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

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.

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Enzymatically polymerised polyphenols prepared from various precursors potentiate antigen-specific immune responses in both mucosal and systemic compartments in mice

PLoS ONE ◽

10.1371/journal.pone.0246422 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0246422

Author(s):

Rui Tada ◽

Miki Ogasawara ◽

Daisuke Yamanaka ◽

Yasuhiro Sakurai ◽

Yoichi Negishi ◽

...

Keyword(s):

Infectious Diseases ◽

Immune Responses ◽

Caffeic Acid ◽

Intranasal Administration ◽

Lavage Fluid ◽

Modern Medicine ◽

Mucosal Vaccine ◽

Mucosal Adjuvant ◽

Mucosal Vaccination ◽

Nasal Vaccine

Despite significant modern medicine progress, having an infectious disease is a major risk factor for humans. Mucosal vaccination is now widely considered as the most promising strategy to defeat infectious diseases; however, only live-attenuated and inactivated mucosal vaccines are used in the clinical field. To date, no subunit mucosal vaccine was approved mainly because of the lack of safe and effective methodologies to either activate or initiate host mucosal immune responses. We have recently elucidated that intranasal administration of enzymatically polymerised caffeic acid potentiates antigen-specific mucosal and systemic antibody responses in mice. However, our earlier study has not confirmed whether these effects are specific to the polymer synthesised from caffeic acid. Here, we show that enzymatically polymerised polyphenols (EPPs) from various phenolic compounds possess mucosal adjuvant activities when administered nasally with an antigen to mice. Potentiation of antigen-specific immune responses by all EPPs tested in this study showed no clear difference among the precursors used. We found that intranasal administration of ovalbumin as the antigen, in combination with all enzymatically polymerised polyphenols used in this study, induced ovalbumin-specific mucosal IgA in the nasal cavity, bronchoalveolar lavage fluid, vaginal fluids, and systemic IgG, especially IgG1, in sera. Our results demonstrate that the mucosal adjuvant activities of polyphenols are not limited to polymerised caffeic acid but are broadly observable across the studied polyphenols. These properties of polyphenols may be advantageous for the development of safe and effective nasal vaccine systems to prevent and/or treat various infectious diseases.

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Nanogel-based pneumococcal surface protein A nasal vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques

Mucosal Immunology ◽

10.1038/mi.2015.5 ◽

2015 ◽

Vol 8 (5) ◽

pp. 1144-1153 ◽

Cited By ~ 50

Author(s):

Y Fukuyama ◽

Y Yuki ◽

Y Katakai ◽

N Harada ◽

H Takahashi ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Th17 Cell ◽

Neutralizing Antibodies ◽

Protein A ◽

Surface Protein ◽

Cell Responses ◽

Pneumococcal Surface Protein A ◽

Nasal Vaccine

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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

Clinical and Vaccine Immunology ◽

10.1128/cvi.00171-12 ◽

2012 ◽

Vol 19 (9) ◽

pp. 1382-1392 ◽

Cited By ~ 14

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.

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

Infection and Immunity ◽

10.1128/iai.00240-13 ◽

2013 ◽

Vol 81 (5) ◽

pp. 1625-1634 ◽

Cited By ~ 82

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.

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DNA vaccines expressing pneumococcal surface protein A (PspA) elicit protection levels comparable to recombinant protein

Journal of Medical Microbiology ◽

10.1099/jmm.0.46217-0 ◽

2006 ◽

Vol 55 (4) ◽

pp. 375-378 ◽

Cited By ~ 14

Author(s):

Daniela M. Ferreira ◽

Eliane N. Miyaji ◽

Maria Leonor S. Oliveira ◽

Michelle Darrieux ◽

Ana Paula M. Arêas ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Recombinant Protein ◽

Dna Vaccines ◽

Protein A ◽

Surface Protein ◽

Humoral Response ◽

Cost Effective ◽

Promising Candidate ◽

Pneumococcal Surface Protein A ◽

Antibody Levels

Pneumococcal surface protein A (PspA) is a promising candidate for the development of cost-effective vaccines against Streptococcus pneumoniae. In the present study, BALB/c mice were immunized with DNA vaccine vectors expressing the N-terminal region of PspA. Animals immunized with a vector expressing secreted PspA developed higher levels of antibody than mice immunized with the vector expressing the antigen in the cytosol. However, both immunogens elicited similar levels of protection against intraperitoneal challenge. Furthermore, immunization with exactly the same fragment in the form of a recombinant protein, with aluminium hydroxide as an adjuvant, elicited even higher antibody levels, but this increased humoral response did not correlate with enhanced protection. These results show that DNA vaccines expressing PspA are able to elicit protection levels comparable to recombinant protein, even though total anti-PspA IgG response is considerably lower.

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