Abstract
A Staphylococcus aureus four-antigen vaccine (SA4Ag) was designed for the prevention of invasive disease in surgical patients. The vaccine is composed of capsular polysaccharide type 5 and type 8 CRM197 conjugates, a clumping factor A mutant (Y338A-ClfA) and manganese transporter subunit C (MntC). S. aureus pathogenicity is characterized by an ability to rapidly adapt to the host environment during infection, which can progress from a local infection to sepsis and invasion of distant organs. To test the protective capacity of the SA4Ag vaccine against progressive disease stages of an invasive S. aureus infection, a deep tissue infection mouse model, a bacteremia mouse model, a pyelonephritis model, and a rat model of infectious endocarditis were utilized. SA4Ag vaccination significantly reduced the bacterial burden in deep tissue infection, in bacteremia, and in the pyelonephritis model. Complete prevention of infection was demonstrated in a clinically relevant endocarditis model. Unfortunately, these positive preclinical findings with SA4Ag did not prove the clinical utility of SA4Ag in the prevention of surgery-associated invasive S. aureus infection.
Highlights
Staphylococcus aureus is a Gram-positive bacterium that is carried asymptomatically in the nares of 20–50% of the general population [1]
SA4Ag is comprised of capsular polysaccharides type 5 and type 8 cross-reactive material 197 (CRM197) -conjugates, ClfA, and manganese transporter subunit C (MntC)
SA4Ag was shown to be able to elicit functional antibody responses in mice, rats and non-human primates, as measured by the opsonophagocytic activity (OPA) assay, which monitors the ability of serum samples to opsonize and induce uptake and killing of target bacteria by a neutrophil-like cell line, or by Competitive Luminex-based immunoassays (cLIA), which monitors the ability of serum to compete with monoclonal antibodies (mAbs) for antigen binding
Summary
Staphylococcus aureus is a Gram-positive bacterium that is carried asymptomatically in the nares of 20–50% of the general population [1]. S. aureus infections following surgery carry high mortality rates, and survivors require an additional 13–17 days in the hospital, significantly increasing healthcare costs [3]. The burden of S. aureus disease is exacerbated by the prevalence of antibiotic-resistant. S. aureus isolates [4], highlighting the need for an effective prophylactic vaccine. A consideration in both development and preclinical evaluation of a S. aureus vaccine is the organism’s ability to rapidly adapt to the host microenvironment [5]. S. aureus can enter normally sterile sites through lesions such as those created during surgery or traumatic injury and rapidly deploy an array of pathogenesis mechanisms, rendering
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