Next generation protein based<i>Streptococcus pneumoniae</i>vaccines

Pichichero, Michael E.; Khan, M. Nadeem; Xu, Qing

doi:10.1080/21645515.2015.1052198

Cited by 60 publications

(51 citation statements)

References 135 publications

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“…In the era of PCVs and rapid evolution of new nonvaccine STs (6, 31), nextgeneration protein-based vaccines are expected to address the shortcomings of existing vaccines (9). The results of the current study provide a new understanding of differences in vaccine-induced protection following PPVs compared to following PCVs.…”

Section: Discussionmentioning

confidence: 79%

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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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Section: Discussionmentioning

confidence: 79%

“…(PPVs) that include as an ingredient surface-exposed, highly conserved proteins expressed by S. pneumoniae (9). However, if PPVs eliminated all S. pneumoniae from the NP in a manner similar to the effect of PCVs, a concern immediately arises regarding the consequences.…”

mentioning

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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“…This is thought to be caused, at least partly, by damaging inflammatory host responses induced by the pneumococcus. Therefore, anti-virulence approaches, such as those based on monoclonal antibodies (mAbs) targeting pneumococcal virulence factors are being considered to improve therapeutic efficacy [11–16]. …”

Section: Introductionmentioning

confidence: 99%

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

et al. 2018

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Streptococcus pneumoniae isolates express up to three neuraminidases (sialidases), NanA, NanB and NanC, all of which cleave the terminal sialic acid of glycan-structures that decorate host cell surfaces. Most research has focused on the role of NanA with limited investigations evaluating the roles of all three neuraminidases in host-pathogen interactions. We generated two highly potent monoclonal antibodies (mAbs), one that blocks the enzymatic activity of NanA and one cross-neutralizing NanB and NanC. Total neuraminidase activity of clinical S. pneumoniae isolates could be inhibited by this mAb combination in enzymatic assays. To detect desialylation of cell surfaces by pneumococcal neuraminidases, primary human tracheal/bronchial mucocilial epithelial tissues were infected with S. pneumoniae and stained with peanut lectin. Simultaneous targeting of the neuraminidases was required to prevent desialylation, suggesting that inhibition of NanA alone is not sufficient to preserve terminal lung glycans. Importantly, we also found that all three neuraminidases increased the interaction of S. pneumoniae with human airway epithelial cells. Lectin-staining of lung tissues of mice pre-treated with mAbs before intranasal challenge with S. pneumoniae confirmed that both anti-NanA and anti-NanBC mAbs were required to effectively block desialylation of the respiratory epithelium in vivo. Despite this, no effect on survival, reduction in pulmonary bacterial load, or significant changes in cytokine responses were observed. This suggests that neuraminidases have no pivotal role in this murine pneumonia model that is induced by high bacterial challenge inocula and does not progress from colonization as it happens in the human host.

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“…We have previously described key features of PPVs [18], the most important of which is selection of proteins shared by all or virtually all strains of the bacteria irrespective of capsular polysaccharide. Many multi-component PPVs in development that target the early stage of colonization include 1 or more surface-exposed, highly conserved proteins expressed by pneumococci that anchor the organism to NP epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…Many multi-component PPVs in development that target the early stage of colonization include 1 or more surface-exposed, highly conserved proteins expressed by pneumococci that anchor the organism to NP epithelial cells. [18] However, the density of capsular polysaccharide on the surface of pneumococci during NP colonization is very different than what occurs with proteins.…”

Section: Introductionmentioning

confidence: 99%

Pneumococcal whole-cell and protein-based vaccines: changing the paradigm

Pichichero

2017

Expert Review of Vaccines

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Introduction. Epidemiologic evaluations of Streptococcus pneumoniae nasopharyngeal (NP) colonization and pneumococcal disease suggest that newer serotypes in future formulations of pneumococcal conjugate vaccines (PCVs) are needed and there may need to be continued reformulations because there are many new emerging serotypes expressed by pneumococci. Areas Covered: Mechanisms of protection by next-generation whole-cell vaccine (WCV) and/or multi-component pneumococcal purified protein vaccines (PPVs) in development for prevention of pneumococcal infections. Expert Commentary: A long-term strategy for prevention of pneumococcal disease will likely include WCV and PPVs. However these vaccines will impact disease pathogenesis in a different manner than PCVs. Prevention of pneumococcal NP colonization should not be expected, nor is it desirable because risks for NP colonization by other replacement organisms into the ecological niche vacated by all pneumococci may have consequences. The expression biology of capsule and surface protein antigens are phase dependent. Therefore, the immune response will be different and the mechanism of protection divergent. WCVs and PPVs may be alternative strategies in low income developing countries to protect against invasive disease and reduce NP carriage load.

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Next generation protein basedStreptococcus pneumoniaevaccines

Cited by 60 publications

References 135 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

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

Pneumococcal whole-cell and protein-based vaccines: changing the paradigm

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