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James B Dale

Publications and source records attributed to James B Dale.

16 recordsLinked to original sources
PubMed2006

Temporal changes in streptococcal M protein types and the near-disappearance of acute rheumatic fever in the United States.

BACKGROUND: The explanation for the very substantial decrease in the incidence of acute rheumatic fever in the United States, particularly over the past 50 years, is unclear. It has been proposed that certain M types of group A streptococci (GAS) include strains that are particularly rheumatogenic and that others are nonrheumatogenic. METHODS: We compared the M type distribution of GAS recovered from children from Chicago, Illinois, with acute pharyngitis during 1961-1968 to that of GAS recovered from Chicago children and children from across the United States in 2000-2004, with attention to changes in M types that previously were associated with rheumatogenic strains. RESULTS: The rheumatogenic types 3, 5, 6, 14, 18, 19, and 29 comprised 49.7% of 468 pharyngeal isolates during 1961-1968 but only 10.6% of 450 Chicago isolates during 2000-2004 (P < .001) and 17.9% of 3969 isolates nationwide during 2000-2004 (P < .001). Significant decreases in types 3, 5, and 6 and virtual disappearance of types 14, 18, 19, and 29 occurred between the 2 study periods. No change in the proportion of type 1 isolates, a highly heterogeneous group that includes some rheumatogenic strains, was observed. The nonrheumatogenic GAS types 2, 4, 22, and 28 increased from 4.9% to approximately 28% of pharyngeal isolates in Chicago and nationwide between the 2 study periods (P < .001). CONCLUSIONS: These data support the concept of rheumatogenic strains of GAS and indicate that the marked decrease in the incidence of acute rheumatic fever in the United States over the past 4 decades is correlated with the replacement of rheumatogenic types by nonrheumatogenic types in cases of acute streptococcal pharyngitis in children. The reasons underlying the observed change in distribution of M types remain to be elucidated.

Acute Disease↗
PubMed2006

Anti-phagocytic mechanisms of Streptococcus pyogenes: binding of fibrinogen to M-related protein.

A key attribute of invasive Streptococcus pyogenes is their ability to resist phagocytosis and multiply in human blood. M-related protein (Mrp) is a major anti-phagocytic factor but the mechanism whereby it helps streptococci to evade phagocytosis has not been demonstrated. We investigated phagocytosis resistance in a strain of serotype M4 by inactivating the mrp gene and also the emm, enn, sof and sfbX genes and by analysing the effect on streptococcal growth in blood and on complement deposition on the bacterial surface. Inactivation of enn4 and sfbX4 had little impact on growth in blood, but ablation of mrp4, emm4 or sof4 reduced streptococcal growth in human blood, confirming that Mrp and Emm are required for optimal resistance to phagocytosis and providing the first indication that Sof may be an anti-phagocytic factor. Moreover, antisera against Mrp4, Emm4 and Sof4 promoted the killing of S. pyogenes, but anti-SfbX serum had no effect. Growth of S. pyogenes in blood was dependent on the presence of fibrinogen and in the absence of fibrinogen there was a twofold increase in complement deposition. Inactivation of mrp4 resulted in a loss of fibrinogen-binding and caused a twofold increase in the binding of C3b that was inhibited by Mg-EGTA. Mrp contained two fibrinogen-binding sites, one of which is within a highly conserved region. These findings indicate that Mrp-fibrinogen interactions prevent surface deposition of complement via the classical pathway, thereby contributing to the ability of these streptococci to resist phagocytosis. This may be a common mechanism for evasion of phagocytosis because Mrp is expressed by approximately half of the clinical isolates of S. pyogenes.

Antigens, Bacterial↗
PubMed2005

Safety and immunogenicity of 26-valent group a streptococcus vaccine in healthy adult volunteers.

BACKGROUND: Group A streptococcus (GAS) causes illness ranging from uncomplicated pharyngitis to life-threatening necrotizing fasciitis, toxic shock, and rheumatic fever. Attempts to develop an M protein-based vaccine have been hindered by the fact that some M proteins elicit both protective antibodies and antibodies that cross-react with human tissues. New molecular techniques have allowed the previous obstacles to be largely overcome. METHODS: The vaccine is comprised of 4 recombinant proteins adsorbed to aluminum hydroxide that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes. Thirty healthy adult subjects received intramuscular 26-valent GAS vaccine (400 microg) at 0, 1, and 4 months, with clinical and laboratory follow-up for safety and immunogenicity using assays for tissue cross-reactive antibodies, type-specific M antibodies to 27 vaccine antigens, and functional (opsonization) activity of M protein antibodies. RESULTS: The incidence of local reactogenicity was similar to that for other aluminum hydroxide-adsorbed vaccines in adults. No subject developed evidence of rheumatogenicity or nephritogenicity, and no induction of human tissue-reactive antibodies was detected. Overall, 26 of 27 antigenic peptides evoked a >4-fold increase in the geometric mean antibody titer over baseline. The mean log2 fold-increase in serum antibody titer (+/- standard error of the mean) for all 27 antigens was 3.67 +/- 0.21. A significant mean log2 reduction in streptococcal bacterial counts in serum samples obtained after immunization was seen in opsonization assays for all M serotypes. CONCLUSIONS: On the basis of epidemiological data demonstrating that the majority of cases of pharyngitis, necrotizing fasciitis, and other invasive streptococcal infections are caused by a limited number of serotypes, this 26-valent vaccine could have significant impact on the overall burden of streptococcal disease.

Adult↗
PubMed2005

Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstacles--report of a National Institute of Allergy and Infectious Diseases workshop.

Infections due to group A streptococci (GAS) represent a public health problem of major proportions in both developing and developed countries. Currently available methods of prevention are either inadequate or ineffective, as attested to by the morbidity and mortality associated with this ubiquitous pathogen worldwide. Advances in molecular biology have shed new light on the pathogenesis of GAS infections and have identified a number of virulence factors as potential vaccine targets. Therefore, the National Institute of Allergy and Infectious Diseases convened an expert workshop in March 2004 to review the available data and to explore the microbiologic, immunologic, epidemiologic, and economic issues involved in development and implementation of a safe and effective GAS vaccine. Participants included scientists and clinicians involved in GAS research, as well as representatives of United States federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, Department of Defense, and National Institute of Allergy and Infectious Diseases), the World Health Organization, and the pharmaceutical industry. This report summarizes the deliberations of the workshop.

Developed Countries↗
PubMed2005

Multivalent group A streptococcal vaccine elicits bactericidal antibodies against variant M subtypes.

Group A streptococci cause a wide spectrum of clinical illness. One of several strategies for vaccine prevention of these infections is based on the type-specific M protein epitopes. A multivalent M protein-based vaccine containing type-specific determinants from 26 different M serotypes is now in clinical trials. Recent epidemiologic studies have shown that, within some serotypes, the amino-terminal M protein sequence may show natural variation, giving rise to subtypes. This raises the possibility that vaccine-induced antibodies against the parent type may not be as effective in promoting bactericidal killing of variant subtypes. In the present study we used rabbit antisera against the 26-valent M protein-based vaccine in bactericidal tests against M1, M3, and M5 streptococci, which were represented by multiple subtypes. We show that the vaccine antibodies effectively promoted in vitro bactericidal activity despite the fact that the M proteins contained naturally occurring variant sequences in the regions corresponding to the vaccine sequence. Our results show that the variant M proteins generally do not result in significant differences in opsonization promoted by rabbit antisera raised against the 26-valent vaccine, suggesting that a multivalent M protein vaccine may not permit variant subtypes of group A streptococci to escape in a highly immunized population.

Amino Acid Sequence↗
PubMed2004

Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial.

CONTEXT: Group A streptococcal infections and their sequelae represent a global health problem. Recent advances have allowed previous obstacles associated with group A streptococcal vaccine development to be overcome. OBJECTIVE: To preliminarily evaluate the safety and immunogenicity of ascending doses of a recombinant fusion peptide group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19, and 24 in healthy volunteers. DESIGN, SETTING, AND PARTICIPANTS: An open-label, uncontrolled, dose-ascending phase 1 vaccine trial of 28 healthy adult volunteers aged 18 to 50 years recruited from the metropolitan area of Baltimore, Md, between October 5, 1999, and February 26, 2003, using newspaper advertisements and posted fliers, and evaluated in the outpatient facility of the Center for Vaccine Development. INTERVENTIONS: Each volunteer received 3 spaced intramuscular injections of 50 microg (n = 8), 100 micro g (n = 10), or 200 microg (n = 10) of hexavalent group A streptococcal vaccine formulated with aluminum hydroxide into the deltoid muscle of alternating arms. MAIN OUTCOME MEASURES: Assessments of clinical safety, including elicitation of antibodies that cross-react with host tissues, and immunogenicity as measured by enzyme-linked immunosorbent assay (ELISA) and assays of opsonophagocytic- and bactericidal-antibody responses. RESULTS: One year of intensive follow-up revealed the vaccine to be well tolerated. There was no evidence of tissue cross-reactive antibodies or immunological complications. At the highest (200 microg) dose, vaccination elicited significant increases in geometric mean antibody levels to all 6 component M antigens by ELISA (all P<.01) and to 5 of 6 M types in the opsonophagocytosis assay (all P<.05). In addition, postvaccination increases in serum bactericidal activity of at least 30% were observed in 31 (55%) of 56 assays. CONCLUSION: These results provide the first evidence in humans that a hybrid fusion protein is a feasible strategy for evoking type-specific opsonic antibodies against multiple serotypes of group A streptococcus without eliciting antibodies that cross-react with host tissues, which represents a critical step in the development of a vaccine.

Adult↗
PubMed2004

Group A streptococcal pharyngitis serotype surveillance in North America, 2000-2002.

Geographic and interseasonal heterogeneity of pharyngeal group A streptococcal (GAS) genotypes (emm types) is poorly characterized. We evaluated emm type and subtype distribution among pediatric pharyngitis isolates obtained from 9 sites in the United States during 2000-2001 (year 1) and from 10 sites in the United States and 1 site in Canada during 2001-2002 (year 2). The 7 predominant types were the same in both years, although their order changed. emm 12, 1, and 28 accounted for 49.2% of year 1 isolates, and emm 1, 12, and 4 accounted for 47.1% of year 2 isolates; 6 types accounted for 72.1% in year 1 and 69.4% in year 2. From year 1 to year 2, the proportions of emm 12 and 28 decreased and emm 1 and 6 increased. Striking intersite and interseasonal variations in the distribution of predominant emm types were observed. We conclude that the most-predominant GAS genotypes were similar for each year despite fluctuations, that intersite and intrasite variations in the distribution of emm types were apparent, and that emm type surveillance is needed as M protein vaccine development proceeds.

Adolescent↗
PubMed2004

Intranasal immunization with multivalent group A streptococcal vaccines protects mice against intranasal challenge infections.

We have previously shown that a hexavalent group A streptococcal M protein-based vaccine evoked bactericidal antibodies after intramuscular injection. In the present study, we show that the hexavalent vaccine formulated with several different mucosal adjuvants and delivered intranasally induced serum and salivary antibodies that protected mice from intranasal challenge infections with virulent group A streptococci. The hexavalent vaccine was formulated with liposomes with or without monophosphorylated lipid A (MPL), cholera toxin B subunit with or without holotoxin, or proteosomes from Neisseria meningitidis outer membrane proteins complexed with lipopolysaccharide from Shigella flexneri. Intranasal immunization with the hexavalent vaccine mixed with these adjuvants resulted in significant levels of antibodies in serum 2 weeks after the final dose. Mean serum antibody titers were equivalent in all groups of mice except those that were immunized with hexavalent protein plus liposomes without MPL, which were significantly lower. Salivary antibodies were also detected in mice that received the vaccine formulated with the four strongest adjuvants. T-cell proliferative assays and cytokine assays using lymphocytes from cervical lymph nodes and spleens from mice immunized with the hexavalent vaccine formulated with proteosomes indicated the presence of hexavalent protein-specific T cells and a Th1-weighted mixed Th1-Th2 cytokine profile. Intranasal immunization with adjuvanted formulations of the hexavalent vaccine resulted in significant levels of protection (80 to 100%) following intranasal challenge infections with type 24 group A streptococci. Our results indicate that intranasal delivery of adjuvanted multivalent M protein vaccines induces protective antibody responses and may provide an alternative to parenteral vaccine formulations.

Adjuvants, Immunologic↗
PubMed2003

Serum opacity factor (SOF) of Streptococcus pyogenes evokes antibodies that opsonize homologous and heterologous SOF-positive serotypes of group A streptococci.

Serum opacity factor (SOF) is a protein expressed by Streptococcus pyogenes that opacifies mammalian serum. SOF is also a virulence factor of S. pyogenes, but it has not been previously shown to elicit a protective immune response. Herein, we report that SOF evokes bactericidal antibodies against S. pyogenes in humans, rabbits, and mice. Rabbit antiserum against purified recombinant SOF2 opsonized SOF-positive M type 2, 4, and 28 S. pyogenes in human blood but had no effect on SOF-negative M type 5 S. pyogenes. Furthermore, affinity-purified human antibodies against SOF2 also opsonized SOF-positive streptococci. A combination of antisera against M2 and SOF2 proteins was dramatically more effective in killing streptococci than either antiserum alone, indicating that antibodies against SOF2 enhance the opsonic efficiency of M protein antibodies. Mice tolerated an intravenous injection of 100 microg of SOF without overt signs of toxicity, and immunization with SOF protected mice against challenge infections with M type 2 S. pyogenes. These data indicate that SOF evokes opsonic antibodies that may protect against infections by SOF-positive serotypes of group A streptococci and suggest that different serotypes of SOF have common epitopes that may be useful vaccine candidates to protect against group A streptococcal infections.

Animals↗
PubMed2002

Mapping the fibrinogen-binding domain of serum opacity factor of group a streptococci.

Serum opacity factor (SOF) is a large, extracellular, and cell-bound protein of group A streptococci that has two known functions, opacification of serum and binding of fibronectin. Herein, we describe a new function of SOF, the binding of fibrinogen. Utilizing purified, truncated recombinant SOF proteins, the fibrinogen-binding domain was localized to a region in the C-terminus of SOF encompassing amino acid residues 844-1047. Western-blot analysis revealed that SOF bound primarily to the beta subunit of fibrinogen. A SOF-negative mutant bound 50% less fibrinogen than did its wild-type parent. Furthermore, fibrinogen blocked the binding of SOF to fibronectin. These data suggest that fibrinogen and fibronectin bind to the same domain within SOF. It remains to be determined whether the binding of fibrinogen to SOF contributes to the virulence of group A streptococci.

Binding Sites↗
PubMed2002

Molecular mechanisms of adhesion, colonization, and invasion of group A streptococci.

The initial step in establishing a bacterial infection is adhesion of the organism to the epithelium of the host. Group A streptococci use multiple adhesins to attach to host cells and the types of adhesins expressed by a particular strain will determine its tissue specificity. Expression of adhesins is regulated in response to changing environmental and growth conditions. Thus, the array of adhesins expressed by a group A streptococcus will depend on the complement of its adhesin genes and on the environment. Expression of some adhesins may trigger internalization of the streptococci by host cells, which may enable the streptococci to evade antibiotics and to facilitate the penetration of deeper tissues. In this review, we present the different molecular mechanisms of adhesion utilized by group A streptococci and how these interactions lead to colonization and invasion.

Adhesins, Bacterial↗
PubMed2002

Antibodies against a synthetic peptide of SagA neutralize the cytolytic activity of streptolysin S from group A streptococci.

Virtually all group A streptococci (GAS) produce streptolysin S (SLS), a cytolytic toxin that is responsible for the beta-hemolysis surrounding colonies of the organisms grown on blood agar. SLS is an important virulence determinant of GAS, and recent studies have identified a nine-gene locus that is responsible for synthesis and transport of the toxin. SLS is not immunogenic; thus, no neutralizing antibodies are evoked during the course of natural infection. In the present study, we show that a synthetic peptide containing amino acid residues 10 to 30 of the putative SLS (SagA) propeptide [SLS(10-30)] coupled to keyhole limpet hemocyanin evoked antibodies in rabbits that completely neutralized the hemolytic activity of the toxin in vitro. Inhibition of hemolysis was reversed by preincubation of the immune serum with soluble, unconjugated peptide, indicating the specificity of the antibodies. In addition, antibodies that were affinity purified over an SLS(10-30) peptide column completely inhibited SLS-mediated hemolysis. The SLS(10-30) antisera did not opsonize group A streptococci; however, when combined with type-specific M protein antisera, the SLS antibodies significantly enhanced phagocytosis mediated by M protein antibodies. Thus, we have shown for the first time that it is possible to raise neutralizing antibodies against one of the most potent bacterial cytolytic toxins known. Our data also provide convincing evidence that the sagA gene actually encodes the SLS peptide of GAS. The synthetic peptide may prove to be an important component of vaccines designed to prevent GAS infections.

Amino Acid Sequence↗
PubMed2002

Immunogenicity of a 26-valent group A streptococcal vaccine.

A multivalent vaccine containing amino-terminal M protein fragments from 26 different serotypes of group A streptococci was constructed by recombinant techniques. The vaccine consisted of four different recombinant proteins that were formulated with alum to contain 400 microg of protein per dose. Rabbits were immunized via the intramuscular route at 0, 4, and 16 weeks. Immune sera were assayed for the presence of type-specific antibodies against the individual recombinant M peptides by enzyme-linked immunosorbent assay and for opsonic antibodies by in vitro opsonization tests and indirect bactericidal tests. The 26-valent vaccine was highly immunogenic and elicited fourfold or greater increases in antibody levels against 25 of the 26 serotypes represented in the vaccine. The immune sera were broadly opsonic and were bactericidal against the majority of the 26 different serotypes. Importantly, none of the immune sera cross-reacted with human tissues. Our results indicate that type-specific, protective M protein epitopes can be incorporated into complex, multivalent vaccines designed to elicit broadly protective opsonic antibodies in the absence of tissue-cross-reactive antibodies.

Animals↗