MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers

Abstract

Staphylococcus aureus (S. aureus) is an important opportunistic pathogen that may cause invasive life-threatening infections, like sepsis and pneumonia. Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed. Although a correlate of protection against staphylococcal diseases is not yet established, several findings suggest that both antibodies and CD4 T cells might contribute to optimal immunity. In this study, we show that adjuvanting a multivalent vaccine (4C-Staph) with MF59, an oil-in-water emulsion licensed in human vaccines, further potentiated antigen-specific IgG titers and CD4 T-cell responses compared to alum and conferred protection in the peritonitis model of S. aureus infection. Moreover, we showed that MF59- and alum-adjuvanted 4C-Staph vaccines induced persistent antigen-specific humoral and T-cell responses, and protected mice from infection up to 4 months after immunization. Furthermore, 4C-Staph formulated with MF59 was used to investigate which immune compartment is involved in vaccine-induced protection. Using CD4 T cell-depleted mice or B cell-deficient mice, we demonstrated that both T and B-cell responses contributed to 4C-Staph vaccine-mediated protective immunity. However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses. This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen.

Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

“…We have recently described a multi-protein vaccine formulation, 4C-Staph, which protects mice from S. aureus infection in different models212223. Since arthrosynovitis and OM are among the most severe S. aureus -dependent diseases in humans345, we wanted to test the efficacy of the vaccine formulation in a mouse model of knee joint infection and evaluate local and systemic host immune responses.…”

“…We have recently demonstrated that an adjuvanted protein combination vaccine, 4C-Staph, conferred significant protection against different S. aureus strains in multiple murine infection models, and that protection was dependent on both humoral and cellular immune responses21222324.…”

Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4 + T Cells

“…MF59 was shown to create an immunocompetent microenvironment at the injection site by inducing chemokines and cytokines as well as recruiting neutrophils, eosinophils, and, later, DCs and macrophages (7). Previous studies on MF59 suggest that an immunocompetent microenvironment with activated innate immune cells and APCs leads to the induction of effector CD4 ϩ T cells, eventually helping B cells to differentiate IgG antibody-secreting plasma cells (17,(33)(34)(35). By using microarray and immunofluorescence analyses, MF59 was determined to be a strong inducer of cytokines, cytokine receptors, adhesion molecules, and antigen-presenting genes FIG 6 MF59 induces acute production of cytokines and chemokines at higher levels than does alum.…”

Community-Associated Meticillin Resistant Staphylococcus aureus: increased burden of infections in children and young people in Queensland and Australia

“…However, a correlate of protection against S. aureus infections is not clearly established, and recent vaccine studies have investigated other S. aureus antigens -e.g. the multi-antigen 4C-Staph vaccine (141).…”

“…Strategies to manage and prevent infections (e.g. multiple hygiene and decolonisation measures) may be attempted in individuals, small communities or in low incidence settings but are problematic on the larger scale (93,95) and efforts to develop successful vaccines continue (141).…”