High Titer Persistent Neutralizing Antibodies Induced by TSST-1 Variant Vaccine Against Toxic Shock Cytokine Storm

Abstract

Staphylococcal superantigen toxins lead to a devastating cytokine storm resulting in shock and multi-organ failure. We have previously assessed the safety and immunogenicity of a recombinant toxic shock syndrome toxin 1 variant vaccine (rTSST-1v) in clinical trials (NCT02971670 and NCT02340338). The current study assessed neutralizing antibody titers after repeated vaccination with escalating doses of rTSST-1v. At study entry, 23 out of 34 subjects (67.6%) had neutralizing antibody titers inhibiting T cell activation as determined by 3H-thymidine incorporation at a serum dilution of ≤1:100 with similar figures for inhibition of IL-2 activation (19 of 34 subjects, 55.9%) as assessed by quantitative PCR. After the first vaccination, numbers of subjects with neutralization titers inhibiting T cell activation (61.7% ≥ 1:1000) and inhibiting IL-2 gene induction (88.2% ≥ 1:1000) increased. The immune response was augmented after the second vaccination (inhibiting T cell activation: 78.8% ≥ 1:1000; inhibiting IL-2 induction: 93.9% ≥ 1:1000) corroborated with a third immunization months later in a small subgroup of subjects. Assessment of IFNγ, TNFα and IL-6 inhibition revealed similar results, whereas neutralization titers did not change in placebo participants. Antibody titer studies show that vaccination with rTSST-1v in subjects with no/low neutralizing antibodies can rapidly induce high titer neutralizing antibodies persisting over months.

Dietary supplementation with spray-dried animal plasma improves vaccine protection in aged mice

“…In addition, many strategies to protect mice against SEB have focused on inhibiting the inflammatory response. Examples of such strategies include attempts to block the activation of T cells (41), which are the main producers of these cytokines, to prevent the interaction of SEB with MHC II (42), to neutralize pro-inflammatory cytokines with antibodies (41), and to administer IL-10 to inhibit cytokine production by Th1 cells (43).…”

Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution

“…TSST is a bacterial superantigen that binds directly to the Vβ region of the T cell receptor and connects the TCR to the MHC protein, independent of a specific antigen [ 31 ]. This activates T cells non-specifically and triggers a cytokine storm [ 34 ].…”

Staphylococcal Enterotoxin B and C Mutants and Vaccine Toxoids

“…Vaccine toxoids of TSST-1 have been prepared, involving alterations of surface amino acid residues that interact with MHC II and/or Vβ2-TCR ( 18 , 19 , 31 ). It is my experience in collaboration with other researchers in the evaluation of large numbers of mutants of TSST-1, SEB, and SEC that alteration of surface amino acids does not change the overall domain three-dimensional structure of these pyrogenic toxin superantigens ( 10 , 11 , 19 , 23 , 32 – 45 ).…”