Retrospective Identification of a Broad IgG Repertoire Differentiating Patients With S. aureus Skin and Soft Tissue Infections From Controls

Abstract

Background: Although the relevance of humoral immunity for protection against S. aureus skin and soft tissue infections (SSTIs) has been suggested by several animal and human studies, the question of which human antibodies may be protective has so far impeded the development of a safe and effective vaccine. Because most adults have developed certain anti-S. aureus antibodies due to S. aureus colonization or infection, we hypothesized that the titers of antibodies to S. aureus in uninfected controls would differ from those in infected patients and would also differ in infected patients from the time of acute infection to a 40-day convalescent serum.Methods: To test these hypotheses, we measured human antibody levels against a panel of 134 unique antigens comprising the S. aureus surfome and secretome in subjects with active culture-confirmed S. aureus SSTIs (cases) and in controls with no infection, using a novel S. aureus protein microarray.Results: Most S. aureus SSTI patients (n = 60) and controls (n = 142) had antibodies to many of the tested S. aureus antigens. Univariate analysis showed statistically weak differences in the IgG levels to some antigens in the SSTI patient (case) sera compared with controls. Antibody levels to most tested antigens did not increase comparing acute with 40-day serum. Multiple logistic regression identified a rich subset of antigens that, by their antibody levels, together correctly differentiated all cases from all controls.Conclusions: Antibodies directed against S. aureus antigens were present both in patients with S. aureus SSTIs and in uninfected control patients. We found that SSTI patients and controls could be distinguished only based on differences in antibody levels to many staphylococcal surface and secreted antigens. Our results demonstrate that in the studied population, the levels of anti-S. aureus antibodies appear largely fixed, suggesting that there may be some level of unresponsiveness to natural infection.

A Comprehensive View on the Human Antibody Repertoire Against Staphylococcus aureus Antigens in the General Population

“…In patients suffering from acute infection caused by S. aureus , Dryla et al ( 30 ) reported increased IgG titers directed against six of 19 staphylococcal antigens ( 30 ). Rigat et al ( 37 ) confirmed the “nearly universal” natural exposure of humans to S. aureus using a panel of 134 antigens, but found only little changes of the antibody levels due to a clinically significant S. aureus infection ( 37 ). All the aforementioned studies were limited in their dynamic range as only one serum dilution was analyzed per sample, rendering them prone to saturation and limit-of-detection effects.…”

A Bioinformatic Approach to Utilize a Patient’s Antibody-Secreting Cells against Staphylococcus aureus to Detect Challenging Musculoskeletal Infections

“…Serologic detection of anti-S. aureus Abs against acute S. aureus infections such as bacteremia and skin infections are being pursued by other investigators (51)(52)(53)(54). A recent study involving 42 children with invasive S. aureus infections demonstrated that anti-LukAB Abs could be a useful diagnostic predictor (55), although leukocidin was not a biomarker for MSKI.…”

Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

“…The non-adjuvanted vaccine induced a rapid and potent antibody response towards the vaccine antigens suggesting that the vaccine induced a memory response, which pre-existed prior to vaccination. This phenomenon can be explained by the fact that humans are virtually all exposed to S. aureus and indeed the presence of antibodies against its antigens in healthy subjects has been documented ( 81 ). The effect for AS03 in boosting the S. aureus vaccine immunogenicity appeared not statistically superior as compared to the non-adjuvanted vaccine ( 82 ).…”

“…Interestingly, vaccine efficacy (as measured through the development of infection-induced skin lesions) was unaffected when mice were pre-exposed intradermally to a low dose of S. aureus prior to vaccination. As mentioned previously, humans are naturally exposed to S. aureus and harbor pre-existing immunity ( 81 ). Pre-exposing mice to S. aureus therefore represents an encouraging degree of humanization to the mouse model.…”