primary antigenic components involved in protective immunity against encapsulated bacterial pathogens. Although immunization of adolescents and adults with polysaccharide antigens has reduced pathogen disease burden, pure polysaccharide vaccines have proved ineffective at conferring protective immunity to infants and the elderly, age cohorts that are deficient in their adaptive immune responses to such antigens. However, T-cell–independent polysaccharide antigens can be converted into more potent immunogens by chemically coupling to a “carrier protein” antigen. Such “conjugate vaccines” efficiently induce antibody avidity maturation, isotype switching, and immunological memory in immunized neonates. These immune responses have been attributed to T-cell recognition of peptides derived from the coupled carrier protein. The covalent attachment of polysaccharide antigens to the carrier protein is thought to be imperative to the immunological properties of conjugate vaccines. Here we provide evidence that covalent attachment to carrier proteins is not required for conversion of T-independent antigens into T-dependent immunogens. Simple entrapment of polysaccharides or a d-amino acid polymer antigen in a cross-linked protein matrix was shown to be sufficient to produce potent immunogens that possess the key characteristics of conventional conjugate vaccines. The versatility and ease of manufacture of these antigen preparations, termed protein capsular matrix vaccines (PCMVs), will likely provide improvements in the manufacture of vaccines designed to protect against encapsulated microorganisms. This in turn could improve the availability of such vaccines to the developing world, which has shown only a limited capacity to afford the cost of conventional conjugate vaccines.

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Section: Discussionmentioning

confidence: 99%

Conjugate-like immunogens produced as protein capsular matrix vaccines

Thanawastien¹,

Cartee²,

Griffin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Maturation of carbohydrate immunity develops slowly during ontogeny [33] and might partly be determined by a course of subclinical immunisation events with exposure to low doses of antigen. In this way, it is quite conceivable that complement deficiency might delay establishment of immunity.…”

Section: C2 Deficiency and Igm/igg Switching 557mentioning

confidence: 99%

Low Concentrations of Immunoglobulin G Antibodies to Salmonella Serogroup C in C2 Deficiency: Suggestion of a Mannan‐Binding Lectin Pathway‐Dependent Mechanism

et al. 1999

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The influence of complement on immune responses to polysaccharides is debatable. We examined the serum concentrations of IgM and IgG antibody against Salmonella O-antigen specific oligosaccharides representing the serogroups B, C and D, and against capsular polysaccharides of Streptococcus pneumoniae serotypes 6 and 23 in C2-deficient adults and in healthy controls. A sharp contrast of findings was found for antibodies against the CO antigen, an activator of the mannan-binding lectin (MBL) pathway of complement activation. The C2-deficient group showed normal IgM and markedly low IgG antibody levels. Similar findings were made in adults with low concentrations of MBL. This suggests that the recruitment of classical pathway C3 convertase through the MBL pathway is critically involved in isotype switching of antibodies against MBL pathway activating antigens during immune system maturation. The findings imply a new role of the MBL pathway, and an additional link between innate and acquired immunity. Specific IgM against BO was moderately low in C2 deficiency. Other differences for the Salmonella antigens were not found. Markedly raised IgM antibody levels against pneumococcal polysaccharides in C2 deficiency probably Salmonella reflected past infections. The absence of a concomitant increase of specific IgG might possibly be explained by impaired IgM to IgG switching.

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“…Conjugation of pneumococcal polysaccharide (PPS) to a carrier protein increases its immunogenicity by converting it from a T-cell independent antigen of type II (TI-2) to a T-cell dependent (TD) antigen. TD antigens have the advantage over TI antigens that immune response can be induced at or shortly after birth and they induce affinity maturation of antibodies and immunological memory (reviewed in [1]) all of which are important to generate strong and long-lasting immunity at an early age. Seven serotypes of PPS conjugated to CRM197, a non-toxic variant of diphtheria toxin [2] was licensed in the year 2000 (Prevnar) and is highly efficacious against invasive pneumococcal disease and pneumonia [3][4][5] and reduces otitis media [6,7], although it needs to be administrated several times before it yields protective antibody (Ab) levels in infants and young children.…”

Section: Introductionmentioning

confidence: 99%

IC31^®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice

et al. 2009

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IC31® is a novel adjuvant which combines the immunostimulatory effects of an 11‐mer antibacterial peptide (KLKL5KLK) and a synthetic oligodeoxynucleotide (ODN1a) which is a Toll‐like receptor 9 agonist without containing cytosine phosphate guanine (CpG) motifs. The effects of IC31® on neonatal immune response to vaccination have not been reported. Neonatal mice were immunized once or twice with a Streptococcus pneumoniae serotype 1 polysaccharide conjugate containing Tetanus Toxoid (Pnc1‐TT) carrier protein, with or without IC31® or CpG‐ODN. IC31® significantly enhanced IgG1, IgG2a and IgG2b antibodies (Ab) to the serotype 1 polysaccharide. One dose of Pnc1‐TT and low dose IC31® elicited high Ab levels that protected the neonatal mice completely from bacteraemia and significantly reduced lung infection following i.n. challenge with serotype 1 pneumococcal strain. One‐sixth of an adult murine dose of IC31® was sufficient and optimal for induction of protective immunity in neonatal mice. Two doses of Pnc1‐TT with or without adjuvants protected the neonatal mice completely, but more rapid Ab response was observed when IC31® was given with the Pnc1‐TT. IC31® is a promising new adjuvant for neonatal vaccinations, rapidly enhancing protective humoral responses when combined with Pnc1‐TT.

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Thymus-Independent and Thymus-Dependent Responses to Polysaccharide Antigens

Cited by 335 publications

References 33 publications

Conjugate-like immunogens produced as protein capsular matrix vaccines

Conjugate-like immunogens produced as protein capsular matrix vaccines

Low Concentrations of Immunoglobulin G Antibodies to Salmonella Serogroup C in C2 Deficiency: Suggestion of a Mannan‐Binding Lectin Pathway‐Dependent Mechanism

IC31^®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice

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Thymus-Independent and Thymus-Dependent Responses to Polysaccharide Antigens

Cited by 335 publications

References 33 publications

Conjugate-like immunogens produced as protein capsular matrix vaccines

Conjugate-like immunogens produced as protein capsular matrix vaccines

Low Concentrations of Immunoglobulin G Antibodies to Salmonella Serogroup C in C2 Deficiency: Suggestion of a Mannan‐Binding Lectin Pathway‐Dependent Mechanism

IC31®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice

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Product

Resources

About

IC31^®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice