scholarly journals Recombinant PhpA Protein, a Unique Histidine Motif-Containing Protein from Streptococcus pneumoniae, Protects Mice against Intranasal Pneumococcal Challenge

2001 ◽  
Vol 69 (6) ◽  
pp. 3827-3836 ◽  
Author(s):  
Ying Zhang ◽  
Amy W. Masi ◽  
Vicki Barniak ◽  
Ken Mountzouros ◽  
Margaret K. Hostetter ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Otitis Media ◽  
Conjugate Vaccine ◽  
Lipid A ◽  
Systemic Disease ◽  
Protein A ◽  
Complement C3 ◽  
Potential Candidate ◽  
Putative Open Reading Frame ◽  
Monophosphoryl Lipid A

ABSTRACT The multivalent pneumococcal conjugate vaccine is effective against both systemic disease and otitis media caused by serotypes contained in the vaccine. However, serotypes not covered by the current conjugate vaccine may still cause pneumococcal disease. To address these serotypes and the remaining otitis media due to Streptococcus pneumoniae, we have been evaluating antigenically conserved proteins from S. pneumoniae as vaccine candidates. A previous report identified a 20-kDa protein with putative human complement C3-proteolytic activity. By utilizing the publicly released pneumococcal genomic sequences, we found the gene encoding the 20-kDa protein to be part of a putative open reading frame of approximately 2,400 bp. We recombinantly expressed a 79-kDa fragment (rPhpA-79) that contains a repeated HxxHxH motif and evaluated it for vaccine potential. The antibodies elicited by the purified rPhpA-79 protein were cross-reactive to proteins from multiple strains of S. pneumoniae and were against surface-exposed epitopes. Immunization with rPhpA-79 protein adjuvanted with monophosphoryl lipid A (for subcutaneous immunization) or a mutant cholera toxin, CT-E29H (for intranasal immunization), protected CBA/N mice against death and bacteremia, as well as reduced nasopharyngeal colonization, following intranasal challenge with a heterologous pneumococcal strain. In contrast, immunization with the 20-kDa portion of the PhpA protein did not protect mice. These results suggest that rPhpA-79 is a potential candidate for use as a vaccine against pneumococcal systemic disease and otitis media.

scholarly journals PppA, a Surface-Exposed Protein of Streptococcus pneumoniae, Elicits Cross-Reactive Antibodies That Reduce Colonization in a Murine Intranasal Immunization and Challenge Model

2005 ◽  
Vol 73 (2) ◽  
pp. 981-989 ◽  
Author(s):  
Bruce A. Green ◽  
Ying Zhang ◽  
Amy W. Masi ◽  
Vicki Barniak ◽  
Michael Wetherell ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Otitis Media ◽  
Conjugate Vaccine ◽  
Lipid A ◽  
Systemic Disease ◽  
Protein A ◽  
Surface Proteins ◽  
Protein Antigens ◽  
Intranasal Immunization ◽  
Monophosphoryl Lipid A

ABSTRACT The multivalent pneumococcal conjugate vaccine is effective against both systemic disease and otitis media caused by serotypes contained in the vaccine. However, serotypes not covered by the present conjugate vaccine may still cause pneumococcal disease. To address these serotypes, and the remaining otitis media due to Streptococcus pneumoniae, efforts have been devoted to identifying protective protein antigens. Immunity to conserved surface proteins important for adhesion, nutrient acquisition, or other functions could result in a reduction of colonization and a lower disease potential. We have been searching for conserved surface-exposed proteins from S. pneumoniae that may be involved in pathogenesis to test as vaccine candidates. Here, an ∼20-kDa protein that has significant homology to a nonheme iron-containing ferritin protein from Listeria innocua and other bactoferritins was identified as pneumococcal protective protein A (PppA). We expressed and purified recombinant PppA (rPppA) and evaluated its potential as a vaccine candidate. The antibodies elicited by purified rPppA were cross-reactive with PppA from multiple strains of S. pneumoniae and were directed against surface-exposed epitopes. Intranasal immunization of BALB/c mice with PppA protein and either a synthetic monophosphoryl lipid A analog, RC529AF, or a cholera toxin mutant, CT-E29H, used as an adjuvant reduced nasopharyngeal colonization in mice following intranasal challenge with a heterologous pneumococcal strain. PppA-specific systemic and local immunoglobulin G (IgG) and IgA antibody responses were induced. The antisera reacted with whole cells of a heterologous S. pneumoniae type 3 strain. These observations indicate that PppA may be a promising candidate for inclusion in a vaccine against pneumococcal otitis media.

scholarly journals Contributions of Pneumolysin, Pneumococcal Surface Protein A (PspA), and PspC to Pathogenicity of Streptococcus pneumoniae D39 in a Mouse Model

2007 ◽  
Vol 75 (4) ◽  
pp. 1843-1851 ◽  
Author(s):  
Abiodun D. Ogunniyi ◽  
Kim S. LeMessurier ◽  
Rikki M. A. Graham ◽  
James M. Watt ◽  
David E. Briles ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Systemic Disease ◽  
Protein A ◽  
Virulence Gene ◽  
Surface Protein ◽  
Invasive Disease ◽  
Upper Respiratory Tract ◽  
Virulence Proteins ◽  
Pneumococcal Surface Protein A ◽  
Genes Encoding

ABSTRACTSuccessful colonization of the upper respiratory tract byStreptococcus pneumoniaeis an essential first step in the pathogenesis of pneumococcal disease. However, the bacterial and host factors that provoke the progression from asymptomatic colonization to invasive disease are yet to be fully defined. In this study, we investigated the effects of single and combined mutations in genes encoding pneumolysin (Ply), pneumococcal surface protein A (PspA), and pneumococcal surface protein C (PspC, also known as choline-binding protein A) on the pathogenicity ofStreptococcus pneumoniaeserotype 2 (D39) in mice. Following intranasal challenge with D39, stable colonization of the nasopharynx was maintained over a 7-day period at a level of approximately 105bacteria per mouse. The abilities of the mutant deficient in PspA to colonize the nasopharynx and to cause lung infection and bacteremia were significantly reduced. Likewise, the PspC mutant and, to a lesser extent, the Ply mutant also had reduced abilities to colonize the nasopharynx. As expected, the double mutants colonized less well than the parent to various degrees and had difficulty translocating to the lungs and blood. A significant additive attenuation was observed for the double and triple mutants in pneumonia and systemic disease models. Surprisingly, the colonization profile of the derivative lacking all three proteins was similar to that of the wild type, indicating virulence gene compensation. These findings further demonstrate that the mechanism of pneumococcal pathogenesis is highly complex and multifactorial but ascribes a role for each of these virulence proteins, alone or in combination, in the process.

scholarly journals Protection against Development of Otitis Media Induced by Nontypeable Haemophilus influenzae by Both Active and Passive Immunization in a Chinchilla Model of Virus-Bacterium Superinfection

1999 ◽  
Vol 67 (6) ◽  
pp. 2746-2762 ◽  
Author(s):  
Lauren O. Bakaletz ◽  
Bobbie-Jo Kennedy ◽  
Laura A. Novotny ◽  
Guy Duquesne ◽  
Joe Cohen ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Otitis Media ◽  
Lipid A ◽  
Protective Efficacy ◽  
Outer Membrane Proteins ◽  
Passive Immunization ◽  
Passive Transfer ◽  
Nontypeable Haemophilus Influenzae ◽  
Recombinant Peptide ◽  
Monophosphoryl Lipid A

ABSTRACT Three separate studies, two involving active-immunization regimens and one involving a passive-transfer protocol, were conducted to initially screen and ultimately more fully assess several nontypeableHaemophilus influenzae outer membrane proteins or their derivatives for their relative protective efficacy in chinchilla models of otitis media. Initial screening of these antigens (P5-fimbrin, lipoprotein D, and P6), delivered singly or in combination with either Freund’s adjuvant or alum, indicated that augmented bacterial clearance from the nasopharynx, the middle ears, or both anatomical sites could be induced by parenteral immunization with P5-fimbrin combined with lipoprotein D, lipoprotein D alone, or the synthetic chimeric peptide LB1 (derived from P5-fimbrin), respectively. Data from a second study, wherein chinchillas were immunized with LB1 or lipoprotein D, each delivered with alum, again indicated that clearance of nontypeable H. influenzae could be augmented by immunization with either of these immunogens; however, when this adjuvant was used, both antibody titers in serum and efficacy were reduced. A third study was performed to investigate passive delivery of antisera directed against either LB1, lipoprotein D, nonacylated lipoprotein D, or a unique recombinant peptide designated LPD-LB1(f)2,1,3. The last three antiserum pools were generated by using the combined adjuvant of alum plus monophosphoryl lipid A. Passive transfer of sera specific for LB1 or LPD-LB1(f)2,1,3 to adenovirus-compromised chinchillas, prior to intranasal challenge with nontypeable H. influenzae, significantly reduced the severity of signs and incidence of otitis media which developed (P ≤ 0.001). Collectively, these data indicate the continued merit of further developing LB1 and LPD-LB1(f)2,1,3 as components of vaccines for otitis media.

scholarly journals Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2056-2065 ◽  
Author(s):  
Jennifer Carlring ◽  
Marika J. Szabo ◽  
Robert Dickinson ◽  
Evy De Leenheer ◽  
Andrew W. Heath
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lipid A ◽  
Keyhole Limpet Hemocyanin ◽  
Potential Candidate ◽  
Antitumor Effects ◽  
Gm Csf ◽  
Humoral Immune ◽  
Monophosphoryl Lipid A

AbstractPersonalized immunotherapy of lymphoma based on tumor idiotype (Id) has shown anti-idiotype humoral immune responses in 40%-50% and cellular immune responses in 50%-75% of follicular lymphoma patients, indicating that this therapy can be clinically successful. We have developed a novel vaccine against lymphoma consisting of an anti-CD40 Ab (ADX40) chemically conjugated to the tumor idiotype A20 and tested it in a murine lymphoma model. BALB/c mice were immunized with 2 doses of immunogen alone or in conjunction with additional adjuvants before tumor challenge. ADX40-Id vaccination resulted in significantly retarded tumor growth and reduced mouse morbidity. Moreover, similar mouse survival was obtained with 2 injections of ADX40-Id as with 8 injections using the standard therapy of keyhole limpet hemocyanin Id + GM-CSF. Co-administration of ADX40-Id with 3-O-deacyl-4′-monophosphoryl lipid A further significantly enhanced vaccine efficacy, resulting in an increased overall survival. Anti-Id–specific Abs were detected at elevated levels after ADX40-Id immunization; however, in vivo depletion of CD4 and/or CD8 T cells before challenge showed that CD8 effector T cells were the major mediators of tumor protection. The results of the present study show that the ADX40-Id conjugate vaccine is a potential candidate as a stand-alone vaccine or in combination with currently licensed adjuvants for lymphoma immunotherapy.

scholarly journals A Comparison of Intramuscular and Subcutaneous Administration of LigA Subunit Vaccine Adjuvanted with Neutral Liposomal Formulation Containing Monophosphoryl Lipid A and QS21

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 494 ◽  
Author(s):  
Teerasit Techawiwattanaboon ◽  
Christophe Barnier-Quer ◽  
Tanapat Palaga ◽  
Alain Jacquet ◽  
Nicolas Collin ◽  
...  
Keyword(s):  
Survival Rate ◽  
Subunit Vaccine ◽  
Lipid A ◽  
Protective Efficacy ◽  
Protein A ◽  
Subcutaneous Administration ◽  
Protective Effects ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
The Impact

Leptospirosis vaccines with higher potency and reduced adverse effects are needed for human use. The carboxyl terminal domain of leptospiral immunoglobulin like protein A (LigAc) is currently the most promising candidate antigen for leptospirosis subunit vaccine. However, LigAc-based vaccines were unable to confer sterilizing immunity against Leptospira infection in animal models. Several factors including antigen properties, adjuvant, delivery system, and administration route need optimization to maximize vaccine efficacy. Our previous report demonstrated protective effects of the recombinant LigAc (rLigAc) formulated with liposome-based adjuvant, called LMQ (neutral liposome combined with monophosphoryl lipid A and Quillaja saponaria fraction 21) in hamsters. This study aimed to evaluate the impact of two commonly used administration routes, intramuscular (IM) and subcutaneous (SC), on immunogenicity and protective efficacy of rLigAc-LMQ administrated three times at 2-week interval. Two IM vaccinations triggered significantly higher levels of total anti-rLigAc IgG than two SC injections. However, comparable IgG titers and IgG2/IgG1 ratio was observed for both routes after the third immunization. The route of vaccine administration did not influence the survival rate (60%) and renal colonization against lethal Leptospira challenge. Importantly, the kidneys of IM group showed no pathological lesions while the SC group showed mild damage. In conclusion, IM vaccination with rLigAc-LMQ not only elicited faster antibody production but also protected from kidney damage following leptospiral infection better than SC immunization. However, both tested routes did not influence protective efficacy in terms of survival rate and the level of renal colonization.

Bacterial Spectrum of Acute Otitis Media in Bulgarian Children during the 10-Valent Pneumococcal Conjugate Vaccine Era

2020 ◽  
Vol 15 (03) ◽  
pp. 135-143
Author(s):  
Lena Setchanova ◽  
Iglika Stancheva ◽  
Diana Popova ◽  
Alexandra Alexandrova ◽  
Ivan Mitov
Keyword(s):  
Streptococcus Pneumoniae ◽  
Otitis Media ◽  
Conjugate Vaccine ◽  
Pneumococcal Conjugate Vaccine ◽  
Acute Otitis Media ◽  
Childhood Vaccination ◽  
Middle Ear Fluid ◽  
High Prevalence ◽  
Culture Positive ◽  
Prevalent Pathogen

Abstract Objective The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in Bulgaria for universal childhood vaccination in 2010. The objective of this study was to describe bacterial pathogens responsible for acute otitis media (AOM) in children in the era of routine PCV10 immunization. Materials and Methods Middle ear fluid (MEF)/otorrhea or nasopharyngeal specimens were collected between May 2012 and April 2017 from 425 children aged < 12 years diagnosed with AOM; 71.5% of them were vaccinated. Capsular types of Streptococcus pneumoniae and Haemophilus influenzae and antimicrobial nonsusceptibility were determined. Results Among 240 children with “severe” AOM, the studied specimens were MEF/otorrhea, and a total of 132 (55.0%) children were culture-positive. The most frequently identified bacteria were S. pyоgenes (31.1%), followed by Staphylococcus aureus (21.2%), S. pneumoniae (20.4%), and nontypeable H. influenzae (12.1%). Among 185 nasopharyngeal specimens obtained from children at the onset of a “mild” AOM episode, 67.0% were culture-positive for otopathogens. The most common pathogens were S. pneumoniae (41.9%), followed by H. influenzae (25.8%), Moraxella catarrhalis (23.4%), and S. pyоgenes (14.5%), alone or in combinations. Among children with pneumococcal AOM (79), PCV10 serotypes (VTs) were 21.5%. A high prevalence (50%) of nonvaccine serotypes 3 (14), 19A (11), and 6C (7) was found among vaccinated children. Rates of nonsusceptibility of S. pneumoniae to penicillin, amoxicillin and erythromycin, and of multidrug resistance, were 51.2, 10.1, 51.2, and 51.2, respectively. The rate of ampicillin-non-susceptibility in H. influenzae was 25%. All M. catarrhalis isolates were β-lactamase producers, and 32.2% of S. pyogenes were erythromycin-resistant. Conclusion Following implementation of PCV10, S. pyogenes was the most prevalent pathogen in children with “severe” AOM. Numbers of S. pneumoniae recovered from MEF/otorrhea significantly decreased, as did the overall proportion of VTs among AOM patients. Streptococcus pneumoniae, H. influenzae, and M. catarrhalis were the most commonly found pathogens in the nasopharynx of children with less severe AOM episodes.

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