Publications by authors named "Thomas A Penfound"

15 Publications

  • Page 1 of 1

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

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

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

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

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

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

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

Potential coverage of a multivalent M protein-based group A streptococcal vaccine.

Vaccine 2013 Mar 31;31(12):1576-81. Epub 2013 Jan 31.

University of Tennessee Health Science Center, Department of Medicine and Veterans Affairs Medical Center Research Service, Memphis, TN, USA.

Background: The greatest burden of group A streptococcal (GAS) disease worldwide is due to acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Safe, effective and affordable vaccines designed to prevent GAS infections that trigger ARF could reduce the overall global morbidity and mortality from RHD. The current study evaluated the potential coverage of a new 30-valent M protein-based vaccine using GAS isolates from school children in Bamako, Mali, a population at high risk for the development of RHD.

Methods: The bactericidal activity of rabbit antisera against the 30-valent vaccine was assessed using a collection of GAS isolates recovered during a study of the epidemiology of pharyngitis in Bamako.

Results: Single isolates representing 42 of 67 emm-types, accounting for 85% of the GAS infections during the study, were evaluated. All (14/14) of the vaccine emm-types in the collection were opsonized (bactericidal killing >50%) and 26/28 non-vaccine types were opsonized. Bactericidal activity was observed against 60% of the total emm-types recovered in Bamako, which accounted for 81% of all infections.

Conclusions: Multivalent vaccines comprised of N-terminal M peptides elicit bactericidal antibodies against a broad range of GAS serotypes, indicating that their efficacy may extend beyond the emm-types included in the vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2013.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593940PMC
March 2013

New 30-valent M protein-based vaccine evokes cross-opsonic antibodies against non-vaccine serotypes of group A streptococci.

Vaccine 2011 Oct 13;29(46):8175-8. Epub 2011 Sep 13.

Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Our previous studies have shown that recombinant multivalent vaccines containing amino-terminal M protein fragments from as many as 26 different serotypes of group A streptococci (GAS) evoked opsonic antibodies in animals and humans. In the present study, we constructed a new 30-valent vaccine containing M protein peptides from GAS serotypes prevalent in North America and Europe. The vaccine was immunogenic in rabbits and evoked bactericidal antibodies against all 30 vaccine serotypes of GAS. In addition, the vaccine antisera also contained significant levels of bactericidal antibodies against 24 of 40 non-vaccine serotypes of GAS. These results indicate that the potential efficacy of the new multivalent vaccine may be greater than predicted based on the "type-specific" M peptides represented.
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http://dx.doi.org/10.1016/j.vaccine.2011.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195966PMC
October 2011

Protective efficacy of group A streptococcal vaccines containing type-specific and conserved M protein epitopes.

Vaccine 2010 Jul 21;28(31):5017-22. Epub 2010 May 21.

Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States.

The amino terminal region of group A streptococcal M proteins evokes type-specific immunity while the conserved C-repeat epitopes evoke cross-protective immunity against multiple serotypes. The present studies were undertaken to compare the protective efficacy of vaccines containing either type-specific (hexavalent vaccine) or conserved C-repeat (J14 vaccine) M protein epitopes and to determine if combination vaccines resulted in enhanced levels of protection. Our results indicated that the protective efficacy of the type-specific vaccine was significantly greater than that of J14 and that the addition of J14 to vaccine formulations did not enhance the level of protection achieved with type-specific formulations.
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http://dx.doi.org/10.1016/j.vaccine.2010.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906646PMC
July 2010

The NH(2)-terminal region of Streptococcus pyogenes M5 protein confers protection against degradation by proteases and enhances mucosal colonization of mice.

J Infect Dis 2010 May;201(10):1580-8

Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.

Background: The NH(2)-terminal sequence of the M protein from group A streptococci defines the serotype of the organism and contains epitopes that evoke bactericidal antibodies.

Methods: To identify additional roles for this region of the M protein, we constructed a mutant of M5 group A streptococci expressing an M protein with a deletion of amino acid residues 3-22 (DeltaNH(2)).

Results: M5 streptococci and the DeltaNH(2) mutant were resistant to phagocytosis and were similarly virulent in mice. However, DeltaNH(2) was significantly less hydrophobic, contained less lipoteichoic acid on its surface, and demonstrated reduced adherence to epithelial cells. These differences were abolished when organisms were grown in the presence of protease inhibitors. Treatment with cysteine proteases or with human saliva resulted in the release of M protein from the DeltaNH(2) mutant at a significantly greater rate than observed with the wild-type M5 strain. Compared with the parent strain, the DeltaNH(2) strain also showed a significant reduction in its ability to colonize the upper respiratory mucosa of mice.

Conclusions: The NH(2) terminus of M5 protein has an important role in protecting the surface protein from proteolytic cleavage, thus preserving its function as an anchor for lipoteichoic acid, which is a primary mediator of adherence to epithelial cells and colonization.
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http://dx.doi.org/10.1086/652005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858045PMC
May 2010
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