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Broad protective immune responses elicited by bacterium-like particle-based intranasal pneumococcal particle vaccine displaying PspA2 and PspA4 fragments.

ABSTRACT: Streptococcus pneumoniae is an infectious pathogen mainly infecting host bodies through the respiratory system. An effective pneumococcal vaccine would be targeted to the mucosa and provide not only protection against invasive infection but also against colonization in the respiratory system. In the present work, we applied bacterium-like particles (BLPs) as an adjuvant for the development of a PspA mucosal vaccine, in which the PspA protein was displayed on the surface of BLPs. Intranasal immunization with the PspA-BLP pneumococcal vaccine, comprised of PspA2 from pneumococcal family 1 and PspA4 from pneumococcal family 2, not only induced a high level of serum IgG antibodies but also a high level of mucosal SIgA antibodies. Analysis of binding of serum antibodies to intact bacteria showed a broad coverage of binding to pneumococcal strains expressing PspA from clade 1 to 5. Immunization with the PspA-BLP vaccine conferred protection against fatal intranasal challenge with both PspA family 1 and family 2 pneumococcal strains regardless of serotype. Therefore, the PspA-BLP pneumococcal vaccine was demonstrated to be a promising strategy for mucosal immunization to enhance both systemic and mucosal immune responses.

SUBMITTER: Lu J

PROVIDER: S-EPMC6422497 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Broad protective immune responses elicited by bacterium-like particle-based intranasal pneumococcal particle vaccine displaying PspA2 and PspA4 fragments.

Lu Jingcai J Guo Jieshi J Wang Dandan D Yu Jinfei J Gu Tiejun T Jiang Chunlai C Kong Wei W Wu Yongge Y

Human vaccines & immunotherapeutics 20181005 2

Streptococcus pneumoniae is an infectious pathogen mainly infecting host bodies through the respiratory system. An effective pneumococcal vaccine would be targeted to the mucosa and provide not only protection against invasive infection but also against colonization in the respiratory system. In the present work, we applied bacterium-like particles (BLPs) as an adjuvant for the development of a PspA mucosal vaccine, in which the PspA protein was displayed on the surface of BLPs. Intranasal immun ...[more]

PMID: 30235046

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Project description:Streptococcus pneumoniae is a bacterial pathogen that causes various diseases of public health concern worldwide. Current pneumococcal vaccines target the capsular polysaccharide surrounding the cells. However, only up to 13 of more than 90 pneumococcal capsular serotypes are represented in the current conjugate vaccines. In this study, we used two experimental approaches to evaluate the potential of Streptococcus mitis, a commensal that exhibits immune cross-reactivity with S. pneumoniae, to confer protective immunity to S. pneumoniae lung infection in mice. First, we assessed the immune response and protective effect of wild-type S. mitis against lung infection by S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4). Second, we examined the ability of an S. mitis mutant expressing the S. pneumoniae type 4 capsule (S. mitis TIGR4cps) to elicit focused protection against S. pneumoniae TIGR4. Our results showed that intranasal immunization of mice with S. mitis produced significantly higher levels of serum IgG and IgA antibodies reactive to both S. mitis and S. pneumoniae, as well as enhanced production of interleukin 17A (IL-17A), but not gamma interferon (IFN-γ) and IL-4, compared with control mice. The immunization resulted in a reduced bacterial load in respiratory tissues following lung infection with S. pneumoniae TIGR4 or D39 compared with control mice. With S. mitis TIGR4cps, protection upon challenge with S. pneumoniae TIGR4 was superior. Thus, these findings show the potential of S. mitis to elicit natural serotype-independent protection against two pneumococcal serotypes and to provide the benefits of the well-recognized protective effect of capsule-targeting vaccines.IMPORTANCEStreptococcus pneumoniae causes various diseases worldwide. Current pneumococcal vaccines protect against a limited number of more than 90 pneumococcal serotypes, accentuating the urgent need to develop novel prophylactic strategies. S. pneumoniae and the commensal Streptococcus mitis share immunogenic characteristics that make S. mitis an attractive vaccine candidate against S. pneumoniae In this study, we evaluated the potential of S. mitis and its mutant expressing pneumococcal capsule type 4 (S. mitis TIGR4cps) to induce protection against S. pneumoniae lung infection in mice. Our findings show that intranasal vaccination with S. mitis protects against S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4) in a serotype-independent fashion, which is associated with enhanced antibody and T cell responses. Furthermore, S. mitis TIGR4cps conferred additional protection against S. pneumoniae TIGR4, but not against D39. The findings highlight the potential of S. mitis to generate protection that combines both serotype-independent and serotype-specific responses.

Project description:Respiratory syncytial virus (RSV) is an important cause of respiratory tract disease in infants and the elderly. Currently, no licensed vaccine against RSV is available. Here we describe the development of a safe and effective intranasal subunit vaccine that is based on recombinant fusion (F) protein bound to the surface of immunostimulatory bacterium-like particles (BLPs) derived from the food-grade bacterium Lactococcus lactis. Different variants of F were analyzed with respect to their conformation and reactivity with neutralizing antibodies, assuming that F proteins mimicking the metastable prefusion form of RSV F expose a more extensive and relevant epitope repertoire than F proteins corresponding to the postfusion structure. Our results indicate that the recombinant soluble ectodomain of RSV F readily adopts a postfusion conformation, generation of which cannot be prevented by C-terminal addition of a trimerization motif, but whose formation is prevented by mutation of the two furin cleavage sites in F. While the putative postfusion form of F is recognized well by the monoclonal antibody Palivizumab, this is much less so for the more potently neutralizing, prefusion-specific antibodies D25 and AM22. Both addition of the trimerization motif and mutation of the furin cleavage sites increased the reactivity of F with D25 and AM22, with the highest reactivity being observed for F proteins in which both these features were combined. Intranasal vaccination of mice or cotton rats with BLPs loaded with this latter prefusion-like F protein (BLP-F), resulted in the potent induction of F-specific immunoglobulins and in significantly decreased virus titers in the lungs upon RSV challenge. Moreover, and in contrast to animals vaccinated with formalin-inactivated RSV, animals that received BLP-F exhibited high levels of F-specific secretory IgA in the nose and RSV-neutralizing antibodies in sera, but did not show symptoms of enhanced disease after challenge with RSV.

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Project description:Vaccine effectiveness is mainly determined by the mechanism mediating protection, emphasizing the importance of unraveling the protective mechanism for novel pneumococcal vaccine development. We previously demonstrated that the regulatory T cell (Treg) immune response has a protective effect against pneumococcal infection elicited by the live-attenuated pneumococcal vaccine SPY1. However, the mechanism underlying this protective effect remains unclear. In this study, a short synthetic peptide (P17) was used to downregulate Tregs during immunization and subsequent challenges in a mouse model. In immunized mice, increase in immune cytokines (IL-12p70, IL-4, IL-5, and IL-17A) induced by SPY1 were further upregulated by P17 treatment, whereas the decrease in the infection-associated inflammatory cytokine TNF-α by SPY1 was reversed. P17 also inhibited the increase in the immunosuppressive cytokine IL-10 and inflammatory mediator IL-6 in immunized mice. More severe pulmonary injuries and more dramatic inflammatory responses with worse survival in P17-treated immunized mice indicated the indispensable role of the Treg immune response in protection against pneumococcal infection by maintaining a balance among acquired immune responses stimulated by SPY1. Further studies revealed that the significant elevation of active transforming growth factor β (TGF-β)1 by SPY1 vaccination activated FOXP3, leading to increased frequencies of CD4+CD25+Foxp3+ T cells. Moreover, SPY1 vaccination elevated the levels of Smad2/3 and phosphor-Smad2/3 and downregulated the negative regulatory factor Smad7 in a time-dependent manner during pneumococcal infection, and these changes were reversed by P17 treatment. These results illustrate that SPY1-stimulated TGF-β1 induced the generation of SPY1-specific Tregs via the Smad2/3 signaling pathway. In addition, SPY1-specific Tregs may participate in protection via the enhanced expression of PD-1 and CTLA-4. The data presented here extend our understanding of how the SPY1-induced acquired Treg immune response contributes to protection elicited by live-attenuated vaccines and may be helpful for the evaluation of live vaccines and other mucosal vaccine candidates.

Dataset Information

Broad protective immune responses elicited by bacterium-like particle-based intranasal pneumococcal particle vaccine displaying PspA2 and PspA4 fragments.

Publications

Broad protective immune responses elicited by bacterium-like particle-based intranasal pneumococcal particle vaccine displaying PspA2 and PspA4 fragments.

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