scholarly journals Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae

2013 ◽  
Vol 81 (5) ◽  
pp. 1625-1634 ◽  
Author(s):  
Il Gyu Kong ◽  
Ayuko Sato ◽  
Yoshikazu Yuki ◽  
Tomonori Nochi ◽  
Haruko Takahashi ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Current Knowledge ◽  
Protein A ◽  
Mucosal Vaccine ◽  
Mucosal Barrier ◽  
Effective Vaccine ◽  
Lethal Challenge ◽  
Content Type ◽  
Nasal Vaccine ◽  
Intranasal Vaccine

ABSTRACTTo establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge withStreptococcus pneumoniaeXen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection.

scholarly journals Evaluation of a Vaccine Formulation against Streptococcus pneumoniae Based on Choline-Binding Proteins

2014 ◽  
Vol 22 (2) ◽  
pp. 213-220 ◽  
Author(s):  
Eliane N. Miyaji ◽  
Cintia F. M. Vadesilho ◽  
Maria Leonor S. Oliveira ◽  
André Zelanis ◽  
David E. Briles ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Binding Proteins ◽  
Choline Chloride ◽  
Protein A ◽  
Surface Protein ◽  
Mass Spectrometry Analysis ◽  
Effective Vaccine ◽  
Lethal Challenge ◽  
Content Type ◽  
Spectrometry Analysis

ABSTRACTStreptococcus pneumoniaehas proteins that are attached to its surface by binding to phosphorylcholine of teichoic and lipoteichoic acids. These proteins are known as choline-binding proteins (CBPs). CBPs are an interesting alternative for the development of a cost-effective vaccine, and PspA (pneumococcal surface protein A) is believed to be the most important protective component among the different CBPs. We sought to use CBPs eluted from pneumococci as an experimental vaccine. Since PspA shows variability between isolates, we constructed strains producing different PspAs. We used the nonencapsulated Rx1 strain, which produces PspA from clade 2 (PspA2), to generate apspA-knockout strain (Rx1 ΔpspA) and strains expressing PspA from clade 1 (Rx1pspA1) and clade 4 (Rx1pspA4). We grew Rx1, Rx1 ΔpspA, Rx1pspA1, and Rx1pspA4in Todd-Hewitt medium containing 0.5% yeast extract and washed cells in 2% choline chloride (CC). SDS-PAGE analysis of the proteins recovered by a CC wash showed few bands, and the CBPs PspA and PspC (pneumococcal surface protein C) were identified by mass spectrometry analysis. Subcutaneous immunization of mice with these full-length native proteins without adjuvant led to significantly higher rates of survival than immunization with diluent after an intranasal lethal challenge with two pneumococcal strains and also after a colonization challenge with one strain. Importantly, immunization with recombinant PspA4 (rPspA4) without adjuvant did not elicit significant protection.

scholarly journals Polymeric Caffeic Acid Acts as a Nasal Vaccine Formulation against Streptococcus pneumoniae Infections in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 585
Author(s):  
Rui Tada ◽  
Hidehiko Suzuki ◽  
Miki Ogasawara ◽  
Daisuke Yamanaka ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Caffeic Acid ◽  
Pathogenic Bacteria ◽  
Protein A ◽  
Surface Protein ◽  
Mucosal Vaccine ◽  
Vaccine Formulation ◽  
Protective Effects ◽  
Mucosal Adjuvant ◽  
Nasal Vaccine

Infectious diseases are the second leading cause of death worldwide, highlighting the importance of the development of a novel and improved strategy for fighting pathogenic microbes. Streptococcus pneumoniae is a highly pathogenic bacteria that causes pneumonia with high mortality rates, especially in children and elderly individuals. To solve these issues, a mucosal vaccine system would be the best solution for the prevention and treatment of these diseases. We have recently reported that enzymatically polymerized caffeic acid (pCA) acts as a mucosal adjuvant when co-administered with antigenic proteins via the nasal route. Moreover, the sources of caffeic acid and horseradish peroxidase are ingredients found commonly in coffee beans and horseradish, respectively. In this study, we aimed to develop a pneumococcal nasal vaccine comprising pneumococcal surface protein A (PspA) and pCA as the mucosal adjuvant. Intranasal immunization with PspA and pCA induced the production of PspA-specific antibody responses in the mucosal and systemic compartments. Furthermore, the protective effects were tested in a murine model of S. pneumoniae infection. Intranasal vaccination conferred antigen-dependent protective immunity against a lethal infection of S. pneumoniae. In conclusion, pCA is useful as a serotype-independent universal nasal pneumococcal vaccine formulation.

scholarly journals Controlled Inflammatory Responses in the Lungs Are Associated with Protection Elicited by a Pneumococcal Surface Protein A-Based Vaccine against a Lethal Respiratory Challenge with Streptococcus pneumoniae in Mice

2012 ◽  
Vol 19 (9) ◽  
pp. 1382-1392 ◽  
Author(s):  
Fernanda A. Lima ◽  
Daniela M. Ferreira ◽  
Adriana T. Moreno ◽  
Patrícia C. D. Ferreira ◽  
Giovana M. P. Palma ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Inflammatory Responses ◽  
Protein A ◽  
Surface Protein ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Pneumococcal Surface Protein A ◽  
Lung Injuries ◽  
Nasal Vaccine ◽  
Respiratory Challenge

ABSTRACTStreptococcus pneumoniaeis a pathogen of great importance worldwide. We have previously described the efficacy of a nasal vaccine composed of the pneumococcal surface protein A and the whole-cell pertussis vaccine as an adjuvant against a pneumococcal invasive challenge in mice. Spread of bacteria to the bloodstream was probably prevented by the high levels of systemic antibodies induced by the vaccine, but bacteria were only cleared from the lungs 3 weeks later, indicating that local immune responses may contribute to survival. Here we show that a strict control of inflammatory responses in lungs of vaccinated mice occurs even in the presence of high numbers of pneumococci. This response was characterized by a sharp peak of neutrophils and lymphocytes with a simultaneous decrease in macrophages in the respiratory mucosa at 12 h postchallenge. Secretion of interleukin-6 (IL-6) and gamma interferon (IFN-γ) was reduced at 24 h postchallenge, and the induction of tumor necrosis factor alpha (TNF-α) secretion, observed in the first hours postchallenge, was completely abolished at 24 h. Before challenge and at 12 h postchallenge, vaccinated mice displayed higher numbers of CD4+T, CD8+T, and B lymphocytes in the lungs. However, protection still occurs in the absence of each of these cells during the challenge, indicating that other effectors may be related to the prevention of lung injuries in this model. High levels of mucosal anti-PspA antibodies were maintained in vaccinated mice during the challenge, suggesting an important role in protection.

scholarly journals Comparison of Immunogenicity and Protection of Two Pneumococcal Protein Vaccines Based on PsaA and PspA

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Jinfei Yu ◽  
Bo Li ◽  
Xiaorui Chen ◽  
Jingcai Lu ◽  
Dandan Wang ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pneumococcal Disease ◽  
Bacterial Load ◽  
Survival Rates ◽  
Mucosal Vaccine ◽  
High Morbidity ◽  
Content Type ◽  
Single Protein ◽  
Specific Igg ◽  
Children Under 5

ABSTRACTStreptococcus pneumoniaeis a major cause of invasive pneumococcal disease, septicemia, and meningitis that can result in high morbidity rates in children under 5 years old. The current polysaccharide-based vaccines can provide type-specific immunity, but a broad-spectrum vaccine would provide greater coverage. Therefore, developing pneumococcal-protein-based vaccines that can extend to more serum types is highly important. In this study, we vaccinated mice via the subcutaneous (s.c.) route with a systemic vaccine that is a mixture of fusion protein PsaA-PspA23 and a single protein, PspA4, with aluminum hydroxide as an adjuvant. As a comparison, mice were immunized intranasally with a mucosal vaccine that is a mixture of PspA2-PA-BLP (where PA is protein anchor and BLP is bacterium-like particle) and PspA4-PA-BLP, via the intranasal (i.n.) route. The two immunization processes were followed by challenge withStreptococcus pneumoniaebacteria from two different PspA families. Specific IgG titers in the serum and specific IgA titers in the mucosa were determined following immunizations. Bacterial loads and survival rates after challenge were compared. Both the systemic vaccine and the mucosal vaccine induced a significant increase of IgG against PspAs. Only the mucosal vaccine also induced specific IgA in the mucosa. The two vaccines provided protection, but each vaccine showed an advantage. The systemic vaccine induced higher levels of serum antibodies, whereas the mucosal vaccine limited the bacterial load in the lung and blood. Therefore, coimmunizations with the two types of vaccines may be implemented in the future.

scholarly journals DprA-Dependent Exit from the Competent State Regulates Multifaceted Streptococcus pneumoniae Virulence

2019 ◽  
Vol 87 (11) ◽  
Author(s):  
Jingjun Lin ◽  
Gee W. Lau
Keyword(s):  
Antibiotic Resistance ◽  
Streptococcus Pneumoniae ◽  
Cell Separation ◽  
Protein A ◽  
Wild Type ◽  
Content Type ◽  
Cellular Processes ◽  
Virulence Attenuation ◽  
Specific Induction ◽  
Competence System

ABSTRACT Streptococcus pneumoniae (pneumococcus) causes multiple infectious diseases. The pneumococcal competence system facilitates genetic transformation, spreads antibiotic resistance, and contributes to virulence. DNA-processing protein A (DprA) regulates the exit of pneumococcus from the competent state. Previously, we have shown that DprA is important in both bacteremia and pneumonia infections. Here, we examined the mechanisms of virulence attenuation in a ΔdprA mutant. Compared to the parental wild-type D39, the ΔdprA mutant enters the competent state when exposed to lower concentrations of the competence-stimulating peptide CSP1. The ΔdprA mutant overexpresses ComM, which delays cell separation after division. Additionally, the ΔdprA mutant overexpresses allolytic factors LytA, CbpD, and CibAB and is more susceptible to detergent-triggered lysis. Disabling of the competent-state-specific induction of ComM and allolytic factors compensated for the virulence loss in the ΔdprA mutant, suggesting that overexpression of these factors contributes to virulence attenuation. Finally, the ΔdprA mutant fails to downregulate the expression of multiple competence-regulated genes, leading to the excessive energy consumption. Collectively, these results indicate that an inability to properly exit the competent state disrupts multiple cellular processes that cause virulence attenuation in the ΔdprA mutant.

scholarly journals Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Theodora Papastamatiou ◽  
John G. Routsias ◽  
Olga Koutsoni ◽  
Eleni Dotsika ◽  
Athanassios Tsakris ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
B Cell ◽  
Protective Efficacy ◽  
Surface Proteins ◽  
Lethal Challenge ◽  
Hyperimmune Serum ◽  
B Cell Epitopes ◽  
Content Type ◽  
Binding Domains

ABSTRACT Four previously identified immunodominant B-cell epitopes, located within known virulent pneumococcal proteins CbpD, PhtD, PhtE, and ZmpB, had shown promising in vivo immunological characteristics, indicating their potential to be used as vaccine antigens. In this study, we further evaluated the opsonophagocytic activity of antibodies against these epitopes and their capacity to protect mice from pneumococcal sepsis. An opsonophagocytic killing assay (OPKA) revealed that OPKA titers of human anti-peptide antibodies against pneumococcal serotypes 1, 3, and 19A were significantly higher ( P < 0.001) than those of the control sera, suggesting their functional potential against virulent clinical isolates. Data obtained from mice actively immunized with any of the selected epitope analogues or with a mixture of these (G_Mix group) showed, compared to controls, enhanced survival against the highly virulent pneumococcal serotype 3 ( P < 0.001). Moreover, passive transfer of hyperimmune serum from G_Mix to naive mice also conferred protection to a lethal challenge with serotype 3, which demonstrates that the observed protection was antibody mediated. All immunized murine groups elicited gradually higher antibody titers and avidity, suggesting a maturation of immune response over time. Among the tested peptides, PhD_pep19 and PhtE_pep40 peptides, which reside within the zinc-binding domains of PhtD and PhtE proteins, exhibited superior immunological characteristics. Recently it has been shown that zinc uptake is of high importance for the virulence of Streptococcus pneumoniae ; thus, our findings suggest that these epitopes deserve further evaluation as novel immunoreactive components for the development of a polysaccharide-independent pneumococcal vaccine.

scholarly journals Conjugation of PspA4Pro with Capsular Streptococcus pneumoniae Polysaccharide Serotype 14 Does Not Reduce the Induction of Cross-Reactive Antibodies

2017 ◽  
Vol 24 (8) ◽  
Author(s):  
Míriam A. da Silva ◽  
Thiago R. Converso ◽  
Viviane M. Gonçalves ◽  
Luciana C. C. Leite ◽  
Martha M. Tanizaki ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Capsular Polysaccharide ◽  
Vaccine Coverage ◽  
Protein A ◽  
Surface Protein ◽  
Cross Reactivity ◽  
Carrier Protein ◽  
Content Type ◽  
Clade 1 ◽  
The Impact

ABSTRACT Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence of infections caused by nonvaccine serotypes of Streptococcus pneumoniae. The use of pneumococcal surface protein A (PspA) as a carrier protein in a conjugate vaccine could help prevent serotype replacement by increasing vaccine coverage and reducing selective pressure of S. pneumoniae serotypes. PspA is present in all pneumococcal strains, is highly immunogenic, and is known to induce protective antibodies. Based on its sequence, PspA has been classified into three families and six clades. A PspA fragment derived from family 2, clade 4 (PspA4Pro), was shown to generate antibodies with a broad range of cross-reactivity, across clades and families. Here, PspA4Pro was modified and conjugated to capsular polysaccharide serotype 14 (PS14). We investigated the impact of conjugation on the immune response induced to PspA4Pro and PS14. Mice immunized with the PS14-mPspA4Pro conjugate produced higher titers of anti-PS14 antibodies than the animals that received coadministered antigens. The conjugate induced antibodies with opsonophagocytic activity against PS14-carrying strains, as well as against a panel of strains bearing PspAs from five clades (encompassing families 1 and 2) bearing a non-PS14 serotype. Furthermore, mice immunized with PS14-mPspA4Pro were protected against nasal colonization with a nonrelated S. pneumoniae strain bearing PspA from clade 1, serotype 6B. These results demonstrate that the cross-reactivity mediated by PspA4Pro is retained following conjugation, supporting the use of PspA4 as a carrier protein in order to enhance pneumococcal vaccine coverage and encourage its further investigation as a candidate in future vaccine designs.

scholarly journals Mucosal Immunization with an Unadjuvanted Vaccine That Targets Streptococcus pneumoniae PspA to Human Fcγ Receptor Type I Protects against Pneumococcal Infection through Complement- and Lactoferrin-Mediated Bactericidal Activity

2011 ◽  
Vol 80 (3) ◽  
pp. 1166-1180 ◽  
Author(s):  
Constantine Bitsaktsis ◽  
Bibiana V. Iglesias ◽  
Ying Li ◽  
Jesus Colino ◽  
Clifford M. Snapper ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Bactericidal Activity ◽  
Protein A ◽  
Pneumococcal Infection ◽  
Lavage Fluid ◽  
Complement C3 ◽  
Type I ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Content Type

Targeting an antigen to Fc receptors (FcR) can enhance the immune response to the antigen in the absence of adjuvant. Furthermore, we recently demonstrated that intranasal immunization with an FcγR-targeted antigen enhances protection against a category A intracellular mucosal pathogen,Francisella tularensis. To determine if a similar strategy could be applied to the important pathogenStreptococcus pneumoniae, we used an improved mucosal FcR-targeting strategy that specifically targets human FcγR type I (hFcγRI). A humanized single-chain antibody component in which the variable domain binds to hFcγRI [anti-hFcγRI (H22)] was linked in a fusion protein with the pneumococcal surface protein A (PspA). PspA is known to elicit protection against pneumococcal sepsis, carriage, and pneumonia in mouse models when administered with adjuvants. Anti-hFcγRI-PspA or recombinant PspA (rPspA) alone was used to intranasally immunize wild-type (WT) and hFcγRI transgenic (Tg) mice in the absence of adjuvant. The hFcγRI Tg mice receiving anti-hFcγRI-PspA exhibited elevatedS. pneumoniae-specific IgA, IgG2c, and IgG1 antibodies in serum and bronchoalveolar lavage fluid. Neither immunogen was effective in protecting WT mice in the absence of adjuvant, but when PspA was targeted to hFcγRI as the anti-hFcγRI-PspA fusion, enhanced protection against lethalS. pneumoniaechallenge was observed in the hFcγRI Tg mice compared to mice given nontargeted rPspA alone. Immune sera from the anti-hFcγRI-PspA-immunized Tg mice showed enhanced complement C3 deposition on bacterial surfaces, and protection was dependent upon an active complement system. Immune serum also showed an enhanced bactericidal activity directed againstS. pneumoniaethat appears to be lactoferrin mediated.

scholarly journals Both Innate Immunity and Type 1 Humoral Immunity to Streptococcus pneumoniae Are Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2

2005 ◽  
Vol 73 (1) ◽  
pp. 298-307 ◽  
Author(s):  
Abdul Q. Khan ◽  
Quanyi Chen ◽  
Zheng-Qi Wu ◽  
James C. Paton ◽  
Clifford M. Snapper
Keyword(s):  
Streptococcus Pneumoniae ◽  
Humoral Immunity ◽  
Protein A ◽  
Surface Protein ◽  
Lethal Challenge ◽  
Humoral Immune ◽  
Extracellular Bacterium

ABSTRACT Little is known regarding the role of Toll-like receptors (TLRs) in regulating protein- and polysaccharide-specific immunoglobulin (Ig) isotype production in response to an in vivo challenge with an extracellular bacterium. In this report we demonstrate that MyD88−/−, but not TLR2−/−, mice are markedly defective in their induction of multiple splenic proinflammatory cytokine- and chemokine-specific mRNAs after intraperitoneal (i.p.) challenge with heat-killed Streptococcus pneumoniae capsular type 14 (S. pneumoniae type 14). This is correlated with analogous responses in splenic cytokine protein release in vitro following addition of S. pneumoniae type 14. Consistent with these data, naïve MyD88−/−, but not TLR2−/−, mice are more sensitive to killing following i.p. challenge with live S. pneumoniae type 14, relative to responses in wild-type mice. However, prior immunization of MyD88−/− mice with heat-killed S. pneumoniae type 14 protects against an otherwise-lethal challenge with live S. pneumoniae type 14. Surprisingly, both MyD88−/− and TLR2−/− mice exhibit striking and equivalent defects in elicitation of type 1 IgG isotypes (IgG3, IgG2b, and IgG2a), but not the type 2 IgG isotype, IgG1, specific for several protein and polysaccharide antigens, in response to i.p. challenge with heat-killed S. pneumoniae type 14. Of note, the type 1 IgG isotype titers specific for pneumococcal surface protein A are reduced in MyD88−/− mice but not TLR2−/− mice. These data suggest that distinct TLRs may differentially regulate innate versus adaptive humoral immunity to intact S. pneumoniae and are the first to implicate a role for TLR2 in shaping an in vivo type 1 IgG humoral immune response to a gram-positive extracellular bacterium.

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