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

Abstract

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

Vaccine development to preventStaphylococcus aureussurgical-site infections

“…Vaccines are promising alternatives to antibiotics; however, antistaphylococcal vaccine development has not yet been successful in humans. Seven investigational S. aureus vaccines are currently undergoing development ( Table ). In this review, focus is placed on two of the seven investigational S. aureus vaccines that have reached advanced clinical trials (developed by GSK and Pfizer).…”

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

“…To date, a TSST-1 toxoid (double mutant G31R-H135A) and an SEB toxoid (triple mutant L45R-Y89A-Y94A), both supplemented with aluminum hydroxide adjuvant, have been tested in phase 1 clinical trials. Both studies showed the vaccines to be safe and well tolerated among healthy vaccines (Table 1) [48,49]. Moreover, both toxoids were still immunogenic and induced a neutralizing antibody response.…”

“…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].…”

Vaccine against toxic shock syndrome in a first-in-man clinical trial

“…Since October, the results on safety and immunogenicity of two additional staphylococcal vaccine studies have been published: one applying modified recombinant staphylococcal B protein [21], the other applying a single-dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy adults [22].…”