Group A Streptococcus Vaccines

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Group A Streptococcus

Streptococcus pyogenes belongs to Lancefield serogroup A and is therefore also known as group A Streptococcal (GAS), which causes infections in humans to cause a number of diseases. This bacterium is ubiquitous in nature and is the main bacterium causing acute pharyngitis, 15-30% of cases of pharyngitis in children and 5-10% of cases of pharyngitis in adults are caused by this bacterium. Streptococcus pyogenes mainly infects the upper respiratory tract and the skin. In addition, the bacteria can cause a variety of invasive systemic infections and is one of the main pathogens of cellulitis (Staphylococcus aureus is also another major pathogen of this disease). Infection with the bacteria may also lead to three severe non-suppurative complications: acute rheumatic fever, rheumatic heart disease as well as acute glomerulonephritis. More seriously, infection with Streptococcus pyogenes is also a significant cause of toxic shock syndrome (TSS) and necrotizing fasciitis (life-threatening skin and soft tissue infections). Skin and the mucosa of the nasopharyngeal are the main colonization sites of GAS and are the main reservoirs for GAS to maintain and spread to other hosts. By being able to escape the innate and adaptive immune responses in saliva, GAS can, therefore, be spread by droplets. In addition, the characteristics of this bacterium colonized in skin tissue also enable it to spread through skin contact between people.

Pathogenicity of Group A Streptococcus

The process by which GAS adheres to host cells involves two stages. The first stage is the weak, hydrophobic interaction of the amphiphilic polymer Lipoteichoic acid (LTA) on the surface of the GSA with the target cell surface components, followed by specific, high-affinity binding occurs as a characteristic in the second stage of adhesion, including lectin-carbohydrate or protein-protein interactions. The surface of GAS cells contains a variety of adhesins associated with bacterial adherence to the surface of host cells. The adhesins of these proteins allow GAS to colonize different tissues of the human body. These adhesins include pili, AgI/II family, fibronectin binding protein, M and M-like proteins, collagen-like protein, Plg binding protein, and laminin binding protein. It is worth noting that the majority of the adhesins are not present in the GAS of all serotypes.

The resistance of various surface molecules and secreted virulence factors to the host's natural immunity makes GAS highly adaptable to the human body. The main mechanisms are enhanced resistance to phagocytosis, antibody opsonization, complement deposition, neutrophil killing, and the action of antimicrobial peptides. The phagocytosis of neutrophils is the main mechanism by which the body clears foreign pathogens. GAS immunoglobulin binding proteins (Sib, FbaA, and PrtF1/SfbI), complement inhibitors (SIC, hyaluronic acid capsule, and M protein), immunoglobulin-degrading enzymes (SpeB, EndoS, and IdeS) and leukocidal toxins (SLS and SLO) are the main forces of the bacteria against this mechanism. The interaction of various virulence factors of the bacteria with the host ultimately leads to bacterial dissemination, tissue damage, and inflammatory responses. In addition to the effects of some surface molecules and secreted virulence factors, GAS can also cause invasive diseases through transcriptional modification, virulence factor expression, and dysregulation of the body's immune homeostasis.

Fig.1 Virulence factors expressed by GAS to combat the host innate immune response.

Fig.2 The interplay between host and bacterial factors leads to tissue destruction, vascular leakage, and hyperinflammation in invasive GAS disease. (Walker MJ and Barnett TC, 2014)

Development of the Group A Streptococcus Vaccines

GAS is very sensitive to penicillin and is, therefore, the drug of the first choice for most GAS infections. In addition, GAS is resistant to macrolides, tetracyclines, and fluoroquinolones. GAS can cause a variety of serious infections and complications and the widespread use of antibiotics may lead to the production of super bacteria, so it is important to develop safe and effective preventive vaccines. Both GAS proteins and molecules have been prepared as vaccines. These targets include membrane-associated proteins, anchorless proteins, cell wall-anchored proteins, secreted proteins, and group A carbohydrate molecules. A large part of the GAS vaccine is targeted at the cell wall-anchored M protein. Previous studies have shown that the hypervariable region of the N-terminus of the M protein may not cause autoimmune diseases, so it may have a protective effect. Currently, 7-valent and 26-valent N-terminal M protein vaccine candidate have entered clinical trials, and the results show that these candidate are well tolerated. Another N-terminal polypeptide vaccine containing 30 GAS serotypes was able to resist the GAS of these 30 serotypes and the GAS of the other 24 serotypes, but this vaccine did not protect the GAS of all popular serotypes. Therefore, scientists are considering the use of the highly conserved C-repeat region of the M protein as a target, and such vaccines have been observed to have some protection. In addition, J8, J14, their derivatives, and StreptInCor containing B-cell and T-cell epitopes that are from the conserved region of the M5 protein have also been extensively studied and shown to produce bactericidal and protective antibodies in animal experiments.

The GAS surface of all serotypes contains group A carbohydrate (GAC), which is also often used as a target for GAS vaccines. GAC could protect mice those immunized with GAC from intraperitoneal and intranasal challenge, but because anti-GAC antibodies are cross-reactive with cytoskeletal proteins and heart valve proteins in the host, there may exist some safety concerns when using the GAC as a vaccine. Other antigens such as SOF/SfbII (serum opacity factor), FbaA (fibronectin binding protein A), protein FA/SfbI, Spa (streptococcal protective antigen), and other virulence factors are also in the testing stage.

The strategy of the use of bioinformatics to analyze the pathogen genome to determine the vaccine targets is called reverse vaccinology, which can quickly identify possible vaccine targets, and is currently the most promising vaccine design method. SpyCEP is a protective antigen of GAS identified by reverse vaccinology. Studies showed that mice immunized with SpyCEP were able to resist the challenge by GAS.

More than a decade of research has enabled Creative Biolabs to grow rapidly into a leading vaccine development specialist in the industry. We always reward our customers with the best quality service and products. Whether you have any problems in vaccine development, we will provide you with the perfect solution.

Reference

1. Walker MJ, Barnett TC. (2014). “Disease manifestations and pathogenic mechanisms of Group A Streptococcus”. Clin Microbiol Rev. 27(2), 264-301.

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