scholarly journals Preclinical Evaluation of the Pht Proteins as Potential Cross-Protective Pneumococcal Vaccine Antigens

2010 ◽  
Vol 79 (1) ◽  
pp. 238-245 ◽  
Author(s):  
Fabrice Godfroid ◽  
Philippe Hermand ◽  
Vincent Verlant ◽  
Philippe Denoël ◽  
Jan T. Poolman
Keyword(s):  
Survival Rates ◽  
Pneumococcal Infection ◽  
Protein Family ◽  
Transfer Model ◽  
Pneumococcal Vaccines ◽  
Protein Antigens ◽  
Human Antibodies ◽  
Lung Colonization ◽  
Vaccine Antigens ◽  
Colonization Model

ABSTRACTCurrent pneumococcal vaccines are composed of capsular polysaccharides (PS) of various serotypes, either as free PS or as protein-PS conjugates. The use of pneumococcus protein antigens that are able to afford protection across the majority of serotypes is envisaged as a relevant alternative and/or complement to the polysaccharides. In this context, based on several studies, the Pht protein family emerged as relevant vaccine candidates. The purpose of the present study was to evaluate the Pht protein family in several preclinical mouse models. Immunization with these antigens was compared with immunization with other pneumococcal antigens, such as CbpA, PspA, and PsaA. In a nasopharyngeal colonization model and in a lung colonization model, the Phts were found to be superior to the other candidates in terms of efficacy of protection and serotype coverage. Likewise, vaccination with PhtD allowed higher animal survival rates after lethal intranasal challenge. Finally, a passive transfer model in which natural anti-PhtD human antibodies were transferred into mice demonstrated significant protection against lethal intranasal challenge. This indicates that natural anti-PhtD human antibodies are able to protect against pneumococcal infection. Our findings, together with the serotype-independent occurrence of the Phts, designate this protein family as valid candidate antigens to be incorporated in protein-based pneumococcal vaccines.

scholarly journals A Review of Pneumococcal Vaccines: Current Polysaccharide Vaccine Recommendations and Future Protein Antigens

2016 ◽  
Vol 21 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Calvin C. Daniels ◽  
P. David Rogers ◽  
Chasity M. Shelton
Keyword(s):  
Conjugate Vaccine ◽  
Pneumococcal Conjugate Vaccine ◽  
Invasive Disease ◽  
Polysaccharide Vaccine ◽  
Pneumococcal Vaccines ◽  
Protein Antigens ◽  
Pneumococcal Infections ◽  
Serotype Replacement ◽  
Vaccine Recommendations ◽  
Vaccine Antigens

This review describes development of currently available pneumococcal vaccines, provides summary tables of current pneumococcal vaccine recommendations in children and adults, and describes new potential vaccine antigens in the pipeline. Streptococcus pneumoniae, the bacteria responsible for pneumonia, otitis media, meningitis and bacteremia, remains a cause of morbidity and mortality in both children and adults. Introductions of unconjugated and conjugated pneumococcal polysaccharide vaccines have each reduced the rate of pneumococcal infections caused by the organism S. pneumoniae. The first vaccine developed, the 23-valent pneumococcal polysaccharide vaccine (PPSV23), protected adults and children older than 2 years of age against invasive disease caused by the 23 capsular serotypes contained in the vaccine. Because PPSV23 did not elicit a protective immune response in children younger than 2 years of age, the 7-valent pneumococcal conjugate vaccine (PCV7) containing seven of the most common serotypes from PPSV23 in pediatric invasive disease was developed for use in children younger than 2 years of age. The last vaccine to be developed, the 13-valent pneumococcal conjugate vaccine (PCV13), contains the seven serotypes in PCV7, five additional serotypes from PPSV23, and a new serotype not contained in PPSV23 or PCV7. Serotype replacement with virulent strains that are not contained in the polysaccharide vaccines has been observed after vaccine implementation and stresses the need for continued research into novel vaccine antigens. We describe eight potential protein antigens that are in the pipeline for new pneumococcal vaccines.

scholarly journals Immunization with a ZmpB-Based Protein Vaccine Could Protect against Pneumococcal Diseases in Mice

2010 ◽  
Vol 79 (2) ◽  
pp. 867-878 ◽  
Author(s):  
Yi Gong ◽  
Wenchun Xu ◽  
Yali Cui ◽  
Xuemei Zhang ◽  
Run Yao ◽  
...  
Keyword(s):  
Polyclonal Antibodies ◽  
Pneumococcal Infection ◽  
A549 Cells ◽  
Passive Immunization ◽  
Vaccine Antigen ◽  
Protein Vaccine ◽  
Survival Times ◽  
Protein Antigens ◽  
Zinc Metalloprotease ◽  
Lung Colonization

ABSTRACTZinc metalloprotease B (ZmpB) is present in all isolated pneumococcal strains and contributes to the pathogenesis of pneumococcal infection. In this study, recombinant ZmpB was cloned and expressed inEscherichia coli. The expression of ZmpB by different pneumococcal strains was detectable by Western blotting with antisera raised to recombinant ZmpB. Flow cytometry analysis demonstrated that anti-ZmpB polyclonal antibodies could bind to the cell surface of the pneumococcal strains analyzed. Both recombinant ZmpB protein and anti-ZmpB polyclonal antibodies significantly inhibited the adhesion ofStreptococcus pneumoniaeD39 to A549 cells. In mouse models, mucosal immunization with recombinant ZmpB could significantly reduce pneumococcal lung colonization caused byS. pneumoniaeserotypes 19F and 14 and significantly increase mice survival times following invasive pneumococcal challenge with different pneumococcal strains, including serotypes 2, 3, 6B, and 14. Furthermore, intraperitoneal immunization with recombinant ZmpB in combination with the recombinant pneumolysin mutant (DeltaA146 Ply) and heat shock protein 40 (DnaJ) could enhance the protection against pneumococcal infection compared to protection provided by single-protein antigens. Passive immunization with hyperimmune antisera against these three antigens also demonstrated that the combination of three hyperimmune antisera could provide better protection than single antisera. Taken together, our results suggest that ZmpB is a good candidate pneumococcal vaccine antigen.

scholarly journals Novel Protein-Based Pneumococcal Vaccines: Assessing the Use of Distinct Protein Fragments Instead of Full-Length Proteins as Vaccine Antigens

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 9 ◽  
Author(s):  
Theano Lagousi ◽  
Paraskevi Basdeki ◽  
John Routsias ◽  
Vana Spoulou
Keyword(s):  
Low Cost ◽  
Specific Protein ◽  
Full Length ◽  
Pneumococcal Vaccines ◽  
Protein Antigens ◽  
Protein Fragments ◽  
Humoral And Cellular Immunity ◽  
Expression Variability ◽  
Efficient Protection ◽  
Antigenic Regions

Non-serotype-specific protein-based pneumococcal vaccines have received extensive research focus due to the limitations of polysaccharide-based vaccines. Pneumococcal proteins (PnPs), universally expressed among serotypes, may induce broader immune responses, stimulating humoral and cellular immunity, while being easier to manufacture and less expensive. Such an approach has raised issues mainly associated with sequence/level of expression variability, chemical instability, as well as possible undesirable reactogenicity and autoimmune properties. A step forward employs the identification of highly-conserved antigenic regions within PnPs with the potential to retain the benefits of protein antigens. Besides, their low-cost and stable construction facilitates the combination of several antigenic regions or peptides that may impair different stages of pneumococcal disease offering even wider serotype coverage and more efficient protection. This review discusses the up-to-date progress on PnPs that are currently under clinical evaluation and the challenges for their licensure. Focus is given on the progress on the identification of antigenic regions/peptides within PnPs and their evaluation as vaccine candidates, accessing their potential to overcome the issues associated with full-length protein antigens. Particular mention is given of the use of newer delivery system technologies including conjugation to Toll-like receptors (TLRs) and reformulation into nanoparticles to enhance the poor immunogenicity of such antigens.

scholarly journals Opening the OPK Assay Gatekeeper: Harnessing Multi-Modal Protection by Pneumococcal Vaccines

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 203
Author(s):  
Riegler ◽  
Mann ◽  
Orihuela ◽  
Tuomanen
Keyword(s):  
Vaccine Development ◽  
Immunocompromised Host ◽  
Pneumococcal Vaccines ◽  
Immune Functions ◽  
Protective Activity ◽  
Protein Antigens ◽  
Single Function ◽  
Cellular Immune ◽  
Opsonophagocytic Killing ◽  
New Evidence

Pneumococcal vaccine development is driven by the achievement of high activity in a single gatekeeper assay: the bacterial opsonophagocytic killing (OPK) assay. New evidence challenges the dogma that anti-capsular antibodies have only a single function that predicts success. The emerging concept of multi-modal protection presents an array of questions that are fundamental to adopting a new vaccine design process. If antibodies have hidden non-opsonic functions that are protective, should these be optimized for better vaccines? What would protein antigens add to protective activity? Are cellular immune functions additive to antibodies for success? Do different organs benefit from different modes of protection? Can vaccine activities beyond OPK protect the immunocompromised host? This commentary raises these issues at a time when capsule-only OPK assay-based vaccines are increasingly seen as a limiting strategy.

Protective activity of the Bordetella pertussis BrkA autotransporter in the murine lung colonization model

Vaccine ◽  
2008 ◽  
Vol 26 (34) ◽  
pp. 4306-4311 ◽  
Author(s):  
Nico Marr ◽  
David C. Oliver ◽  
Vincianne Laurent ◽  
Jan Poolman ◽  
Philippe Denoël ◽  
...  
Keyword(s):  
Bordetella Pertussis ◽  
Protective Activity ◽  
Murine Lung ◽  
Lung Colonization ◽  
Colonization Model

scholarly journals Expression of Toll-Like Receptor 2 by Dendritic Cells Is Essential for the DnaJ-ΔA146Ply-Mediated Th1 Immune Response against Streptococcus pneumoniae

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Xiaofang Wang ◽  
Taixian Yuan ◽  
Jun Yuan ◽  
Yufeng Su ◽  
Xiaoyu Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Protective Immunity ◽  
Survival Rates ◽  
Pneumococcal Infection ◽  
Toll Like Receptor ◽  
Pneumococcal Strain ◽  
Ifn Γ ◽  
Subcutaneous Immunization ◽  
Th1 Immune Response

ABSTRACT The fusion protein DnaJ-ΔA146Ply could induce cross-protective immunity against pneumococcal infection via mucosal and subcutaneous immunization in mice in the absence of additional adjuvants. DnaJ and Ply are both Toll-like receptor 4 (TLR4) but not TLR2 ligands. However, we found that TLR2 −/− mice immunized subcutaneously with DnaJ-ΔA146Ply showed significantly lower survival rates and higher bacterial loads in nasal washes than did wild-type (WT) mice after being challenged with pneumococcal strain D39 or 19F. The gamma interferon (IFN-γ) level in splenocytes decreased in TLR2 −/− mice, indicating that Th1 immunity elicited by DnaJ-ΔA146Ply was impaired in these mice. We explored the mechanism of protective immunity conferred by DnaJ-ΔA146Ply and the role of TLR2 in this process. DnaJ-ΔA146Ply effectively promoted dendritic cell (DC) maturation via TLR4 but not the TLR2 signaling pathway. In a DnaJ-ΔA146Ply-treated DC and naive CD4 + T cell coculture system, the deficiency of TLR2 in DCs resulted in a significant decline of IFN-γ production and Th1 subset differentiation. The same effect was observed in adoptive-transfer experiments. In addition, TLR2 −/− DCs showed remarkably lower levels of the Th1-polarizing cytokine IL-12p70 than did WT DCs, suggesting that TLR2 was indispensable for DnaJ-ΔA146Ply-induced IL-12 production and Th1 proliferation. Thus, our findings illustrate that dendritic cell expression of TLR2 is essential for optimal Th1 immune response against pneumococci in mice immunized subcutaneously with DnaJ-ΔA146Ply.

scholarly journals Genetic Immunization with the Region Encoding the α-Helical Domain of PspA Elicits Protective Immunity againstStreptococcus pneumoniae

2001 ◽  
Vol 69 (9) ◽  
pp. 5456-5463 ◽  
Author(s):  
Joseph R. Bosarge ◽  
James M. Watt ◽  
D. Olga McDaniel ◽  
Edwin Swiatlo ◽  
Larry S. McDaniel
Keyword(s):  
Protein A ◽  
Survival Rates ◽  
Serum Antibody ◽  
Pneumococcal Infection ◽  
Surface Protein ◽  
Eukaryotic Expression ◽  
Dependent Manner ◽  
Genetic Immunization ◽  
Helical Domain ◽  
Dose Dependent

ABSTRACT Pneumococcal surface protein A (PspA) is a pneumococcal virulence factor capable of eliciting protection against pneumococcal infection in mice. Previous studies have demonstrated that the protection is antibody mediated. Here we examined the ability ofpspA to elicit a protective immune response following genetic immunization of mice. Mice were immunized by intramuscular injections with a eukaryotic expression vector encoding the α-helical domain of PspA/Rx1. Immunization induced a PspA-specific serum antibody response, and immunized mice survived pneumococcal challenge. Survival and antibody responses occurred in a dose-dependent manner, the highest survival rates being seen with doses of 10 μg or greater. The ability of genetic immunization to elicit cross-protection was demonstrated by the survival of immunized mice challenged with pneumococcal strains differing in capsule and PspA types. Also, immunized mice were protected from intravenous and intratracheal challenges with pneumococci. Similar to the results seen with immunization with PspA, the survival of mice genetically immunized with pspA was antibody mediated. There was no decline in the level of protection 7 months after immunization. These results support the use of genetic immunization to elicit protective immune responses against extracellular pathogens.

scholarly journals Pneumococcal Choline-Binding Proteins Involved in Virulence as Vaccine Candidates

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 181
Author(s):  
Julio Sempere ◽  
Mirella Llamosí ◽  
Idoia del Río Menéndez ◽  
Beatriz López Ruiz ◽  
Mirian Domenech ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Pneumococcal Infection ◽  
Infection Process ◽  
Protein Antigens ◽  
Antibiotic Resistant ◽  
Conjugate Vaccines ◽  
Vaccine Candidates ◽  
Vaccine Serotypes ◽  
Wide Range ◽  
Potential Vaccine

Streptococcus pneumoniae is a pathogen responsible for millions of deaths worldwide. Currently, the available vaccines for the prevention of S. pneumoniae infections are the 23-valent pneumococcal polysaccharide-based vaccine (PPV-23) and the pneumococcal conjugate vaccines (PCV10 and PCV13). These vaccines only cover some pneumococcal serotypes (up to 100 different serotypes have been identified) and are unable to protect against non-vaccine serotypes and non-encapsulated pneumococci. The emergence of antibiotic-resistant non-vaccine serotypes after these vaccines is an increasing threat. Therefore, there is an urgent need to develop new pneumococcal vaccines which could cover a wide range of serotypes. One of the vaccines most characterized as a prophylactic alternative to current PPV-23 or PCVs is a vaccine based on pneumococcal protein antigens. The choline-binding proteins (CBP) are found in all pneumococcal strains, giving them the characteristic to be potential vaccine candidates as they may protect against different serotypes. In this review, we have focused the attention on different CBPs as vaccine candidates because they are involved in the pathogenesis process, confirming their immunogenicity and protection against pneumococcal infection. The review summarizes the major contribution of these proteins to virulence and reinforces the fact that antibodies elicited against many of them may block or interfere with their role in the infection process.

scholarly journals Typing complex meningococcal vaccines to understand diversity and population structure of key vaccine antigens

2018 ◽  
Vol 3 ◽  
pp. 151 ◽  
Author(s):  
Charlene M. C. Rodrigues ◽  
Hannah Chan ◽  
Caroline Vipond ◽  
Keith Jolley ◽  
Odile B. Harrison ◽  
...  
Keyword(s):  
Capsular Polysaccharide ◽  
Vaccine Development ◽  
Membrane Vesicles ◽  
Shotgun Proteomics ◽  
Outer Membrane Vesicles ◽  
Amino Acid Sequences ◽  
Protein Antigens ◽  
Structured Population ◽  
Vaccine Antigens ◽  
Successful Approach

Background:Protein-conjugate capsular polysaccharide vaccines can potentially control invasive meningococcal disease (IMD) caused by five (A, C, W, X, Y) of the six IMD-associated serogroups.  Concerns raised by immunological similarity of the serogroup B capsule, to human neural cell carbohydrates, has meant that ‘serogroup B substitute’ vaccines target more variable subcapsular protein antigens.  A successful approach using outer membrane vesicles (OMVs) as major vaccine components had limited strain coverage. In 4CMenB (Bexsero®), recombinant proteins have been added to ameliorate this problem. Methods:Here, scalable, portable, genomic techniques were used to investigate the Bexsero®OMV protein diversity in meningococcal populations. Shotgun proteomics identified 461 proteins in the OMV, defining a complex proteome. Amino acid sequences for the 24 proteins most likely to be involved in cross-protective immune responses were catalogued within thePubMLST.org/neisseriadatabase using a novel OMV peptide Typing (OMVT) scheme.Results:Among these proteins there was variation in the extent of diversity and association with meningococcal lineages, identified as clonal complexes (ccs), ranging from the most conserved peptides (FbpA, NEISp0578, and putative periplasmic protein, NEISp1063) to the most diverse (TbpA, NEISp1690).  There were 1752 unique OMVTs identified amongst 2492/3506 isolates examined by whole-genome sequencing (WGS). These OMVTs were grouped into clusters (sharing ≥18 identical OMVT peptides), with 45.3% of isolates assigned to one of 27 OMVT clusters. OMVTs and OMVT clusters were strongly associated with cc, genogroup, and Bexsero®antigen variants, demonstrating that combinations of OMV proteins exist in discrete, non-overlapping combinations associated with genogroup and Bexsero®Antigen Sequence Type. This highly structured population of IMD-associated meningococci is consistent with strain structure models invoking host immune selection.Conclusions:The OMVT scheme facilitates region-specific WGS investigation of meningococcal diversity and is an open-access, portable tool with applications for vaccine development, especially in the choice of antigen combinations, assessment and implementation.

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