Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults

Seiberling, Michael; Bologa, Monica; Brookes, Roger H.; Ochs, Martina M.; Go, Kerry W.; Neveu, David; Kamtchoua, Thierry; Lashley, Peter; Yuan, Tao; Gurunathan, Sanjay

doi:10.1016/j.vaccine.2012.10.080

Cited by 59 publications

(51 citation statements)

References 22 publications

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“…Godfroid et al also showed a role for anti-PhtD human antibody in protection against lethal intranasal challenge in a mouse model (49); however, they did not use Fabs. Vaccination of rhesus macaques with PhtD has been shown to elicit protection against pneumonia (50) and is currently in human clinical trials (51). To our surprise, antibodies specific to Ply, which do not have a role in blocking adherence of S. pneumoniae to human lung epithelial cells, showed the greatest level of protection against NP colonization in mice.…”

Section: Discussionmentioning

confidence: 94%

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

et al. 2014

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bStreptococcus pneumoniae adherence to human epithelial cells (HECs) is the first step in pathogenesis leading to infections. We sought to determine the role of human antibodies against S. pneumoniae protein vaccine candidates PhtD, PcpA, and Ply in preventing adherence to lung HECs in vitro and mouse nasopharyngeal (NP) colonization in vivo. Human anti-PhtD, -PcpA, and -Ply antibodies were purified and Fab fragments generated. Fabs were used to test inhibition of adherence of TIGR4 and nonencapsulated strain RX1 to A549 lung HECs. The roles of individual proteins in adherence were tested using isogenic mutants of strain TIGR4. Anti-PhtD, -PcpA, and -Ply human antibodies were assessed for their ability to inhibit NP colonization in vivo by passive transfer of human antibody in a murine model. Human antibodies generated against PhtD and PcpA caused a decrease in adherence to A549 cells (P < 0.05). Anti-PhtD but not anti-PcpA antibodies showed a protective role against mouse NP colonization. To our surprise, anti-Ply antibodies also caused a significant (P < 0.05) reduction in S. pneumoniae colonization. Our results support the potential of PhtD, PcpA, and Ply protein vaccine candidates as alternatives to conjugate vaccines to prevent non-serotype-specific S. pneumoniae colonization and invasive infection.

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Section: Discussionmentioning

confidence: 94%

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

et al. 2014

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“…The Pht proteins are an important family of surface-associated virulence factors with potential to be used in novel pneumococcal protein-based vaccines (13)(14)(15)(16). In this work we have investigated whether the four Pht proteins act redundantly in contributing to Zn 2ϩ homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…The Pht proteins, and PhtD in particular, are targets of several novel protein-based pneumococcal vaccines currently in development. The efficacy of these formulations may depend upon stimulation of an opsonophagocytic antibody response against these surface antigens as well as blockade of their function by antibody binding (13)(14)(15)(16). As a consequence, if the Pht proteins are redundant, cross-reactive antibodies that bind to all four proteins would be required to elicit protection based on blockade of the function(s) of the proteins, whereas if they are not redundant, such a protective effect may be derived from single Pht protein-specific antibodies.…”

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confidence: 99%

Overlapping Functionality of the Pht Proteins in Zinc Homeostasis of Streptococcus pneumoniae

et al. 2014

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Streptococcus pneumoniae is a globally significant pathogen that causes a range of diseases, including pneumonia, sepsis, meningitis, and otitis media. Its ability to cause disease depends upon the acquisition of nutrients from its environment, including transition metal ions such as zinc. The pneumococcus employs a number of surface proteins to achieve this, among which are four highly similar polyhistidine triad (Pht) proteins. It has previously been established that these proteins collectively aid in the delivery of zinc to the ABC transporter substrate-binding protein AdcAII. Here we have investigated the contribution of each individual Pht protein to pneumococcal zinc homeostasis by analyzing mutant strains expressing only one of the four pht genes. Under conditions of low zinc availability, each of these mutants showed superior growth and zinc accumulation profiles relative to a mutant strain lacking all four genes, indicating that any of the four Pht proteins are able to facilitate delivery of zinc to AdcAII. However, optimal growth and zinc accumulation in vitro and pneumococcal survival and proliferation in vivo required production of all four Pht proteins, indicating that, despite their overlapping functionality, the proteins are not dispensable without incurring a fitness cost. We also show that surface-attached forms of the Pht proteins are required for zinc recruitment and that they do not contribute to defense against extracellular zinc stress.

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“…The Pht proteins are an important family of pneumococcal surface virulence factors notable for their promising efficacy in preventing pneumococcal colonization and disease in preclinical vaccine trials (9,16,17,30). However, they lack any recognizable motifs thought to mediate surface attachment, and they presumably use a novel mechanism to attach to the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Surface Association of Pht Proteins of Streptococcus pneumoniae

2013

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Streptococcus pneumoniae is a major human pathogen responsible for massive global morbidity and mortality. The pneumococcus attaches a variety of proteins to its cell surface, many of which contribute to virulence; one such family are the polyhistidine triad (Pht) proteins PhtA, PhtB, PhtD, and PhtE. In this study, we have examined the mechanism of Pht surface attachment using PhtD as a model. Analysis of deletion and point mutants identified a three-amino-acid region of PhtD (Q27-H28-R29) that is critical for the process. The analogous region in PhtE was also necessary for its attachment to the cell surface. Furthermore, we show that a large proportion of the total amount of each Pht protein is released into bacterial culture supernatants. Other surface proteins were also released, albeit to lesser extents, and this was not due to pneumococcal autolysis. The extent of release of surface proteins was strain dependent and was not affected by the capsule. Lastly, we compared the fitness of wild-type and ⌬phtABDE pneumococci in vivo in a mouse coinfection model. Release of Pht proteins by the wild type did not complement the mutant strain, consistent with surface-attached rather than soluble forms of the Pht proteins playing the major role in virulence. The significant degree of release of Pht proteins from intact bacteria may have implications for the use of these proteins in novel vaccines.

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Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults

Cited by 59 publications

References 22 publications

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

Overlapping Functionality of the Pht Proteins in Zinc Homeostasis of Streptococcus pneumoniae

Surface Association of Pht Proteins of Streptococcus pneumoniae

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