Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus

Abstract

Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7-10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17-secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus.Staphylococcus aureus | vaccine | TLR7 | adjuvant | Hla C urrent antibiotics are not efficacious against emerging multidrug-resistant strains of Staphylococcus aureus, a major human pathogen. Therefore, there is an urgent need to develop vaccines to target this pathogen. Two prophylactic vaccines have been tested recently for efficacy in humans: StaphVAX, which contained capsular polysaccharides type 5 and 8 (CP5 and CP8), and V710, based on a single protein antigen (IsdB) (1, 2). Both vaccines failed in phase III efficacy trials (3, 4). On the basis of these disappointing results and taking into account that S. aureus produces a plethora of virulence and immune evasion factors, different vaccine candidates, constituted by multiple components, are currently in phase I/II trials, but efficacy data are not available yet (5). In line with the multicomponent strategy, our laboratory has undertaken a vaccine discovery project aiming at the identification of conserved antigens, which play important roles in S. aureus virulence and pathogenicity. The main objective of the study was to combine the selected antigens in the presence of appropriate adjuvants and to demonstrate protective efficacy against a panel of genetically different S. aureus clinical isolates in different mouse models. ResultsAntigen Selection. The antigens included in our candidate combination vaccine were selected among surface and secreted factors previously shown to be protective and involved in S. aureus virulence. Two of them, the ferric hydroxamat...

Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence

“…This vaccine provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1-skewed immune response and IL-17-secreting T cells (127). Among the five antigens were two Lpp, FhuD2 and conserved staphylococcal antigen 1A (Csa1A).…”

Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

“…We recently described an aluminum hydroxide-adjuvanted vaccine formulation, fourcomponent S. aureus vaccine (4C-Staph), which included five S. aureus antigens: a genetically detoxified derivative of the secreted alpha-toxin hemolysin (Hla), two surface-exposed antigens, FhuD2 and Csa1A, and EsxAB, a protein fusion of two secreted proteins, EsxA and EsxB. This formulation was able to protect mice from infection in different murine models, and induction of functional 4C-Staph-specific antibodies seemed to play a major role in achieving protection (6). The use of systemic infections (abscess, peritonitis, and pneumonia models) or skin infections resulting in dermonecrosis hampered a deeper analysis of immune humoral factors and cellular components possibly associated with protection at the site of infection.…”

Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting

“…Recently, eicacy of a combination vaccine, 4C-Staph (four-component S. aureus vaccine), was evaluated [90]. 4C-Staph is composed of detoxiied α-Hemolysin, a fusion of ess extracellular A (EsxA) and ess extracellular B (EsxB), two staphylococcal surface proteins, which are ferric hydroxamate-binding lipoprotein (FhuD2) and conserved staphylococcal antigen 1A (Csa1A).…”