Publications by authors named "James B Dale"

63 Publications

Utility of Human Immune Responses to GAS Antigens as a Diagnostic Indicator for ARF: A Systematic Review.

Front Cardiovasc Med 2021 20;8:691646. Epub 2021 Jul 20.

Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Previous studies have established that streptococcal antibody titer is correlated with a diagnosis of acute rheumatic fever (ARF). However, results vary in the usefulness of GAS antibodies, particularly anti-streptolysin-O (ASO) and anti-DNase B, in confirming a recent GAS infection. Therefore, we sought to provide, from published studies, an evidence-based synthesis of the correlation of streptococcal serology to establish the usefulness of immunological data in aiding the diagnosis of ARF. These findings are anticipated to have implications where echocardiography is not freely available, especially where ARF is rampant. We conducted a comprehensive search across a number of databases. Applying a priori criteria, we selected articles reporting on studies, regardless of study design, that evaluate the levels of antibodies against GAS-specific antigens in ARF subjects against control values or a published standard. Data were extracted onto data extraction forms, captured electronically, and analyzed using Stata software. Risk of bias was assessed in included studies using the Newcastle-Ottawa Scale (NOS). The search strategy yielded 534 studies, from which 24 met the inclusion criteria, reporting on evaluation of titers for SLO ( = 10), DNase B ( = 9), anti-streptokinase (ASK) ( = 3) amongst others. Elevation in titers was determined by comparison with controls and upper limit of normal (ULN) antibody values as determined in healthy individuals. Meta-analysis of case-controlled studies revealed moderate odds ratio (OR) correlations between ARF diagnosis and elevated titers for SLO (OR = 10.57; 95% CI, 3.36-33.29; 10 studies) and DNAse B (OR = 6.97; 95% CI, 2.99-16.27; 7 studies). While providing support for incorporating SLO and DNase B in the diagnosis of ARF, we present the following reflections: an elevation in SLO and DNase B levels are not consistently associated with an ARF diagnosis; increasing the number of GAS proteins in the test is warranted to improve sensitivity; paired (acute and convalescent) samples could provide a more accurate indication of a rising titer. Use of community-based controls as a standard is not a reliable marker by which to gauge recent GAS infection.
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http://dx.doi.org/10.3389/fcvm.2021.691646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329041PMC
July 2021

Design of Broadly Cross-Reactive M Protein-Based Group A Streptococcal Vaccines.

J Immunol 2021 08 2;207(4):1138-1149. Epub 2021 Aug 2.

Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN;

Group A streptococcal infections are a significant cause of global morbidity and mortality. A leading vaccine candidate is the surface M protein, a major virulence determinant and protective Ag. One obstacle to the development of M protein-based vaccines is the >200 different M types defined by the N-terminal sequences that contain protective epitopes. Despite sequence variability, M proteins share coiled-coil structural motifs that bind host proteins required for virulence. In this study, we exploit this potential Achilles heel of conserved structure to predict cross-reactive M peptides that could serve as broadly protective vaccine Ags. Combining sequences with structural predictions, six heterologous M peptides in a sequence-related cluster were predicted to elicit cross-reactive Abs with the remaining five nonvaccine M types in the cluster. The six-valent vaccine elicited Abs in rabbits that reacted with all 11 M peptides in the cluster and functional opsonic Abs against vaccine and nonvaccine M types in the cluster. We next immunized mice with four sequence-unrelated M peptides predicted to contain different coiled-coil propensities and tested the antisera for cross-reactivity against 41 heterologous M peptides. Based on these results, we developed an improved algorithm to select cross-reactive peptide pairs using additional parameters of coiled-coil length and propensity. The revised algorithm accurately predicted cross-reactive Ab binding, improving the Matthews correlation coefficient from 0.42 to 0.74. These results form the basis for selecting the minimum number of N-terminal M peptides to include in potentially broadly efficacious multivalent vaccines that could impact the overall global burden of group A streptococcal diseases.
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http://dx.doi.org/10.4049/jimmunol.2100286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355175PMC
August 2021

Cross-reactive immunogenicity of group A streptococcal vaccines designed using a recurrent neural network to identify conserved M protein linear epitopes.

Vaccine 2021 03 26;39(12):1773-1779. Epub 2021 Feb 26.

Department of Biological Sciences, The University of Alabama in Huntsville, Huntsville, AL 35899, United States. Electronic address:

The M protein of group A streptococci (Strep A) is a major virulence determinant and protective antigen. The N-terminal sequence of the protein defines the more than 200 M types of Strep A and also contains epitopes that elicit opsonic antibodies, some of which cross-react with heterologous M types. Current efforts to develop broadly protective M protein-based vaccines are directed at identifying potential cross-protective epitopes located in the N-terminal regions of cluster-related M proteins for use as vaccine antigens. In this study, we have used a comprehensive approach using the recurrent neural network ABCpred and IEDB epitope conservancy analysis tools to predict 16 residue linear B-cell epitopes from 117 clinically relevant M types of Strep A (~88% of global Strep A infections). To examine the immunogenicity of these epitope-based vaccines, nine peptides that together shared ≥60% sequence identity with 37 heterologous M proteins were incorporated into two recombinant hybrid protein vaccines, in which the epitopes were repeated 2 or 3 times, respectively. The combined immune responses of immunized rabbits showed that the vaccines elicited significant levels of antibodies against all nine vaccine epitopes present in homologous N-terminal 1-50 amino acid synthetic M peptides, as well as cross-reactive antibodies against 16 of 37 heterologous M peptides predicted to contain similar epitopes. The epitope-specificity of the cross-reactive antibodies was confirmed by ELISA inhibition assays and functional opsonic activity was assayed in HL-60-based bactericidal assays. The results provide important information for the future design of broadly protective M protein-based Strep A vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045747PMC
March 2021

Systematic Review and Meta-analysis of the Prevalence of Group A Streptococcal Clusters in Africa To Inform Vaccine Development.

mSphere 2020 07 15;5(4). Epub 2020 Jul 15.

AFROStrep Research Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town & Groote Schuur Hospital, Cape Town, South Africa

An -cluster based system was proposed as a standard typing scheme to facilitate and enhance future studies of group A (GAS) epidemiological surveillance, M protein function, and vaccine development strategies. We provide an evidence-based distribution of GAS clusters in Africa and assess the potential coverage of the new 30-valent vaccine in terms of an cluster-based approach. Two reviewers independently assessed studies retrieved from a comprehensive search and extracted relevant data. Meta-analyses were performed (random-effects model) to aggregate cluster prevalence estimates. Eight studies ( = 1,595 isolates) revealed the predominant clusters as E6 (18%; 95% confidence interval [CI], 12.6% to 24.0%), followed by E3 (14%; 95% CI, 11.2% to 17.4%) and E4 (13%; 95% CI, 9.5% to 16.0%). There was negligible variation in clusters with regard to regions, age, and socioeconomic status across the continent. Considering an cluster-based vaccine strategy, which assumes cross-protection within clusters, the 30-valent vaccine currently in clinical development would provide hypothetical coverage to 80.3% of isolates in Africa. This systematic review indicates the most predominant GAS cluster in Africa is E6 followed by E3, E4, and D4. The current 30-valent vaccine would provide considerable coverage across the diversity of cluster types in Africa. Future efforts could be directed toward estimating the overall potential coverage of the new 30-valent vaccine based on cross-opsonization studies with representative panels of GAS isolates from populations at highest risk for GAS diseases. Low vaccine coverage is of grave public health concern, particularly in developing countries where epidemiological data are often absent. To inform vaccine development for group A (GAS), we report on the epidemiology of the M protein clusters from GAS infections in Africa, where GAS-related illnesses and their sequelae, including rheumatic fever and rheumatic heart disease, are of a high burden. This first report of clusters across the continent indicates a high probably of coverage by the M protein-based vaccine currently undergoing testing were an -cluster based approach to be used.
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http://dx.doi.org/10.1128/mSphere.00429-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364215PMC
July 2020

Immunotherapy targeting the Streptococcus pyogenes M protein or streptolysin O to treat or prevent influenza A superinfection.

PLoS One 2020 23;15(6):e0235139. Epub 2020 Jun 23.

Division of Basic Biomedical Sciences, The Sanford School of Medicine of the University of South Dakota, Vermillion, SD, United States of America.

Viral infections complicated by a bacterial infection are typically referred to as coinfections or superinfections. Streptococcus pyogenes, the group A streptococcus (GAS), is not the most common bacteria associated with influenza A virus (IAV) superinfections but did cause significant mortality during the 2009 influenza pandemic even though all isolates are susceptible to penicillin. One approach to improve the outcome of these infections is to use passive immunization targeting GAS. To test this idea, we assessed the efficacy of passive immunotherapy using antisera against either the streptococcal M protein or streptolysin O (SLO) in a murine model of IAV-GAS superinfection. Prophylactic treatment of mice with antiserum to either SLO or the M protein decreased morbidity compared to mice treated with non-immune sera; however, neither significantly decreased mortality. Therapeutic use of antisera to SLO decreased morbidity compared to mice treated with non-immune sera but neither antisera significantly reduced mortality. Overall, the results suggest that further development of antibodies targeting the M protein or SLO may be a useful adjunct in the treatment of invasive GAS diseases, including IAV-GAS superinfections, which may be particularly important during influenza pandemics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235139PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310742PMC
September 2020

Update on group A streptococcal vaccine development.

Curr Opin Infect Dis 2020 06;33(3):244-250

Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD, Australia.

Purpose Of Review: There is a global need for well tolerated, effective, and affordable vaccines to prevent group A streptococcal infections and their most serious complications. The aim of this review is to highlight the recent progress in the identification of promising vaccine antigens and new approaches to vaccine design that address the complexities of group A streptococcal pathogenesis and epidemiology.

Recent Findings: Combination vaccines containing multiple shared, cross-protective antigens have proven efficacious in mouse and nonhuman primate models of infection. The development of complex multivalent M protein-based vaccines is continuing and several have progressed through early-stage human clinical trials. Formulations of vaccines containing universal T-cell epitopes, toll-like receptor agonists, and other adjuvants more potent than alum have been shown to enhance protective immunogenicity. Although the group A streptococcal vaccine antigen landscape is populated with a number of potential candidates, the clinical development of vaccines has been impeded by a number of factors. There are now concerted global efforts to raise awareness about the need for group A streptococcal vaccines and to support progress toward eventual commercialization and licensure.

Summary: Preclinical antigen discovery, vaccine formulation, and efficacy studies in animal models have progressed significantly in recent years. There is now a need to move promising candidates through the clinical development pathway to establish their efficacy in preventing group A streptococcal infections and their complications.
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http://dx.doi.org/10.1097/QCO.0000000000000644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326309PMC
June 2020

Structure-based group A streptococcal vaccine design: Helical wheel homology predicts antibody cross-reactivity among streptococcal M protein-derived peptides.

J Biol Chem 2020 03 6;295(12):3826-3836. Epub 2020 Feb 6.

Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United States.

Group A streptococcus (Strep A) surface M protein, an α-helical coiled-coil dimer, is a vaccine target and a major determinant of streptococcal virulence. The sequence-variable N-terminal region of the M protein defines the M type and also contains epitopes that promote opsonophagocytic killing of streptococci. Recent reports have reported considerable cross-reactivity among different M types, suggesting the prospect of identifying cross-protective epitopes that would constitute a broadly protective multivalent vaccine against Strep A isolates. Here, we have used a combination of immunological assays, structural biology, and cheminformatics to construct a recombinant M protein-based vaccine that included six Strep A M peptides that were predicted to elicit antisera that would cross-react with an additional 15 nonvaccine M types of Strep A. Rabbit antisera against this recombinant vaccine cross-reacted with 10 of the 15 nonvaccine M peptides. Two of the five nonvaccine M peptides that did not cross-react shared high sequence identity (≥50%) with the vaccine peptides, implying that high sequence identity alone was insufficient for cross-reactivity among the M peptides. Additional structural analyses revealed that the sequence identity at corresponding polar helical-wheel heptad sites between vaccine and nonvaccine peptides accurately distinguishes cross-reactive from non-cross-reactive peptides. On the basis of these observations, we developed a scoring algorithm based on the sequence identity at polar heptad sites. When applied to all epidemiologically important M types, this algorithm should enable the selection of a minimal number of M peptide-based vaccine candidates that elicit broadly protective immunity against Strep A.
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http://dx.doi.org/10.1074/jbc.RA119.011258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086045PMC
March 2020

Prevalence of group A β-hemolytic streptococcal throat carriage and prospective pilot surveillance of streptococcal sore throat in Ugandan school children.

Int J Infect Dis 2020 Apr 20;93:245-251. Epub 2020 Jan 20.

Cincinnati Children's Hospital Medical Center, Cincinnati Ohio, USA.

Objectives: Group A β-hemolytic Streptococcus (GAS), also known as Streptococcus pyogenes, is responsible for an annual 600 million cases of acute pharyngitis globally, with 92% of those infections occurring in low-resource settings. Further knowledge of the acute streptococcal pharyngitis burden in low-resource settings is essential if serious post-streptococcal complications - rheumatic fever (RF) and its long-term sequel rheumatic heart disease (RHD) - are to be prevented.

Methods: Two studies were conducted in school-aged children (5-16 years): a cross-sectional study of streptococcal pharyngeal carriage followed by a prospective cohort study of streptococcal sore throat over 4 weeks from March to April 2017.

Results: The cross-sectional study revealed an overall prevalence of GAS carriage of 15.9% (79/496, 95% confidence interval 12.8-19.5%). Among 532 children enrolled in the prospective cohort study, 358 (67%) reported 528 sore throats, with 221 (41.1%) experiencing at least one GAS-positive sore throat. The overall GAS-positive rate for sore throat was 41.8% (221/528).

Conclusions: The GAS pharyngeal carriage rates seen in Uganda (15.9%, 95% confidence interval 12.8-19.5%) are higher than the most recent pooled results globally, at 12% (range 6-28%). Additionally, pilot data suggest a substantially higher percentage of sore throat that was GAS-positive (41.8%) compared to pooled global rates when active recruitment is employed.
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http://dx.doi.org/10.1016/j.ijid.2020.01.013DOI Listing
April 2020

Safety and immunogenicity of a 30-valent M protein-based group a streptococcal vaccine in healthy adult volunteers: A randomized, controlled phase I study.

Vaccine 2020 02 13;38(6):1384-1392. Epub 2019 Dec 13.

Division of Infectious Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

Background: Streptococcus pyogenes (group A Streptococcus, Strep A) is a widespread pathogen that continues to pose a significant threat to human health. The development of a Strep A vaccine remains an unmet global health need. One of the major vaccine strategies is the use of M protein, which is a primary virulence determinant and protective antigen. Multivalent recombinant M protein vaccines are being developed with N-terminal M peptides that contain opsonic epitopes but do not contain human tissue cross-reactive epitopes.

Methods: We completed a Phase I trial of a recombinant 30-valent M protein-based Strep A vaccine (Strep A vaccine, StreptAnova™) comprised of four recombinant proteins containing N-terminal peptides from 30 M proteins of common pharyngitis and invasive and/or rheumatogenic serotypes, adjuvanted with aluminum hydroxide. The trial was observer-blinded and randomized in a 2:1 ratio for intramuscular administration of Strep A vaccine or an alum-based comparator in healthy adult volunteers, at 0, 30 and 180 days. Primary outcome measures were assessments of safety, including assays for antibodies that cross-reacted with host tissues, and immunogenicity assessed by ELISA with the individual vaccine peptides and by opsonophagocytic killing (OPK) assays in human blood.

Results: Twenty-three Strep A-vaccinated participants and 13 controls completed the study. The Strep A vaccine was well-tolerated and there was no clinical evidence of autoimmunity and no laboratory evidence of tissue cross-reactive antibodies. The vaccine was immunogenic and elicited significant increases in geometric mean antibody levels to 24 of the 30 component M antigens by ELISA. Vaccine-induced OPK activity was observed against selected M types of Strep A in vaccinated participants that seroconverted to specific M peptides.

Conclusion: The Strep A vaccine was well tolerated and immunogenic in healthy adults, providing strong support for further clinical development. [ClinicalTrials.gov NCT02564237].
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http://dx.doi.org/10.1016/j.vaccine.2019.12.005DOI Listing
February 2020

Controlled human infection for vaccination against Streptococcus pyogenes (CHIVAS): Establishing a group A Streptococcus pharyngitis human infection study.

Vaccine 2019 06 14;37(26):3485-3494. Epub 2019 May 14.

Tropical Diseases, Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia; Infectious Diseases Unit, Department of General Medicine, The Royal Children's Hospital Melbourne, Victoria, Australia.

Group A Streptococcus (GAS) is a highly-adapted and human-restricted pathogen responsible for a high global burden of disease across a diverse clinical spectrum. Vaccine development has been impeded by scientific, regulatory, and commercial obstacles. Human infection studies (HIS) are increasingly contributing to drug, diagnostics, and vaccine development, reducing uncertainty at early stages, especially for pathogens with animal models that incompletely reproduce key elements of human disease. We review the small number of historical GAS HIS and present the study protocol for a dose-ranging inpatient study in healthy adults. The primary objective of the study is to establish a new GAS pharyngitis HIS with an attack rate of at least 60% as a safe and reliable platform for vaccine evaluation and pathogenesis research. According to an adaptive dose-ranging study design, emm75 GAS doses manufactured in keeping with principles of Good Manufacturing Practice will be directly applied by swab to the pharynx of carefully screened healthy adult volunteers at low risk of severe complicated GAS disease. Participants will remain as closely monitored inpatients for up to six days, observed for development of the primary outcome of acute symptomatic pharyngitis, as defined by clinical and microbiological criteria. All participants will be treated with antibiotics and followed as outpatients for six months. An intensive sampling schedule will facilitate extensive studies of host and organism dynamics during experimental pharyngitis. Ethics approval has been obtained and the study has been registered at ClinicalTrials.gov (NCT03361163).
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http://dx.doi.org/10.1016/j.vaccine.2019.03.059DOI Listing
June 2019

Development of an Opsonophagocytic Killing Assay Using HL-60 Cells for Detection of Functional Antibodies against .

mSphere 2018 12 19;3(6). Epub 2018 Dec 19.

Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA

The clinical development of group A streptococcal (GAS) vaccines will require the implementation of a standardized, high-throughput assay to measure the activity of functional opsonic antibodies in vaccine recipients. In the present study, we adapted and modified the HL-60-based protocol that was developed for the detection of opsonic antibodies against for use with multiple M types of GAS. Modifications of the assay conditions permitted the evaluation of 21 different M types of GAS in the assay. The specificity of the antibody-mediated opsonization was demonstrated by inhibition with homologous, but not heterologous, M proteins. Maximum rates of opsonophagocytic killing (OPK) of 14 different M types promoted by rabbit antiserum against the 30-valent M protein-based vaccine were comparable in whole-blood and HL-60 assays. Data are also presented showing OPK serum titers (opsonic index) of naturally acquired human antibodies present in IVIG [intravenous immune globulin (human)]. Results of the HL-60 assay performed on different days using 21 different M types of GAS and IVIG as the antibody source were significantly concordant. This report indicates that the OPK assay conditions may be optimized for the measurement of opsonic antibodies against a number of epidemiologically important M types of GAS and, once standardized, should facilitate the clinical development of effective vaccines to prevent these infections. Measuring functional opsonic antibodies against group A streptococci is an important component of the clinical development path for effective vaccines. Prior studies have used an assay developed over 60 years ago that relied on whole human blood as the source of phagocytes and complement, both of which are critical components of antibody-mediated killing assays. In this study, we adapted an assay that uses the HL-60 human promyelocytic leukemia cell line as phagocytic cells and baby rabbit serum as a source of complement for detection of opsonic antibodies against group A streptococci. On the basis of some of the known biological characteristics of the bacteria, we modified the assay conditions to support the evaluation of 21 epidemiologically important M types and demonstrated the utility and reproducibility of the assay for measurement of functional opsonic antibody levels.
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http://dx.doi.org/10.1128/mSphere.00617-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300688PMC
December 2018

Clinical and microbiological response of mice to intranasal inoculation with Lactococcus lactis expressing Group A Streptococcus antigens, to be used as an anti-streptococcal vaccine.

Microbiol Immunol 2018 Nov;62(11):711-719

Laboratory of Microbiology, Department of Clinical Laboratories, School of Medicine, Pontifical Catholic University of Chile, Santiago 8331010, Chile.

Protein subunit vaccines are often preferred because of their protective efficacy and safety. Lactic acid bacteria expressing heterologous antigens constitute a promising approach to vaccine development. However, their safety in terms of toxicity and bacterial clearance must be evaluated. Anti-Streptococcus pyogenes (S. pyogenes) vaccines face additional safety concerns because they may elicit autoimmune responses. The assessment of toxicity, clearance and autoimmunity of an anti-streptococcal vaccine based on Lactococcus lactis (L. lactis) expressing 10 different M protein fragments from S. pyogenes (L. lactis-Mx10) is here reported. Clearance of L. lactis from the oropharynges of immunocompetent mice and mice devoid of T/B lymphocytes mice was achieved without using antibiotics. The absence of autoimmune responses against human tissues was demonstrated with human brain, heart and kidney. Assessment of toxicity showed that leucocyte counts and selected serum biochemical factors were not affected in L. lactis-Mx10-immunized mice. In contrast, mice immunized with L. lactis wild type vector (L. lactis-WT) showed increased neutrophil and monocyte counts and altered histopathology of lymph nodes, lungs and nasal epithelium. Two days after immunization, L. lactis-Mx10-immunized and L. lactis-WT-immunized mice weighed significantly less than unimmunized mice. However, both groups of immunized mice recovered their body weights by Day 6. Our results demonstrate that L. lactis-WT, but not the vaccine L. lactis-Mx10, induces alterations in certain hematologic and histopathological variables. We consider these data a major contribution to data on L. lactis as a bacterial vector for vaccine delivery.
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http://dx.doi.org/10.1111/1348-0421.12657DOI Listing
November 2018

Caution Indicated in Extrapolating Carditis in Rats to Rheumatic Heart Disease in Humans.

J Infect Dis 2019 01;219(4):674-675

Ann and Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, Illinois.

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http://dx.doi.org/10.1093/infdis/jiy560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941615PMC
January 2019

Group A Streptococcal Virulence: New Lessons.

J Pediatric Infect Dis Soc 2019 May;8(2):160-161

University of Tennessee Health Science Center, Memphis.

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http://dx.doi.org/10.1093/jpids/piy059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317147PMC
May 2019

Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection.

Cell 2018 05 10;173(5):1083-1097.e22. Epub 2018 May 10.

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The nervous system, the immune system, and microbial pathogens interact closely at barrier tissues. Here, we find that a bacterial pathogen, Streptococcus pyogenes, hijacks pain and neuronal regulation of the immune response to promote bacterial survival. Necrotizing fasciitis is a life-threatening soft tissue infection in which "pain is out of proportion" to early physical manifestations. We find that S. pyogenes, the leading cause of necrotizing fasciitis, secretes streptolysin S (SLS) to directly activate nociceptor neurons and produce pain during infection. Nociceptors, in turn, release the neuropeptide calcitonin gene-related peptide (CGRP) into infected tissues, which inhibits the recruitment of neutrophils and opsonophagocytic killing of S. pyogenes. Botulinum neurotoxin A and CGRP antagonism block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection. We conclude that targeting the peripheral nervous system and blocking neuro-immune communication is a promising strategy to treat highly invasive bacterial infections. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959783PMC
May 2018

Protective immunity induced by an intranasal multivalent vaccine comprising 10 Lactococcus lactis strains expressing highly prevalent M-protein antigens derived from Group A Streptococcus.

Microbiol Immunol 2018 Jun 11;62(6):395-404. Epub 2018 Jun 11.

Millennium Institute of Immunology and Immunotherapy, Department of Molecular Genetics and Microbiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.

Streptococcus pyogenes (group A Streptococcus) causes diseases ranging from mild pharyngitis to severe invasive infections. The N-terminal fragment of streptococcal M protein elicits protective antibodies and is an attractive vaccine target. However, this N- terminal fragment is hypervariable: there are more than 200 different M types. In this study, an intranasal live bacterial vaccine comprising 10 strains of Lactococcus lactis, each expressing one N-terminal fragment of M protein, has been developed. Live bacterial-vectored vaccines cost less to manufacture because the processes involved are less complex than those required for production of protein subunit vaccines. Moreover, intranasal administration does not require syringes or specialized personnel. Evaluation of individual vaccine types (M1, M2, M3, M4, M6, M9, M12, M22, M28 and M77) showed that most of them protected mice against challenge with virulent S. pyogenes. All 10 strains combined in a 10-valent vaccine (M×10) induced serum and bronchoalveolar lavage IgG titers that ranged from three- to 10-fold those of unimmunized mice. After intranasal challenge with M28 streptococci, survival of M×10-immunized mice was significantly higher than that of unimmunized mice. In contrast, when mice were challenged with M75 streptococci, survival of M×10-immunized mice did not differ significantly from that of unimmunized mice. Mx-10 immunized mice had significantly less S. pyogenes in oropharyngeal washes and developed less severe disease symptoms after challenge than did unimmunized mice. Our L. lactis-based vaccine may provide an alternative solution to development of broadly protective group A streptococcal vaccines.
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http://dx.doi.org/10.1111/1348-0421.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013395PMC
June 2018

Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity.

Clin Infect Dis 2017 Oct;65(9):1523-1531

Group A Streptococcus Research Group, Murdoch Childrens Research Institute, Melbourne, Australia.

Background: Group A Streptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into >220 different emm types, is immunogenic and elicits protective antibodies. A major obstacle for vaccine development has been the traditional understanding that immunity following infection is restricted to a single emm type. However, recent evidence has led to the hypothesis of immune cross-reactivity between emm types.

Methods: We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 major emm clusters (E4, E6, and D4). Pre- and postinfection sera were assayed by enzyme-linked immunosorbent assay with N-terminal M peptides and bactericidal assays using the infecting-type strain, emm cluster-related strains, and nonrelated strains.

Results: Twenty of the 53 paired sera demonstrated a ≥4-fold increase in antibody titer against the infecting type. When tested against all cluster-related M peptides, we found that 9 of 17 (53%) paired sera had a ≥4-fold increase in antibody titer to cluster-related strains as well. When grouped by cluster, the mean change to cluster-related emm types in E4 and E6 was >4-fold (5.9-fold and 19.5-fold, respectively) but for D4 was 3.8-fold. The 17 paired sera were tested in bactericidal assays against selected cluster-related and nonrelated strains. While the responses were highly variable, numerous instances of cross-reactive killing were observed.

Conclusions: These data demonstrate that M type-specific and cross-reactive immune responses occur following skin infection. The cross-reactive immune responses frequently align with emm clusters, raising new opportunities to design multivalent vaccines with broad coverage.
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http://dx.doi.org/10.1093/cid/cix599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263703PMC
October 2017

Prospective Longitudinal Analysis of Immune Responses in Pediatric Subjects After Pharyngeal Acquisition of Group A Streptococci.

J Pediatric Infect Dis Soc 2017 Jun;6(2):187-196

University of Tennessee Health Science Center and Department of Veterans Affairs Research Service, Memphis, Tennessee.

Background.: Despite the significant burden of disease associated with infection by group A streptococcus (GAS), little is known about the human immune response to GAS antigens after natural infection.

Methods.: We evaluated 195 serum samples obtained prospectively over a consecutive 24-month period from 41 pediatric subjects who experienced a new pharyngeal GAS acquisition. An enzyme-linked immunoassay was used to determine the kinetics and antigen specificity of antibodies against 13 shared GAS antigens and 18 type-specific M peptides. The majority of the antigens tested are currently being considered as vaccine candidates.

Results.: Twelve M types of GAS were recovered from 41 subjects who experienced 51 new GAS acquisitions that elicited antibody responses against at least 1 of the 31 antigens tested (immunologically significant new GAS acquisitions). The immune responses to the 13 shared antigens were highly variable. Increases in antibody levels were detected against a mean of 3.5 shared antigens (range, 1-8). Antibody responses to the homologous M peptide were observed in 32 (63%) of the 51 episodes. Seven subjects acquired more than 1 M type of GAS. There were no new immunologically significant acquisitions of an M type against which the subject had preexisting antibodies to the homologous M peptide. Of the subjects with new GAS acquisition, 65% were asymptomatic, yet immune responses were detected against 1 or more GAS antigens. Immune responses to streptolysin O and/or deoxyribonuclease B were observed after 67% of the new GAS acquisitions. Persistently positive (>12 weeks) throat culture results were returned for 20% of the 41 subjects despite immune responses to homologous M peptides and/or shared antigens.

Conclusions.: The availability of throat culture results, GAS isolates, and serial serum samples collected prospectively over a 2-year period of observation provided a unique opportunity for us to assess the serologic status of pediatric subjects before and after new pharyngeal acquisitions of GAS. With the exception of antibody responses to the homologous M peptides, no clear pattern of immune responses against the remaining GAS antigens was seen. There were no new immunologically significant acquisitions of emm types of GAS against which the subjects had preexisting elevated levels of antibodies against the homologous M peptide. The observation that 65% of new GAS acquisitions caused no symptoms yet were immunologically significant suggests that the majority of infections are not detected, which would result in missed opportunities for primary prevention of rheumatic fever and rheumatic heart disease with appropriate antimicrobial therapy.
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http://dx.doi.org/10.1093/jpids/piw070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207265PMC
June 2017

Trivalent M-related protein as a component of next generation group A streptococcal vaccines.

Clin Exp Vaccine Res 2017 Jan 25;6(1):45-49. Epub 2017 Jan 25.

Department of Medicine, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, USA.; Department of Medicine, Veterans Affairs Medical Center, Memphis, TN, USA.; Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, USA.

Purpose: There is a need to broaden protective coverage of M protein-based vaccines against group A streptococci (GAS) because coverage of the current 30-valent M protein vaccine does not extend to all types. An additional GAS antigen and virulence factor that could potentially extend vaccine coverage is M-related protein (Mrp). Previous work indicated that there are three structurally related families of Mrp (MrpI, MrpII, and MrpIII) and peptides of all three elicited bactericidal antibodies against multiple types. The purpose of this study was to determine if a recombinant form containing Mrp from the three families would evoke bactericidal antiserum and to determine if this antiserum could enhance the effectiveness of antisera to the 30-valent M protein vaccine.

Materials And Methods: A trivalent recombinant Mrp (trMrp) protein containing N-terminal fragments from the three families (trMrp) was constructed, purified and used to immunize rabbits. Anti-trMrp sera contained high titers of antibodies against the trMrp immunogen and recombinant forms representing MrpI, MrpII, and MrpIII.

Results: The antisera opsonized types of GAS representing each Mrp family and also opsonized types not covered by the 30-valent M protein-based vaccine. Importantly, a combination of trMrp and 30-valent M protein antiserum resulted in higher levels of opsonization of GAS than either antiserum alone.

Conclusion: These findings suggest that trMrp may be an effective addition to future constructs of GAS vaccines.
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http://dx.doi.org/10.7774/cevr.2017.6.1.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292357PMC
January 2017

Structure-based design of broadly protective group a streptococcal M protein-based vaccines.

Vaccine 2017 01 24;35(1):19-26. Epub 2016 Nov 24.

Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Oak Ridge, TN, United States; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics, Oak Ridge, TN, United States.

Background: A major obstacle to the development of broadly protective M protein-based group A streptococcal (GAS) vaccines is the variability within the N-terminal epitopes that evoke potent bactericidal antibodies. The concept of M type-specific protective immune responses has recently been challenged based on the observation that multivalent M protein vaccines elicited cross-reactive bactericidal antibodies against a number of non-vaccine M types of GAS. Additionally, a new "cluster-based" typing system of 175M proteins identified a limited number of clusters containing closely related M proteins. In the current study, we used the emm cluster typing system, in combination with computational structure-based peptide modeling, as a novel approach to the design of potentially broadly protective M protein-based vaccines.

Methods: M protein sequences (AA 16-50) from the E4 cluster containing 17 emm types of GAS were analyzed using de novo 3-D structure prediction tools and the resulting structures subjected to chemical diversity analysis to identify sequences that were the most representative of the 3-D physicochemical properties of the M peptides in the cluster. Five peptides that spanned the range of physicochemical attributes of all 17 peptides were used to formulate synthetic and recombinant vaccines. Rabbit antisera were assayed for antibodies that cross-reacted with E4 peptides and whole bacteria by ELISA and for bactericidal activity against all E4GAS.

Results: The synthetic vaccine rabbit antisera reacted with all 17 E4M peptides and demonstrated bactericidal activity against 15/17 E4GAS. A recombinant hybrid vaccine containing the same E4 peptides also elicited antibodies that cross-reacted with all E4M peptides.

Conclusions: Comprehensive studies using structure-based design may result in a broadly protective M peptide vaccine that will elicit cluster-specific and emm type-specific antibody responses against the majority of clinically relevant emm types of GAS.
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http://dx.doi.org/10.1016/j.vaccine.2016.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143202PMC
January 2017

The Cape Town Clinical Decision Rule for Streptococcal Pharyngitis in Children.

Pediatr Infect Dis J 2017 03;36(3):250-255

From the *Department of Medicine, Groote Schuur Hospital and University of Cape Town; and †Division of Clinical Pharmacology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa; ‡Division of Medical Microbiology, Department of Pathology, Faculty of Medicine & Health Sciences, Stellenbosch University & NHLS Tygerberg, Tygerberg, South Africa; §College of Public Health & Health Informatics, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; and ¶Division of Infectious Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.

Background: Existing clinical decision rules (CDRs) to diagnose group A streptococcal (GAS) pharyngitis have not been validated in sub-Saharan Africa. We developed a locally applicable CDR while evaluating existing CDRs for diagnosing GAS pharyngitis in South African children.

Methods: We conducted a prospective cohort study and enrolled 997 children 3-15 years of age presenting to primary care clinics with a complaint of sore throat, and whose parents provided consent. Main outcome measures were signs and symptoms of pharyngitis and a positive GAS culture from a throat swab. Bivariate and multivariate analyses were used to develop the CDR. In addition, the diagnostic effectiveness of 6 existing rules for predicting a positive culture in our cohort was assessed.

Results: A total of 206 of 982 children (21%) had a positive GAS culture. Tonsillar swelling, tonsillar exudates, tender or enlarged anterior cervical lymph nodes, absence of cough and absence of rhinorrhea were associated with positive cultures in bivariate and multivariate analyses. Four variables (tonsillar swelling and one of tonsillar exudate, no rhinorrhea, no cough), when used in a cumulative score, showed 83.7% sensitivity and 32.2% specificity for GAS pharyngitis. Of existing rules tested, the rule by McIsaac et al had the highest positive predictive value (28%), but missed 49% of the culture-positive children who should have been treated.

Conclusion: The new 4-variable CDR for GAS pharyngitis (ie, tonsillar swelling and one of tonsillar exudate, no rhinorrhea, no cough) outperformed existing rules for GAS pharyngitis diagnosis in children with symptomatic sore throat in Cape Town.
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http://dx.doi.org/10.1097/INF.0000000000001413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303124PMC
March 2017

One More Disguise in the Stealth Behavior of Streptococcus pyogenes.

mBio 2016 05 17;7(3). Epub 2016 May 17.

University of Tennessee Health Science Center, Department of Medicine, Memphis, Tennessee, USA.

The ability to hide in the animal kingdom is essential for survival; the same is true for bacteria. Streptococcus pyogenes is considered one of the more successful stealth bacteria in its production of a hyaluronic acid capsule that is chemically identical to the hyaluronic acid lining human joints. It has also acquired the capacity to enter eukaryotic cells to avoid the onslaught of the host's immune defenses, as well as drugs. From this intracellular vantage point, it may remain dormant from days to weeks, only to cause disease again at a later time, perhaps causing a relapse in a drug-treated patient. We now learn that it is able to enter macrophages as well, enabling the Streptococcus to use this "Trojan horse" approach to be transported to distant sites in the body.
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http://dx.doi.org/10.1128/mBio.00661-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959674PMC
May 2016

Status of research and development of vaccines for Streptococcus pyogenes.

Vaccine 2016 06 29;34(26):2953-2958. Epub 2016 Mar 29.

Centre for International Child Health, University of Melbourne, Melbourne, Australia; Group A Streptococcal Research Group, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, Université Libre de Bruxelles, Brussels, Belgium.

Streptococcus pyogenes is an important global pathogen, causing considerable morbidity and mortality, especially in low and middle income countries where rheumatic heart disease and invasive infections are common. There is a number of promising vaccine candidates, most notably those based on the M protein, the key virulence factor for the bacterium. Vaccines against Streptococcus pyogenes are considered as impeded vaccines because of a number of crucial barriers to development. Considerable effort is needed by key players to bring current vaccine candidates through phase III clinical trials and there is a clear need to develop a roadmap for future development of current and new candidates.
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http://dx.doi.org/10.1016/j.vaccine.2016.03.073DOI Listing
June 2016

Protective immunogenicity of group A streptococcal M-related proteins.

Clin Vaccine Immunol 2015 Mar 28;22(3):344-50. Epub 2015 Jan 28.

Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA.

Many previous studies have focused on the surface M proteins of group A streptococci (GAS) as virulence determinants and protective antigens. However, the majority of GAS isolates express M-related protein (Mrp) in addition to M protein, and both have been shown to be required for optimal virulence. In the current study, we evaluated the protective immunogenicity of Mrp to determine its potential as a vaccine component that may broaden the coverage of M protein-based vaccines. Sequence analyses of 33 mrp genes indicated that there are three families of structurally related Mrps (MrpI, MrpII, and MrpIII). N-terminal peptides of Mrps were cloned, expressed, and purified from M type 2 (M2) (MrpI), M4 (MrpII), and M49 (MrpIII) GAS. Rabbit antisera against the Mrps reacted at high titers with the homologous Mrp, as determined by enzyme-linked immunosorbent assay, and promoted bactericidal activity against GAS emm types expressing Mrps within the same family. Mice passively immunized with rabbit antisera against MrpII were protected against challenge infections with M28 GAS. Assays for Mrp antibodies in serum samples from 281 pediatric subjects aged 2 to 16 indicated that the Mrp immune response correlated with increasing age of the subjects. Affinity-purified human Mrp antibodies promoted bactericidal activity against a number of GAS representing different emm types that expressed an Mrp within the same family but showed no activity against emm types expressing an Mrp from a different family. Our results indicate that Mrps have semiconserved N-terminal sequences that contain bactericidal epitopes which are immunogenic in humans. These findings may have direct implications for the development of GAS vaccines.
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http://dx.doi.org/10.1128/CVI.00795-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340887PMC
March 2015

Streptococcal pharyngitis in schoolchildren in Bamako, Mali.

Pediatr Infect Dis J 2015 May;34(5):463-8

From the *Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics and ¶Division of Geographic Medicine, Department of Medicine, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland; †Centre pour le Développement des Vaccins-Mali, Bamako, Mali; ‡Department of Pediatrics, University of Virginia, Charlottesville, Virginia; and §University of Tennessee Health Science Center and Veterans Affairs Medical Center Research Service, Memphis, Tennessee.

Background: Group A streptococcus (GAS) pharyngitis is associated with high rates of rheumatic heart disease in developing countries. We sought to identify guidelines for empiric treatment of pharyngitis in low-resource settings. To inform the design of GAS vaccines, we determined the emm types associated with pharyngitis among African schoolchildren.

Methods: Surveillance for pharyngitis was conducted among children 5-16 years of age attending schools in Bamako, Mali. Students were encouraged to visit a study clinician when they had a sore throat. Enrollees underwent evaluation and throat swab for isolation of GAS. Strains were emm typed by standard methods.

Results: GAS was isolated from 449 (25.5%) of the 1,759 sore throat episodes. Painful cervical adenopathy was identified in 403 children (89.8%) with GAS infection and was absent in 369 uninfected children (28.2%). Emm type was determined in 396 (88.2%) of the 449 culture-positive children; 70 types were represented and 14 types accounted for 49% of isolates. Based on the proportion of the 449 isolates bearing emm types included in the 30-valent vaccine (31.0%) plus nonvaccine types previously shown to react to vaccine-induced bactericidal antibodies (44.1%), the vaccine could protect against almost 75% of GAS infections among Bamako schoolchildren.

Conclusions: Two promising strategies could reduce rheumatic heart disease in low-resource settings. Administering antibiotics to children with sore throat and tender cervical adenopathy could treat most GAS-positive children while reducing use of unnecessary antibiotics for uninfected children. Broad coverage against M types associated with pharyngitis in Bamako schoolchildren might be achieved with the 30-valent GAS vaccine under development.
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http://dx.doi.org/10.1097/INF.0000000000000608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400231PMC
May 2015

In memoriam: Gene H. Stollerman.

Clin Infect Dis 2014 Dec 8;59(12):1805-6. Epub 2014 Sep 8.

Medical Service, Miami Veterans Affairs Health Care System, Florida.

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http://dx.doi.org/10.1093/cid/ciu718DOI Listing
December 2014

Added value of the emm-cluster typing system to analyze group A Streptococcus epidemiology in high-income settings.

Clin Infect Dis 2014 Dec 12;59(11):1651-2. Epub 2014 Aug 12.

Group A Streptococcus Research Group, Murdoch Childrens Research Institute Centre for International Child Health, University of Melbourne.

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http://dx.doi.org/10.1093/cid/ciu649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227576PMC
December 2014

Group A streptococcus expresses a trio of surface proteins containing protective epitopes.

Clin Vaccine Immunol 2014 Oct 30;21(10):1421-5. Epub 2014 Jul 30.

Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA Department of Veterans Affairs Medical Center, Memphis, Tennessee, USA

Group A streptococci (GAS) (Streptococcus pyogenes) are common causes of infections in humans for which there is no licensed vaccine. Decades of work has focused on the role of the surface M protein in eliciting type-specific protective immunity. Recent studies have identified additional surface proteins of GAS that contain opsonic epitopes. In the present study, we describe a serotype M65 GAS originally isolated during an epidemiologic study in Bamako, Mali, which simultaneously expressed M, M-related protein (Mrp), and streptococcal protective antigen (Spa) on the bacterial surface. The emm, mrp, and spa genes were sequenced from PCR amplicons derived from the M65 chromosome. Rabbit antisera raised against synthetic peptides copying the N-terminal regions of M, Mrp, and Spa were highly specific for each peptide, reacted with the surface of M65 GAS, and promoted bactericidal activity against the organism. A mixture of antisera against all three peptides was most effective in the bactericidal assays. Immunofluorescence microscopy revealed that the M, Mrp, and Spa antisera bound to the bacterial surface in the presence of human plasma proteins and resulted in the deposition of complement. Five additional spa genes were identified in the Mrp-positive GAS serotypes, and their sequences were determined. Our results indicate that there are multiple antigens on the surface of GAS that evoke antibodies that promote bacterial killing. A more complete understanding of the relative contributions of M, Mrp, and Spa in eliciting protective immunity may aid in the development of GAS vaccines with enhanced coverage and efficacy.
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http://dx.doi.org/10.1128/CVI.00448-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266352PMC
October 2014

Vaccination against the M protein of Streptococcus pyogenes prevents death after influenza virus: S. pyogenes super-infection.

Vaccine 2014 Sep 29;32(40):5241-9. Epub 2014 Jul 29.

Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States. Electronic address:

Influenza virus infections are associated with a significant number of illnesses and deaths on an annual basis. Many of the deaths are due to complications from secondary bacterial invaders, including Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The β-hemolytic bacteria S. pyogenes colonizes both skin and respiratory surfaces, and frequently presents clinically as strep throat or impetigo. However, when these bacteria gain access to normally sterile sites, they can cause deadly diseases including sepsis, necrotizing fasciitis, and pneumonia. We previously developed a model of influenza virus:S. pyogenes super-infection, which we used to demonstrate that vaccination against influenza virus can limit deaths associated with a secondary bacterial infection, but this protection was not complete. In the current study, we evaluated the efficacy of a vaccine that targets the M protein of S. pyogenes to determine whether immunity toward the bacteria alone would allow the host to survive an influenza virus:S. pyogenes super-infection. Our data demonstrate that vaccination against the M protein induces IgG antibodies, in particular those of the IgG1 and IgG2a isotypes, and that these antibodies can interact with macrophages. Ultimately, this vaccine-induced immunity eliminated death within our influenza virus:S. pyogenes super-infection model, despite the fact that all M protein-vaccinated mice showed signs of illness following influenza virus inoculation. These findings identify immunity against bacteria as an important component of protection against influenza virus:bacteria super-infection.
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http://dx.doi.org/10.1016/j.vaccine.2014.06.093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146501PMC
September 2014
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