Pneumococcal serotype 3 otitis media, limited effect of polysaccharide conjugate immunisation and strain characteristics

Poolman, Jan; Kriz, Pavla; Feron, Christiane; Di-Paolo, Emmanuel; Henckaerts, Isabelle; Miseur, A.; Wauters, Dominique; Prymula, Roman; Schuerman, Lode

doi:10.1016/j.vaccine.2009.03.017

Cited by 65 publications

(38 citation statements)

References 48 publications

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“…In study G, the immunogenicity, safety, and efficacy of the 11-valent prototype vaccine 11Pn-PD were analyzed in comparison to a control group receiving a hepatitis A vaccine. Detailed results with regard to the immunogenicity and safety of 11Pn-PD (33,35,36,43), PHiD-CV (2,6,46,51), and the coadministered vaccines (24) have been reported previously. All studies were conducted with healthy children between the ages of 6 and 16 weeks at the time of the first vaccine dose and between the ages of 11 and 18 months at the time of the booster dose.…”

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confidence: 91%

Impact of the Conjugation Method on the Immunogenicity of Streptococcus pneumoniae Serotype 19F Polysaccharide in Conjugate Vaccines

Poolman

Frasch

Nurkka

et al. 2011

Clin Vaccine Immunol

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We found that conjugation of the serotype 19F polysaccharide using reductive amination (as in 7vCRM) resulted in the formation of at least one additional epitope that is not present in the native form of the 19F polysaccharide or following 19F conjugation using a bifunctional spacer (as in the prototype vaccine 7vOMPC) or cyanylation (as in PHiD-CV). We also found that pneumococcal vaccines conjugated using cyanylation induce more opsonophagocytic antibodies against serotype 19F and a considerably higher level of cross-opsonophagocytic antibodies against serotype 19A than vaccines conjugated using reductive amination. In conclusion, these results suggest that the conjugation method can influence the functionality of the antibodies induced against the homologous serotype 19F and the cross-reactive serotype 19A of S. pneumoniae. 7vCRM (Prevenar/Prevnar; Pfizer, Inc.) contains capsular polysaccharides of Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, each conjugated to the nontoxic cross-reacting mutant diphtheria toxin CRM 197 . Serotype 19A was not included in 7vCRM, because it was expected that the immunological similarities with vaccine serotype 19F would elicit sufficient cross-protection, as observed for serotype 6B and the related serotype 6A (26,38,48,52). Serotypes 19F and 19A are indeed closely related biochemically (38, 52). Serotype 19A and 19F polysaccharides are composed of similar trisaccharide units polymerized through phosphate diester groups and differ only in the position of the linkage to the ␣-L-rhamnose residue: ␣(132) for 19F and ␣(133) for 19A (19,29

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confidence: 91%

Impact of the Conjugation Method on the Immunogenicity of Streptococcus pneumoniae Serotype 19F Polysaccharide in Conjugate Vaccines

Poolman

Frasch

Nurkka

et al. 2011

Clin Vaccine Immunol

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“…Understanding the mechanism(s) by which antibodies to PPS3 mediate protection is important. ST3 pneumonia is associated with a higher risk of death than other STs (29,55), severe ST3 disease attributed to serotype replacement has been reported in children (4,11), and to date, although data from the newly introduced 13-valent pneumococcal capsular polysaccharide-protein conjugate vaccine are not yet available, investigational ST3 conjugate vaccines failed to prevent ST3 mucosal disease (36).…”

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confidence: 99%

A Serotype 3 Pneumococcal Capsular Polysaccharide-Specific Monoclonal Antibody Requires Fcγ Receptor III and Macrophages To Mediate Protection against Pneumococcal Pneumonia in Mice

et al. 2012

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cAntibodies to pneumococcal capsular polysaccharide (PPS) are required for PPS-based vaccine-mediated protection against Streptococcus pneumoniae. Previous work established that 1E2, a mouse IgG1 to PPS3 that does not induce serotype 3 (ST3) S. pneumoniae killing by phagocytes in vitro, protects mice from death after intranasal infection with ST3, but its efficacy was abrogated in Fc␥R (F common gamma receptor)-deficient mice. In this study, we determined whether 1E2 efficacy against pulmonary ST3 infection requires Fc␥RIII. 1E2 did not protect Fc␥RIII-deficient (Fc␥RIII ؊/؊ ) mice. Studies of the mechanism of 1E2-mediated effects showed that it resulted in a marked reduction in lung inflammation in ST3-infected wild-type (Wt [C57BL/6]) mice that was abrogated in Fc␥RIII ؊/؊ mice. 1E2 had no effect on early bacterial clearance in the lungs of ST3-infected Wt, Fc␥RIIB ؊/؊ , or Fc␥RIII ؊/؊ mice, but it reduced levels of bacteremia and serum macrophage inflammatory protein-2) (MIP-2), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-␣) in Wt and Fc␥RIIB ؊/؊ mice, strains in which it is protective. As previous work showed that neutrophils were dispensable for 1E2 efficacy, we investigated whether macrophages are required for 1E2 efficacy against intranasal infection with ST3 and found that its efficacy was abrogated in Wt mice depleted of macrophages intranasally. In vitro studies revealed that1E2 promoted ST3 internalization by naïve alveolar macrophages but did not induce early intracellular killing. Macrophages from 1E2-treated ST3-infected mice studied ex vivo exhibited more apoptosis than those from Fc␥RIII ؊/؊ mice. These findings suggest that 1E2 mediates protection against ST3 in mice by affecting the inflammatory response, perhaps in part via macrophage apoptosis, rather than by inducing early bacterial clearance.

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“…The efficacy of pneumococcal capsular polysaccharide (PPS)-based vaccines has been linked to their ability to elicit serotype-specific IgG that promotes phagocytosis and killing of the homologous pneumococcal ST in vitro (13,27,43,46). However, given that ST3 has emerged as a replacement ST that causes severe disease (23,25), it is concerning that an investigational conjugate vaccine containing an ST3 moiety did not protect against ST3 disease in children (37). The foregoing, together with evidence that ST3 is associated with a higher risk of severe disease and death than other serotypes (3,23,35), suggests the need for new strategies to prevent disease with ST3.…”

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Aggregation of Streptococcus pneumoniae by a Pneumococcal Capsular Polysaccharide-Specific Human Monoclonal IgM Correlates with Antibody Efficacy In Vivo

Fabrizio

Manix

Guimarães

et al. 2010

Clin Vaccine Immunol

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Acquired antibody immunity to Streptococcus pneumoniae (pneumococcus) has been linked to serotype (ST)-specific opsonic antibodies to the relevant pneumococcal capsular polysaccharide (PPS) that mediate protection by enhancing the bactericidal effect of host phagocytes. Despite the well-recognized role of opsonic IgG in host defense against pneumococcus, PPS-specific monoclonal antibodies (MAbs) that mediate protection against lethal challenge with ST3 pneumococcus in mice but do not promote phagocytic killing in vitro (nonopsonic antibodies) have been described. In this study, we sought to determine the biological activity of one such MAb, A7 (a human PPS3-specific IgM), and the mechanism by which it mediates protection. In vitro studies demonstrated that coincubation of A7 with ST3 in the absence of phagocytes or a complement source resulted in a reduction in CFU on blood agar plates that was largely reversible by sonication. A chromogenic cellular proliferation assay demonstrated that A7 did not affect replication of ST3 in liquid culture. The ability of A7 to induce aggregation of ST3 was confirmed by fluorescence microscopy and flow cytometry: A7 induced aggregation of ST3, and in the presence of a complement source, A7 promoted deposition of complement component 3 (C3) on aggregated bacteria in a dose-dependent fashion. Similarly, administration of preincubated mixtures of A7 and ST3 intraperitoneally to mice protected them from the lethality of ST3 in a dose-dependent fashion. These findings suggest that A7-mediated aggregation enhances resistance to ST3, most likely by enhancing C3 deposition on the ST3 capsule, thereby promoting host antipneumococcal activity in vivo.Despite the availability of antibiotics and two vaccines for Streptococcus pneumoniae (pneumococcus), mortality attributable to pneumococcal disease remains a significant global problem (1, 23). Concerns about ongoing pneumococcal antibiotic resistance, poor vaccine immunogenicity in immunocompromised patients, and serotype (ST) replacement stemming from use of the conjugate vaccine (23,25,29,38) underscore the critical need for a better understanding of correlates of pneumococcal immunity. The efficacy of pneumococcal capsular polysaccharide (PPS)-based vaccines has been linked to their ability to elicit serotype-specific IgG that promotes phagocytosis and killing of the homologous pneumococcal ST in vitro (13,27,43,46). However, given that ST3 has emerged as a replacement ST that causes severe disease (23,25), it is concerning that an investigational conjugate vaccine containing an ST3 moiety did not protect against ST3 disease in children (37). The foregoing, together with evidence that ST3 is associated with a higher risk of severe disease and death than other serotypes (3,23,35), suggests the need for new strategies to prevent disease with ST3.

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Pneumococcal serotype 3 otitis media, limited effect of polysaccharide conjugate immunisation and strain characteristics

Cited by 65 publications

References 48 publications

Impact of the Conjugation Method on the Immunogenicity of Streptococcus pneumoniae Serotype 19F Polysaccharide in Conjugate Vaccines

Impact of the Conjugation Method on the Immunogenicity of Streptococcus pneumoniae Serotype 19F Polysaccharide in Conjugate Vaccines

A Serotype 3 Pneumococcal Capsular Polysaccharide-Specific Monoclonal Antibody Requires Fcγ Receptor III and Macrophages To Mediate Protection against Pneumococcal Pneumonia in Mice

Aggregation of Streptococcus pneumoniae by a Pneumococcal Capsular Polysaccharide-Specific Human Monoclonal IgM Correlates with Antibody Efficacy In Vivo

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