Safety, tolerability, and immunogenicity of a recombinant toxic shock syndrome toxin (rTSST)-1 variant vaccine: a randomised, double-blind, adjuvant-controlled, dose escalation first-in-man trial

Schwameis, Michael; Roppenser, Bernhard; Firbas, Christa; Gruener, Corina S; Model, Nina; Stich, Norbert; Roetzer, Andreas; Buchtele, Nina; Jilma, Bernd; Eibl, Martha M.

doi:10.1016/s1473-3099(16)30115-3

Cited by 29 publications

(36 citation statements)

References 38 publications

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“…Toxic shock syndrome toxin (TSST) represents another superantigen produced by S. aureus. The results of a phase 1 trial of a recombinant detoxified toxic shock syndrome toxin 1 variant (rTSST-1v) vaccine were recently published and demonstrated that vaccine showed tolerability and immunogenicity (28). A long-range goal would include the design of a vaccine candidate that will protect against the broad range of staphylococcal superantigens and other toxins.…”

Section: Discussionmentioning

confidence: 99%

Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax

Chen

Pasetti

Adhikari

et al. 2016

Clin Vaccine Immunol

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S everal staphylococcal enterotoxins (SEs) are bacterial superantigens (SAgs) produced by Staphylococcus aureus. The serologically and genetically distinct SEs (A, A1, A2, B, C, C1, C2, C3, D, E, G, H, and I) bind to major histocompatibility complex class II (MHC-II) proteins and to T-cell antigen receptors (TCRs), bypassing processing by antigen-presenting cells (1). Since T-cell engagement with SAgs is independent of clonal specificity, picomolar concentrations of a SAg can result in the polyclonal activation of large subsets of peripheral T cells (up to 20%) (2-4). The nonspecific activation of lymphocytes and the subsequent overwhelming production of cytokines make the clinical effects of SAgs potentially lethal. During the 1960s, staphylococcal enterotoxin B (SEB) became a focus of interest because aerosolization of minute amounts could be used to produce an incapacitating biological weapon (5).Strategies to counteract the effects of SAgs are currently limited to treatment of the infection, which thereby limits toxin production. There are currently no approved vaccines for Staphylococcus aureus or SEB. There is evidence that anti-SEB antibodies capable of neutralizing the effect of the SAg can abrogate the superantigenic activation of the immune system and be protective for the host (6, 7). Nonetheless, efforts to develop SEB vaccines require caution because biological inactivation must be complete and the critical antigenic structural epitopes must be preserved.An Escherichia coli-expressed recombinant SEB (rSEB) mutant containing mutations in the hydrophobic binding loop (L45R), the polar binding pocket (Y89A), and the disulfide loop (Y94A) was developed using a structure-based rational approach (8) wherein site-specific mutagenesis was used to direct mutations at the MHC-II binding site (9-11). In a limited number of animal challenge studies, parenteral immunization with a nonadjuvanted rSEB mutant elicited anti-SEB IgG antibodies in mice and rhesus monkeys that could be measured by enzyme-linked immunosorbent assay (ELISA) and that correlated with protection (9). Nasal and oral immunization with the rSEB mutant, given with cholera toxin (CT) as an adjuvant, also elicited anti-SEB antibodies and protected against lethal challenge (10). In expanded studies, mice and rhesus monkeys parenterally immunized with the rSEB mutant plus an alum adjuvant demonstrated anti-SEB antibodies that correlated with protection; animals that achieved anti-SEB titers of Ն10 4 were 100% protected, those with titers of ϳ10 3 had partial

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Section: Discussionmentioning

confidence: 99%

Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax

Chen

Pasetti

Adhikari

et al. 2016

Clin Vaccine Immunol

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“…On that basis, inactivating mutations have been predicted and experimentally confirmed for a number of staphylococcal SAgs [45][46][47]. The development of detoxified SEB and TSST-1 mutants is most advanced [48,49]. An effective vaccine against SAgs would encompass the detoxified antigen in combination with adjuvants that stimulate a robust antibody response necessary for direct neutralization of the toxin and an appropriate T cell response targeted at clearing the pathogen [50].…”

Section: Vaccination Against Sagsmentioning

confidence: 99%

Allergy—A New Role for T Cell Superantigens of Staphylococcus aureus?

Abdurrahman

Schmiedeke

Bachert

et al. 2020

Toxins

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Staphylococcus aureus superantigens (SAgs) are among the most potent T cell mitogens known. They stimulate large fractions of T cells by cross-linking their T cell receptor with major histocompatibility complex class-II molecules on antigen presenting cells, resulting in T cell proliferation and massive cytokine release. To date, 26 different SAgs have been described in the species S. aureus; they comprise the toxic shock syndrome toxin (TSST-1), as well as 25 staphylococcal enterotoxins (SEs) or enterotoxin-like proteins (SEls). SAgs can cause staphylococcal food poisoning and toxic shock syndrome and contribute to the clinical symptoms of staphylococcal infection. In addition, there is growing evidence that SAgs are involved in allergic diseases. This review provides an overview on recent epidemiological data on the involvement of S. aureus SAgs and anti-SAg-IgE in allergy, demonstrating that being sensitized to SEs-in contrast to inhalant allergens-is associated with a severe disease course in patients with chronic airway inflammation. The mechanisms by which SAgs trigger or amplify allergic immune responses, however, are not yet fully understood. Here, we discuss known and hypothetical pathways by which SAgs can drive an atopic disease. Key Contribution:There is growing evidence for an involvement of S. aureus SAgs in allergies. Colonization with S. aureus and the presence of IgE antibodies against SAgs (also known as SE-IgE) are strongly linked with allergic sensitization and severe chronic inflammatory airway diseases. Here, we discuss possible mechanisms by which SAgs can drive/or exacerbate an allergic immune response.

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“…The scFvs were demonstrated to be able to inhibit TSST-1-mediated T cell activation and pro-inlammatory cytokine production. Besides, a recombinant TSST-1 vaccine (Biomedizinische Forschungs gmbH) has been completed in phase I clinical study and proved to possess a good safety proile with no observable severe adverse events occurred [23,24].…”

Section: Staphylococcal Superantigens As Antibody Targetsmentioning

confidence: 99%

Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting

Zhang¹,

Su²,

Wu³

2017

Physiology and Pathology of Immunology

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Multidrug-resistant bacteria (MDR) are increasing rapidly and posing a global threat to mankind. Alternative strategies other than antibiotics have to be explored urgently. In this chapter, we review the current status of nonantibiotics strategies including antibodybased therapy and vaccine development for targeting Gram-positive strains (methicillinresistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium) and MDR Gram-negative strains (Acinetobacter baumannii and Pseudomonas aeruginosa). Biologicsbased clinical progress against these bacterial infections is updated.

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Safety, tolerability, and immunogenicity of a recombinant toxic shock syndrome toxin (rTSST)-1 variant vaccine: a randomised, double-blind, adjuvant-controlled, dose escalation first-in-man trial

Cited by 29 publications

References 38 publications

Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax

Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax

Allergy—A New Role for T Cell Superantigens of Staphylococcus aureus?

Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting

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