Clinical Studies of Pneumococcal Vaccines in Infants. I. Reactogenicity and Immunogenicity of Two Polyvalent Polysaccharide Vaccines

Sell, Sarah H.; Wright, Peter F.; Vaughn, William K.; Thompson, Juliette; Schiffman, Gerald

doi:10.1093/clinids/3.supplement_1.s97

Cited by 78 publications

(32 citation statements)

References 7 publications

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“…The immune system does not respond uniformly to all serotypes of pneumococcus. Serotype 6, for example, does not elicit a good response even when the children are vaccinated against this serotype [4,5,7,14]. However, in the present study children who had high levels of IgG anti-PPS antibody for a particular serotype tended to show a relatively high response to other serotypes and high IgA for that serotype.…”

Section: Discussioncontrasting

confidence: 76%

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Levels of anti-pneumococcal antibodies in young children in Papua New Guinea

et al. 1993

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SUMMARYAnti-pneumococcal polysaccharide antibody (anti-PPS) levels were measured in 153 serum samples collected from children aged between 2 and 47 months living in the highlands of Papua New Guinea (PNG). Fifty-seven of the samples were collected during acute episodes of lower respiratory tract infection (ALRI). Total IgA and IgG increased steadily with age; however, no association was found between the levels of these antibodies and the health status of the child. Total IgM levels showed little relationship to the age of the child but under 12 months of age levels were somewhat higher on average in children with pneumonia. For most of eight pneumococcal serotypes tested, specific IgG levels were found to decline rapidly in the first 6-8 months, reaching a minimum at approximately 12 months of age. Serotype 3 was exceptional in having very low titres in the youngest children. A separate analysis of 24 cord sera suggested that antibodies to this serotype do not usually cross the placenta in PNG. Children with pneumonia tended to have lower levels of specific IgG than healthy controls of the same age.

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Section: Discussioncontrasting

confidence: 76%

“…S. POMAT AND OTHERS does not stimulate an antibody response in young children as efficiently as it does in adults [4,5]. However, antibody responses to pneumococcal polysaccharides, both natural and vaccine-related, in children living in the highlands of Papua New Guinea are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Levels of anti-pneumococcal antibodies in young children in Papua New Guinea

et al. 1993

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“…This vaccine is licensed and recommended for adults >65 y and younger subjects with conditions, such as asplenia, that predispose to pneumococcal infection. Because of the extreme age dependence of the human antipolysaccharide response, however, CP vaccine is ineffective in infants (16)(17)(18). Another seminal finding of the Rockefeller group, shown with pneumococcus, was that coupling of CPs or even their immunodeterminant sugars to carrier proteins increases the CP-reactive antibody response (19,20).…”

Section: History Of Vaccinationmentioning

confidence: 99%

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Malley

Anderson

2012

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

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For prevention of Streptococcus pneumoniae (pneumococcus) infections in infancy, protein-conjugated capsular polysaccharide vaccines provide serotype-specific, antibody-mediated immunity but do not cover all of the 90+ capsule serotypes. Therefore, microbiologists have sought protective noncapsular antigens common to all strains. Alternatively, we investigated killed cells of a noncapsulated strain, which expose many such common antigens. Given to mice intranasally, this vaccine elicits antibody-independent, CD4+ T lymphocyte-dependent accelerated clearance of pneumococci of various serotypes from the nasopharynx mediated by the cytokine IL-17A. Such immunity may reproduce the natural resistance that develops in infants before capsular antibodies arise. Given by injection, the killed cell vaccine induces bifunctional immunity: plasma antibodies protective against fatal pneumonia challenge, as well as IL-17A–mediated nasopharyngeal clearance. Human testing of this inexpensive candidate vaccine by intramuscular injection is planned. Bacterial cellular vaccines are complex—a challenge for reproducibility. However, when several known protective antigens were deleted, the killed pneumococcal vaccine was still protective. This antigenic redundancy may prevent vaccine escape variants by recombinational loss, which is frequent in pneumococcus. Biochemically defined immunogens with bifunctional activity have also been devised. These immunogens are three-component conjugates in which cell wall teichoic acid (a common antigen capable of T cell activation) is coupled to a genetic fusion of two common pneumococcal proteins: a protective surface antigen and a derivative of pneumolysin, which provides TLR4 agonist activity and induces antitoxic immunity. Such constructs induce accelerated clearance when given intranasally and induce both immune mechanisms when injected. The defined composition permits analysis of structure-function activity.

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“…Although the licensed 14-and 23-valent pneumococcal capsular polysaccharide (PnPS) vaccines are safe and effective in reducing the incidence of invasive disease in healthy adults (5, 24), they are weakly immunogenic in children less than 2 years old and in the elderly, the two groups at highest risk (8,22,25,31). Whereas PSs are T-cellindependent immunogens, conjugates in which the PS is covalently attached to a protein carrier elicit a T-cell-dependent antisaccharide response even in infants, as evidenced by a booster effect upon subsequent immunizations.…”

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confidence: 99%

Immunogenicity in a Mouse Model of a Conjugate Vaccine Made with a Synthetic Single Repeating Unit of Type 14 Pneumococcal Polysaccharide Coupled to CRM197

Mawas¹,

Niggemann

Jones

et al. 2002

Infect Immun

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Oligosaccharides (OSs) related to the pneumococcal type 14 capsular polysaccharide (Pn14PS) were studied for their ability to inhibit the binding between anti-PS14 antisera and native PS14. A synthetic tetrasaccharide corresponding to the repeating unit of the Pn14PS, a hexasaccharide mimic, and an octasaccharide fragment obtained by Pn14PS depolymerization were good inhibitors. CRM197 conjugates of the tetrasaccharide and an octasaccharide mimic were prepared by using either adipic acid diester or diethyl squarate linkers. The conjugate with the tetrasaccharide chains induced anti-Pn14PS antibodies when injected subcutaneously into mice, as determined by an enzyme-linked immunosorbent assay, and antibody titers increased with oligosaccharide loading. The adipic acid-linked tetrasaccharide conjugates elicited higher antibody titers than those prepared with a squarate spacer. The lower anti-Pn14PS antibody response of the octasaccharide mimic conjugate indicates the importance of the backbone galactose residue for an appropriate antibody response. The OS-CRM197 conjugate prepared from a single repeat unit of the Pn14PS is a potential vaccine candidate.Streptococcus pneumoniae is a major cause of morbidity and mortality in children and adults in both industrialized and developing countries (10). Although the licensed 14-and 23-valent pneumococcal capsular polysaccharide (PnPS) vaccines are safe and effective in reducing the incidence of invasive disease in healthy adults (5, 24), they are weakly immunogenic in children less than 2 years old and in the elderly, the two groups at highest risk (8,22,25,31). Whereas PSs are T-cellindependent immunogens, conjugates in which the PS is covalently attached to a protein carrier elicit a T-cell-dependent antisaccharide response even in infants, as evidenced by a booster effect upon subsequent immunizations. A number of PnPS serotypes have been conjugated to various carrier proteins and have been shown to be immunogenic and protective in various animal models (13,20,30) and in humans (1, 32). Intact PS, small oligosaccharides (OSs), or OSs of undefined length have been used to prepare those conjugates (3, 13, 36). The capsular polysaccharide of S. pneumoniae type 14 (Fig. 1) consists of a branched tetrasaccharide repeating unit (21) which is identical to the asialo core antigen of the type III group B Streptococcus PS (38). The poor immunogenicity of the Pn14PS compared to other PnPSs (18) may be due to structural similarities between antigenic determinants of the Pn14PS and human OS structures (e.g., human milk OSs and blood group carbohydrate structures). To avoid cross-reactivity with human tissue and the induction of autoreactive antibodies (6), we have been investigating the synthesis of well-defined OS fragments (26,27) corresponding to the Pn14PS to enable specific protective epitopes to be defined. Inhibition studies were performed both with synthetic OS structures and fragments from PS degradation to determine optimal OSs for conjugation. The protein carrier used in...

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Clinical Studies of Pneumococcal Vaccines in Infants. I. Reactogenicity and Immunogenicity of Two Polyvalent Polysaccharide Vaccines

Cited by 78 publications

References 7 publications

Levels of anti-pneumococcal antibodies in young children in Papua New Guinea

Levels of anti-pneumococcal antibodies in young children in Papua New Guinea

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Immunogenicity in a Mouse Model of a Conjugate Vaccine Made with a Synthetic Single Repeating Unit of Type 14 Pneumococcal Polysaccharide Coupled to CRM197

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