Safety and immunogenicity of an investigational vaccine containing two common pneumococcal proteins in toddlers: A phase II randomized clinical trial

Prymula, Roman; Pazdiora, P; Traskine, Magali; Rüggeberg, Jens U.; Borys, Dorota

doi:10.1016/j.vaccine.2014.03.066

Cited by 56 publications

(37 citation statements)

References 29 publications

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“…As a vaccine, we used S. pneumoniae histidine triad protein D (PhtD), a highly conserved, surface-exposed adhesin protein that facilitates attachment to the NP and lung epithelium cells (10)(11)(12). PhtD as a vaccine component has been shown to be protective in a number of mouse S. pneumoniae infection models (11,13,14) and is included in vaccines currently in human trials (15)(16)(17). In our current mouse study, the outcome of PhtD vaccinemediated prevention of invasive S. pneumoniae pathogenesis proved comparable to that achieved with PCV13 vaccination.…”

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confidence: 99%

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

Khan

Pichichero

2017

Infect Immun

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An increase in Streptococcus pneumoniae nasopharynx (NP) colonization density during a viral coinfection initiates pathogenesis. To mimic natural S. pneumoniae pathogenesis, we commensally colonized the NPs of adult C57BL/6 mice with S. pneumoniae serotype (ST) 6A or 8 and then coinfected them with mouseadapted H1N1 influenza A virus (PR/8/34). S. pneumoniae established effective commensal colonization, and influenza virus coinfection caused S. pneumoniae NP density to increase, resulting in bacteremia and mortality. We then studied histidine triad protein D (PhtD), an S. pneumoniae adhesin vaccine candidate, for its ability to prevent invasive S. pneumoniae disease in adult and infant mice. In adult mice, the efficacy of PhtD vaccination was compared with that of PCV13. Vaccination with PCV13 led to a greater reduction of S. pneumoniae NP density (Ͼ2.5 log units) than PhtD vaccination (ϳ1-log-unit reduction). However, no significant difference was observed with regard to the prevention of S. pneumoniae bacteremia, and there was no difference in mortality. Depletion of CD4 ϩ T cells in PhtD-vaccinated adult mice, but not PCV13-vaccinated mice, caused a loss of vaccine-induced protection. In infant mice, passive transfer of antisera or CD4 ϩ T cells from PhtD-vaccinated adult mice led to a nonsignificant reduction in NP colonization density, whereas passive transfer of antisera and CD4 ϩ T cells was needed to cause a significant reduction in NP colonization density. For the first time, these data show an outcome with regard to prevention of invasive S. pneumoniae pathogenesis with a protein vaccine similar to that which occurs with a glycoconjugate vaccine despite a less robust reduction in NP bacterial density.

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confidence: 99%

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

Khan

Pichichero

2017

Infect Immun

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“…Ply, a cholesteroldependent cytolysin, is an important factor in pneumococcal pathogenicity, interfering in the cellular immune response and in the activation of the complement system during pneumococcal infection (11,12). PspA and pneumolysoids have been studied in preclinical and clinical trials, showing an ability to induce a protective antibodydependent response (13)(14)(15)(16)(17).…”

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confidence: 99%

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

Goulart

Rodríguez

Kanno

et al. 2017

Clin Vaccine Immunol

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Pneumococcal diseases remain a substantial cause of mortality in young children in developing countries. The development of potentially serotypetranscending vaccines has been extensively studied; ideally, such a vaccine should include antigens that are able to induce protection against colonization (likely mediated by interleukin-17A [IL-17A]) and invasive disease (likely mediated by antibody). The use of strong adjuvants or alternative delivery systems that are able to improve the immunological response of recombinant proteins has been proposed but poses potential safety and practical concerns in children. We have previously constructed a recombinant Mycobacterium bovis BCG strain expressing a pneumococcal surface protein A (PspA)-PdT fusion protein (rBCG PspA-PdT) that was able to induce an effective immune response and protection against sepsis in a prime-boost strategy. Here, we constructed two new rBCG strains expressing the pneumococcal proteins SP 0148 and SP 2108, which confer IL-17A-dependent protection against pneumococcal colonization in mouse models. Immunization of mice with rBCG 0148 or rBCG 2108 in a prime-boost strategy induced IL-17A and gamma interferon (IFN-␥) production. The combination of these rBCG strains with rBCG PspA-PdT (rBCG Mix), followed by a booster dose of the combined recombinant proteins (rMix) induced an IL-17A response against SP 0148 and SP 2108 and a humoral response characterized by increased levels of IgG2c against PspA and functional antibodies against pneumolysin. Furthermore, immunization with the rBCG Mix prime/rMix booster (rBCG Mix/ rMix) provides protection against pneumococcal colonization and sepsis. These results suggest the use of combined rBCG strains as a potentially serotype-transcending pneumococcal vaccine in a prime-boost strategy, which could provide protection against pneumococcal colonization and sepsis.KEYWORDS protection, Streptococcus pneumoniae, cytokines, recombinant BCG N asopharynx colonization is the first step in the establishment of pneumococcal disease. This colonization process, which affects virtually 100% of young children, can either remain asymptomatic or lead to pathogenic conditions, such as otitis, sinusitis, pneumonia, meningitis, or sepsis (1). Indeed, epidemiologic evidence suggests that in response to pneumococcal carriage, both serotype-specific and -independent immunity to subsequent carriage develop (2, 3).Pneumococcal vaccines available are based on pure polysaccharides or polysaccha-

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“…S. pneumoniae encodes four related Pht proteins, PhtA, PhtB, PhtD, and PhtE, which are thought to be predominantly anchored in the pneumococcal cell wall (7,8). The exposure of the Pht proteins on the cell surface has led to significant investigation into their potential use in next-generation pneumococcal vaccines, with clinical trials up to phase II having been completed (9)(10)(11)(12)(13). Despite this, their contribution to Zn 2ϩ acquisition has only recently been revealed.…”

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The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

et al. 2016

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Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain five histidine (His) triad motifs that are believed to facilitate zinc binding and therefore play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs have not been addressed. We examined the effects of mutating each of the five His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake, and PhtD expression studies show that the His triad closest to the protein's amino terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino-and carboxyl-terminal His triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlight the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence.

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Safety and immunogenicity of an investigational vaccine containing two common pneumococcal proteins in toddlers: A phase II randomized clinical trial

Abstract: All investigational vaccine formulations were well-tolerated and immunogenic when administered to toddlers as a 2-dose primary vaccination followed by a booster dose.

Cited by 56 publications

References 29 publications

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

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