TBA225, a fusion toxoid vaccine for protection and broad neutralization of staphylococcal superantigens (original) (raw)

superantigens (sAgs) play a major role in the pathogenesis of Staphylococcus aureus and are associated with several diseases, including food poisoning, bacterial arthritis, and toxic shock syndrome. Monoclonal antibodies to these SAgs, primarily TSST-1, SEB and SEA have been shown to provide protection in animal studies and to reduce clinical severity in bacteremic patients. Here we quantify the pre-existing antibodies against sAgs in many human plasma and IVIG samples and demonstrate that in a major portion of the population these antibody titers are suboptimal and IVIG therapy only incrementally elevates the anti-sAg titers. our in vitro neutralization studies show that a combination of antibodies against SEA, SEB,and TSST-1 can provide broad neutralization of staphylococcal SAgs. We report a single fusion protein (tBA 225) consisting of the toxoid versions of TSST-1, SEB and SEA and demonstrate its immunogenicity and protective efficacy in a mouse model of toxic shock. Antibodies raised against this fusion vaccine provide broad neutralization of purified SAgs and culture supernatants of multiple clinically relevant S. aureus strains. our data strongly supports the use of this fusion protein as a component of an anti-virulence based multivalent toxoid vaccine against S. aureus disease. Staphylococcus aureus (SA) is a leading cause of hospital and community-associated infections worldwide with no effective vaccines available 1. The remarkable ability of SA to cause a wide range of diseases from skin and soft tissue infections (SSTI) to life threatening sepsis and pneumonia is in part due to its ability to escape the immune response using a plethora of virulence factors: the superantigenic and pore-forming toxins, coagulase, capsular polysaccharide, adhesins, proteases, and complement inactivating exoproteins 2. Since its first emergence in the 1960s methicillin-resistant SA (MRSA) has become endemic in healthcare settings, and more recently also within the community, posing a major global challenge 3,4. There have hence been increasing efforts directed towards the development of vaccines and therapeutics for SA infections. However, to date, no successful vaccine or antibody against SA infections has been developed, and there has been a spate of clinical trial failures on this front 1,5-8. Targeting SA toxins represent an alternative approach as "anti-virulence" vaccine for prevention of severe SA disease. Staphylococcal pore forming toxins alpha and gamma hemolysins and leukotoxins play critical roles in immune evasion, by killing cells of the first line of defense such as neutrophils, monocytes, and macrophages, providing iron for bacterial growth by lysing red blood cells, or enabling dissemination of bacteria through killing of cells with critical barrier function such as epithelial cells 2. Pyrogenic superantigens (SAgs) represent a major family of SA toxins composed of staphylococcal enterotoxins (SEs) and toxic shock syndrome toxin 1 (TSST-1). In contrast to conventional antigens that undergo proteolytic processing by antigen presenting cells to be presented as MHC/peptide complex to T cells, SAgs cross-link T cell receptor (TCR) with MHC Class II and activate up to 30% of T cells 9 leading to a massive release of cytokines and chemokines, enhanced expression and activation of cell-adhesion molecules, increased T-cell proliferation, and eventually T cell apoptosis or anergy. This sequence of events can culminate in toxic shock syndrome (TSS), a life-threatening condition characterized by rash, hypotension, fever, and multisystem dysfunction 10. Antibodies play an important role in protection against TSS, thus individuals that do not seroconvert towards the offending toxin due to hypo responsive T-cells 11 and/ or T-cell dependent B-cell apoptosis 12 are more likely to experience recurring bouts. Furthermore, SAgs impact the virulence of SA strains through induction of a local excessive inflammatory response, immune subversion by