A fully human monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) with functional activity in vitro and in vivo.

A fully human monoclonal antibody (CS-D7, IgG1) specific for the iron regulated surface determinant B (IsdB) of Staphylococcus aureus was isolated from the Cambridge Antibody Technology (CAT) scFv antibody library. As compared to previously described IsdB specific murine monoclonals, CS-D7 has a unique, non-overlapping binding site on IsdB, and exhibits increased in vivo activity. The antibody recognizes a conformational epitope spanning amino acids 50 to 285 and has a binding affinity of 340 (± 75) pM for IsdB. CS-D7 bound to a wide variety of S. aureus strains, but not to an isdB deletion mutant. The antibody mediated opsonophagocytic (OP) killing in vitro and mediated significant protection in vivo. In a murine lethal sepsis model, the antibody conferred protection from death when dosed prior to challenge, but not when dosed after challenge. Importantly, in a central venous catheter (CVC) model in rats, the antibody reduced bacteremia and prevented colonization of indwelling catheters. Protection was observed when rats were dosed with CS-D7 prior to challenge as well as post challenge. IsdB is currently being investigated for clinical efficacy against S. aureus infection, and the activity of this human IsdB specific antibody supplements the growing body of evidence to support targeting this antigen for vaccine development.

Intramuscular injection of parathyroid autografts is a viable option after total parathyroidectomy.

INTRODUCTION: Surgical transplantation of parathyroid gland into muscle is an established technique after total parathyroidectomy for renal hyperparathyroidism. However, no study has examined the role of injecting parathyroid tissue in these patients. We compared the outcome of surgical transplantation of parathyroid glands by implantation ("implant") versus that of intramuscular injection ("inject"). METHODS: Patients who had total parathyroidectomy for tertiary hyperparathyroidism due to chronic renal failure from 2001-2008 are included in this study. For the implant group, a parathyroid gland is divided into 10-12 pieces (each of 2-mm in diameter) before embedding into the deltoid or brachioradialis muscle. Patients in the inject group, each had a finely minced gland injected into the deltoid. Postoperatively, the graft is deemed to be functioning if 1) serum PTH is normal, or 2) serum calcium is normal in the absence of calcium supplements or reduced dosage requirements; these assays are performed at least 1 month after initial surgery. Recurrence is defined by the presence of hyperparathyroidism requiring autograft excision. RESULTS: A total of 66 patients (23 men, 43 women) were included in the study. The implant group comprised 31 patients (mean age 49.9 +/- 14.0), and the inject group had 35 patients (mean age 49.2 +/- 10.4; P = 0.80). The mean follow-up period for implant was longer at 40.1 months compared with 16.2 months for inject (P = 0.001). Operative time for implant was slightly longer at 111 min versus 106 min for inject (P = 0.51). Graft function was achieved in 27 (87.1%) implant patients and 20 (69%) inject patients (P = 0.08). Recurrence was seen in four (12.9%) implant patients compared with one (2.9%) inject patient, after a mean period of 28.8 months. This difference was not statistically significant (P = 0.18). CONCLUSIONS: Intramuscular injection of parathyroid tissue is a feasible alternative to surgical transplantation by implantation after total parathyroidectomy in tertiary hyperparathyroidism. The injection method was slightly faster to perform. However, injection achieved a slightly lower graft function rate but the risk of autograft hyperplasia also was lower.

A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model.

Staphylococcus aureus is a major cause of nosocomial infections worldwide, and the rate of resistance to clinically relevant antibiotics, such as methicillin, is increasing; furthermore, there has been an increase in the number of methicillin-resistant S. aureus community-acquired infections. Effective treatment and prevention strategies are urgently needed. We investigated the potential of the S. aureus surface protein iron surface determinant B (IsdB) as a prophylactic vaccine against S. aureus infection. IsdB is an iron-sequestering protein that is conserved in diverse S. aureus clinical isolates, both methicillin resistant and methicillin sensitive, and it is expressed on the surface of all isolates tested. The vaccine was highly immunogenic in mice when it was formulated with amorphous aluminum hydroxyphosphate sulfate adjuvant, and the resulting antibody responses were associated with reproducible and significant protection in animal models of infection. The specificity of the protective immune responses in mice was demonstrated by using an S. aureus strain deficient for IsdB and HarA, a protein with a high level of identity to IsdB. We also demonstrated that IsdB is highly immunogenic in rhesus macaques, inducing a more-than-fivefold increase in antibody titers after a single immunization. Based on the data presented here, IsdB has excellent prospects for use as a vaccine against S. aureus disease in humans.