Performance of a Four-Antigen Staphylococcus aureus Vaccine in Preclinical Models of Invasive S. aureus Disease

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.

Keywords: ClfA; MntC; SA4Ag vaccine; Staphylococcus aureus; animal models; conjugated polysaccharide; invasive disease; protection; sepsis; surgery-associated infection.

Figure 1

SA4Ag antigens are immunogenic in preclinical species. Immune responses against SA4Ag antigens CP5, CP8, ClfA, and MntC were measured before (pre) and after (PD) immunization. Rodents were immunized three times subcutaneously with SA4Ag + AlPO₄ prior to sample collection post-dose 3 (PD3). Non-human primates (NHP) were immunized a single time with SA4Ag without adjuvant. Anti-capsular immune responses were measured by the OPA assay for CP5 (A) and CP8 (B). Anti-protein immune responses were measured by cLIA for ClfA (C) and MntC (D). Human responses to a single unadjuvanted dose of SA4Ag are included as a comparator, adapted from [27].

Figure 1

SA4Ag antigens are immunogenic in preclinical species. Immune responses against SA4Ag antigens CP5, CP8, ClfA, and MntC were measured before (pre) and after (PD) immunization. Rodents were immunized three times subcutaneously with SA4Ag + AlPO₄ prior to sample collection post-dose 3 (PD3). Non-human primates (NHP) were immunized a single time with SA4Ag without adjuvant. Anti-capsular immune responses were measured by the OPA assay for CP5 (A) and CP8 (B). Anti-protein immune responses were measured by cLIA for ClfA (C) and MntC (D). Human responses to a single unadjuvanted dose of SA4Ag are included as a comparator, adapted from [27].

Figure 2

Immunization with SA4Ag reduces bacterial burden in a S. aureus pyelonephritis model. Female CD-1 mice (n = 5) were vaccinated at weeks 0, 3, and 6, with SA4Ag or with vehicle alone. Two weeks after the final vaccination animals were challenged with ~2 × 10⁸ S. aureus Reynolds. Two days post-challenge, the mice were euthanized and kidneys collected. Bacteria in kidneys were enumerated (colony-forming unit [CFU]/kidney). p value was calculated by Student’s t-test.