One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A

Abstract

A rapidly acting, single dose vaccine against Staphylococcus aureus would be highly beneficial for patients scheduled for major surgeries or in intensive care units. Here we show that one immunization with a multicomponent S. aureus candidate vaccine, 4C-Staph, formulated with a novel TLR7-dependent adjuvant, T7-alum, readily protected mice from death and from bacterial dissemination, both in kidney abscess and peritonitis models, outperforming alum-formulated vaccine. This increased efficacy was paralleled by higher vaccine-specific and α-hemolysin-neutralizing antibody titers and Th1/Th17 cell responses. Antibodies played a crucial protective role, as shown by the lack of protection of 4C-Staph/T7-alum vaccine in B-cell-deficient mice and by serum transfer experiments. Depletion of effector CD4+ T cells not only reduced survival but also increased S. aureus load in kidneys of mice immunized with 4C-Staph/T7-alum. The role of IL-17A in the control of bacterial dissemination in 4C-Staph/T7-alum vaccinated mice was indicated by in vivo neutralization experiments. We conclude that single dose 4C-Staph/T7-alum vaccine promptly and efficiently protected mice against S. aureus through the combined actions of antibodies, CD4+ effector T cells, and IL-17A. These data suggest that inclusion of an adjuvant that induces not only fast antibody responses but also IL-17-producing cell-mediated effector responses could efficaciously protect patients scheduled for major surgeries or in intensive care units.

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

“…We have previously shown that the 4C-Staph formulation is effective in reducing S. aureus systemic infection in different murine models21222324. Immunization of mice with this formulation was associated in the present model with reduction of the bacterial load both in knee joints and kidneys (Fig.…”

“…This may positively affect the control of the infection not only because a greater number of viable B cells is present in situ and produces specific IgG, but also because the antigen presenting activity may be exerted more efficiently70. The second change that we observed concerned the specific CD4+ T cells induced by vaccination with 4C-Staph, and which we have previously shown to protect mice against septic death2324. In fact, we observed that, in mice immunized with the 4C-staph formulation, a significantly higher number of CD4+ T effector memory lymphocytes was present in the knee joints as compared to the blood, and that these cells were mainly associated with the presence of Th0-Th2 but also of Th1-like cytokines, as was to be expected on the basis of the alum adjuvant used (Fig.…”

“…This is also supported by the fact that the use of an effective vaccine against a major human pathogen responsible for SA, H. influenzae type B , resulted in the complete disappearance of this disease6. Although a vaccine against S. aureus is not yet available, we have recently demonstrated that immunization of mice with a multi-component protein-based vaccine (4C-Staph) was able to ameliorate the outcome of S. aureus infection in different in vivo models and that protection was dependent on both the humoral and cellular responses induced by vaccination21222324. We therefore set up a S. aureus infection model, resulting in a consistent bacterial infection of murine joints, in which we tested the ability of the proposed 4C-Staph formulation to reduce the burden of bacterial infection in the knees.…”

“…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.…”

The role of vaccines in fighting antimicrobial resistance (AMR)

“…54 In addition, a separate 4 component S. aureus vaccine (4C-Staph) formulated with a TLR7-dependent adjuvant is under development. 55 …”