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

Mancini, Francesca; Monaci, Elisabetta; Lofano, Giuseppe; Torre, Antonina; Bacconi, Marta; Tavarini, Silvia; Sammicheli, Chiara; Arcidiacono, Letizia; Galletti, Bruno; Laera, Donatello; Pallaoro, Michele; Tuscano, Giovanna; Fontana, Maria Rita; Bensi, Giuliano; Grandi, Guido; Rossi-Paccani, Silvia; Nuti, Sandra; Rappuoli, Rino; Gregorio, Ennio De; Bagnoli, Fábio; Soldaini, Elisabetta; Bertholet, Sylvie

doi:10.1371/journal.pone.0147767

Cited by 48 publications

(41 citation statements)

References 48 publications

(55 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 54%

“…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.…”

Section: Discussionmentioning

confidence: 88%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Corrado

Donato

Maccari

et al. 2016

Sci Rep

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Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use.Staphylococcus aureus is a human pathogen responsible for a variety of diseases ranging from minor/mild skin infections to life threatening diseases 1 . It is a major cause of bacteremia, which frequently leads to severe complications like endocarditis, toxic shock syndrome, septic arthritis (SA) and osteomyelitis (OM) 2 . Among others, joint-related diseases deserve special attention because of their rapid evolution and serious clinical outcomes, such as intense pain and impairment due to bone erosion requiring urgent intervention [3][4][5] . Joint infections are frequently localized in the knees and hips, and monoarticular disease is more frequent and less severe than polyarticular infection 6,7 . The mortality rate associated with these infections is around 5-20% in the adult population 3 , but can reach 50% depending on delayed diagnosis, immunodeficiency, older age 3,4 and pre-existing underlying conditions, such as rheumatoid arthritis and diabetes 3,8,9 . Joint and bone disruption is caused by the activity of bacteria in the joints, as well as by uncontrolled activation of the host immune system sustaining a local destructive inflammatory state, which can eventually result in chronic disease [10][11][12][13] . OM is often not treatable with antibiotics, a problem that is presently more evident with the increasing emergence of antibiotic-resistant S. aureus strains [14][15][16][17][18][19] . On the other hand, early application of antibiotic treatment can be efficacious for SA, which however often requires surgical intervention 3,4,7,20 .Given these premises, the development of an efficacious vaccine able to prevent S. aureus-mediated SA and OM would be highly desirable. We have recently demonstrated that an adjuvanted protein comb...

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Corrado

Donato

Maccari

et al. 2016

Sci Rep

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

Section: Vaccines In Late Stage Development With Potential To Reduce Amrmentioning

confidence: 99%

The role of vaccines in fighting antimicrobial resistance (AMR)

Jansen

Anderson

2018

Human Vaccines & Immunotherapeutics

104

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The problem of antimicrobial resistance (AMR) and the associated morbidity and mortality due to antibiotic resistant bacterial pathogens is not new. However, AMR has been increasing at an alarming rate with appearances of diseases caused by bacteria exhibiting resistance to not just one but multiple classes of antibiotics. The World Health Organization (WHO) supported by governments, health ministries and health agencies has formulated global action plans to combat the rise in AMR, supporting a number of proven initiatives such as antimicrobial stewardship, investments in development of new classes of antibiotics, and educational programs designed to eliminate inappropriate antibiotic use. Vaccines as tools to reduce AMR have historically been under-recognized, yet the positive effect in reducing AMR has been well established. For example Haemophilus influenzae type B (Hib) as well as Streptococcus pneumoniae (pneumococcal) conjugate vaccines have impressive track records in not only preventing life threatening diseases caused by these bacteria, but also reducing antibiotic use and AMR. This paper will describe the drivers of antibiotic use and subsequent development of AMR; it will make the case how existing vaccines are already participating in combatting AMR, describe future prospects for the role of new vaccines in development to reduce AMR, and highlight challenges associated with future vaccine development to combat AMR.

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