PspA Family Fusion Proteins Delivered by Attenuated<i>Salmonella enterica</i>Serovar Typhimurium Extend and Enhance Protection against<i>Streptococcus pneumoniae</i>

Wei, Xin; Li, Yuhua; Mo, Hua; Roland, Kenneth L.; Curtiss, Roy

doi:10.1128/iai.00486-09

Cited by 48 publications

(44 citation statements)

References 64 publications

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“…When tested singly, antibodies to such antigens can be protective in animal models; these antibodies seem less potent than capsular antibody, but they can be additive or even synergistic when more than one specificity is used together (38,39). There have been clinical trials of some of these antibodies as purified proteins (40)(41)(42), and attenuated Salmonella typhi engineered to express one such protein (43,44) is currently in phase I testing as an oral vaccine. However, none have yet shown protection in humans, much less in infancy.…”

Section: Noncapsular Components As Immunogensmentioning

confidence: 99%

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Malley

Anderson

2012

Proc. Natl. Acad. Sci. U.S.A.

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For prevention of Streptococcus pneumoniae (pneumococcus) infections in infancy, protein-conjugated capsular polysaccharide vaccines provide serotype-specific, antibody-mediated immunity but do not cover all of the 90+ capsule serotypes. Therefore, microbiologists have sought protective noncapsular antigens common to all strains. Alternatively, we investigated killed cells of a noncapsulated strain, which expose many such common antigens. Given to mice intranasally, this vaccine elicits antibody-independent, CD4+ T lymphocyte-dependent accelerated clearance of pneumococci of various serotypes from the nasopharynx mediated by the cytokine IL-17A. Such immunity may reproduce the natural resistance that develops in infants before capsular antibodies arise. Given by injection, the killed cell vaccine induces bifunctional immunity: plasma antibodies protective against fatal pneumonia challenge, as well as IL-17A–mediated nasopharyngeal clearance. Human testing of this inexpensive candidate vaccine by intramuscular injection is planned. Bacterial cellular vaccines are complex—a challenge for reproducibility. However, when several known protective antigens were deleted, the killed pneumococcal vaccine was still protective. This antigenic redundancy may prevent vaccine escape variants by recombinational loss, which is frequent in pneumococcus. Biochemically defined immunogens with bifunctional activity have also been devised. These immunogens are three-component conjugates in which cell wall teichoic acid (a common antigen capable of T cell activation) is coupled to a genetic fusion of two common pneumococcal proteins: a protective surface antigen and a derivative of pneumolysin, which provides TLR4 agonist activity and induces antitoxic immunity. Such constructs induce accelerated clearance when given intranasally and induce both immune mechanisms when injected. The defined composition permits analysis of structure-function activity.

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Section: Noncapsular Components As Immunogensmentioning

confidence: 99%

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Malley

Anderson

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Broad-coverage vaccines based on PspA would thus depend on the use of more than one molecule or on the choice of specific PspA molecules (37). In animal models, protection elicited by vaccines composed of PspA is often accompanied by the induction of high levels of specific antibodies (10,22,24,44) which, upon binding to pneumococcal surface, promote the deposition of complement (9,12,47,57) and enhance killing by lactoferrin (9,48). In addition, the use of adjuvants that elicit Th1 immune responses against PspA seems to optimize protection (4,19,20).…”

mentioning

confidence: 99%

“…Different immunization strategies and animal models were used to confirm PspA as a good vaccine candidate (4,12,36,57). This antigen has already undergone a phase I clinical trial and was shown to be immunogenic in humans (38).…”

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confidence: 99%

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

Lima

Ferreira

Moreno

et al. 2012

Clin Vaccine Immunol

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Streptococcus pneumoniae is 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-␥) was reduced at 24 h postchallenge, and the induction of tumor necrosis factor alpha (TNF-␣) 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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“…PspA is commonly expressed by all capsular serotypes of S. pneumoniae (15) and is classified into 3 families (family 1, clades 1 and 2; family 2, clades 3 through 5; and family 3, clade 6) according to sequence similarities (14). Given that parenteral immunization with PspA induces cross-reactive neutralizing immune responses in mice (16)(17)(18) and humans (19), using PspA as a serotype-independent common antigen for the development of pneumococcal vaccines seems to be an ideal strategy.…”

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confidence: 99%

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

et al. 2013

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kTo 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 with Streptococcus pneumoniae Xen10, 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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PspA Family Fusion Proteins Delivered by AttenuatedSalmonella entericaSerovar Typhimurium Extend and Enhance Protection againstStreptococcus pneumoniae

Cited by 48 publications

References 64 publications

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

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

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

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