Contribution of cryptic epitopes in designing a group A streptococcal vaccine

Ozberk, Victoria; Pandey, Manisha; Good, Michael F.

doi:10.1080/21645515.2018.1462427

Cited by 16 publications

(16 citation statements)

References 137 publications

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“…Most vaccine developments and trials targeted for S. pyogenes are currently focused on the M proteins and their fragments, with the leading ones targeting the N-terminal or the C-repeat region [36]. We have previously shown that peptides in the M protein C-region containing the EEKQISDASRmotif ( Table 1) are potent epitopes for opsonizing antibodies and crucial for the interaction and internalization with monocytic cells; a result corroborated here [4].…”

Section: Discussionsupporting

confidence: 62%

Structural determination ofStreptococcus pyogenesM1 protein interactions with human immunoglobulin G using integrative structural biology

Khakzad

Happonen

Karami

et al. 2020

Preprint

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Streptococcus pyogenes (Group A streptococcus; GAS) is an important human pathogen responsible for mild to severe, life-threatening infections. GAS expresses a wide range of virulence factors, including the M family proteins. The M proteins allow the bacteria to evade parts of the human immune defenses by triggering the formation of a dense coat of plasma proteins surrounding the bacteria, including IgGs. However, the molecular level details of the M1-IgG interaction have remained unclear. Here, we characterized the structure and dynamics of this interaction interface in human plasma on the surface of live bacteria using integrative structural biology, combining cross-linking mass spectrometry and molecular dynamics (MD) simulations. We show that the primary interaction is formed between the S-domain of M1 and the conserved IgG Fc-domain. In addition, we show evidence for a so far uncharacterized interaction between the A-domain and the IgG Fc-domain. Both these interactions mimic the protein G-IgG interface of group C and G streptococcus. These findings underline a conserved scavenging mechanism used by GAS surface proteins that block the IgG-receptor (FcγR) to inhibit phagocytic killing. We additionally show that we can capture Fab-bound IgGs in a complex background and identify the specific M1 epitopes targeted on live bacteria. Our results elucidate the M1-IgG interaction network involved in inhibition of phagocytosis and reveal important M1 peptides that can be further investigated as future vaccine targets.

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Section: Discussionsupporting

confidence: 62%

Structural determination ofStreptococcus pyogenesM1 protein interactions with human immunoglobulin G using integrative structural biology

Khakzad

Happonen

Karami

et al. 2020

Preprint

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“…Instead, pathogens may "hide" regions, known as cryptic epitopes, which are normally not very immunogenic but may be protective (30). Targeting cryptic epitopes is of interest for vaccine development against pathogens, such as group A streptococcus, and could be a promising new direction in C. trachomatis vaccine development (32). Together, our present study is of particular interest in the context of vaccine development.…”

Section: Discussionmentioning

confidence: 88%

Antibodies to Variable Domain 4 Linear Epitopes of theChlamydia trachomatisMajor Outer Membrane Protein Are Not Associated with Chlamydia Resolution or Reinfection in Women

Collar

Linville

Core

et al. 2020

mSphere

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Chlamydia trachomatis is an obligate intracellular bacterium. C. trachomatis infection is the most prevalent bacterial sexually transmitted infection and can lead to pelvic inflammatory disease and infertility in women. There is no licensed vaccine for C. trachomatis prevention, in part due to gaps in our knowledge of C. trachomatis-specific immune responses elicited during human infections. Previous investigations of the antibody response to C. trachomatis have identified immunodominant antigens and antibodies that can neutralize infection in cell culture. However, epitope-specific responses to C. trachomatis are not well characterized, and the impact of these antibodies on infection outcome is unknown. We recently developed a technology called deep sequence-coupled biopanning that uses bacteriophage virus-like particles to display peptides from antigens and affinity select against human serum IgG. Here, we used this technology to map C. trachomatis-specific antibodies in groups of women with defined outcomes following C. trachomatis infection: (i) C. trachomatis negative upon presentation for treatment (“spontaneous resolvers”), (ii) C. trachomatis negative at a 3-month follow-up visit after treatment (“nonreinfected”), and (iii) C. trachomatis positive at a 3-month follow-up after treatment (“reinfected”). This analysis yielded immunodominant epitopes that had been previously described but also identified new epitopes targeted by human antibody responses to C. trachomatis. We focused on human antibody responses to the C. trachomatis variable domain 4 serovar-conserved region of the major outer membrane protein (VD4-MOMP), a previously described immunodominant epitope. All three groups of women produced IgG to the VD4-MOMP, suggesting that detection of serum antibodies to VD4-MOMP in women with urogenital C. trachomatis infection is not associated with protection against reinfection. IMPORTANCE C. trachomatis infection is the most common bacterial sexually transmitted infection, and infection in women can lead to pelvic inflammatory disease and infertility. No licensed vaccine exists to prevent C. trachomatis infection, and investigations of the natural immune response may inform the design of targeted vaccines for C. trachomatis. Our study fills a gap in knowledge regarding the epitope specificity of antibody responses that are elicited in response to C. trachomatis infection in women. We identified several new B cell epitopes for C. trachomatis antigens and confirmed B cell epitopes that have been identified by other methods. Our finding that women produce antibodies to the VD4-MOMP regardless of infection outcome provides insight into vaccine development, suggesting that vaccines targeting VD4-MOMP may need to elicit higher-titer antibody responses than natural infection imparts or that additional vaccine targets should be pursued in the future.

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“…The intensive analysis of 176 emm GAS types [80] has produced a new emm cluster-specific system, which could provide protection to different emm types within the same cluster [75,81]. Five N-terminal M peptides from the E4 emm cluster, containing 17 GAS emm types that are prevalent in the United States, were selected [75].…”

Section: Major Antigen Targets For Gas Vaccinesmentioning

confidence: 99%

Recent Advances in the Development of Peptide Vaccines and Their Delivery Systems against Group A Streptococcus

et al. 2019

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Group A Streptococcus (GAS) infection can cause a variety of diseases in humans, ranging from common sore throats and skin infections, to more invasive diseases and life-threatening post-infectious diseases, such as rheumatic fever and rheumatic heart disease. Although research has been ongoing since 1923, vaccines against GAS are still not available to the public. Traditional approaches taken to develop vaccines for GAS failed due to poor efficacy and safety. Fortunately, headway has been made and modern subunit vaccines that administer minimal bacterial components provide an opportunity to finally overcome previous hurdles in GAS vaccine development. This review details the major antigens and strategies used for GAS vaccine development. The combination of antigen selection, peptide epitope modification and delivery systems have resulted in the discovery of promising peptide vaccines against GAS; these are currently in preclinical and clinical studies.

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Contribution of cryptic epitopes in designing a group A streptococcal vaccine

Cited by 16 publications

References 137 publications

Structural determination ofStreptococcus pyogenesM1 protein interactions with human immunoglobulin G using integrative structural biology

Structural determination ofStreptococcus pyogenesM1 protein interactions with human immunoglobulin G using integrative structural biology

Antibodies to Variable Domain 4 Linear Epitopes of theChlamydia trachomatisMajor Outer Membrane Protein Are Not Associated with Chlamydia Resolution or Reinfection in Women

Recent Advances in the Development of Peptide Vaccines and Their Delivery Systems against Group A Streptococcus

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