A Novel Staphylococcus aureus Vaccine: Iron Surface Determinant B Induces Rapid Antibody Responses in Rhesus Macaques and Specific Increased Survival in a Murine S. aureus Sepsis Model

Abstract

Staphylococcus aureus is a major cause of nosocomial infections worldwide, and the rate of resistance to clinically relevant antibiotics, such as methicillin, is increasing; furthermore, there has been an increase in the number of methicillin-resistant S. aureus community-acquired infections. Effective treatment and prevention strategies are urgently needed. We investigated the potential of the S. aureus surface protein iron surface determinant B (IsdB) as a prophylactic vaccine against S. aureus infection. IsdB is an iron-sequestering protein that is conserved in diverse S. aureus clinical isolates, both methicillin resistant and methicillin sensitive, and it is expressed on the surface of all isolates tested. The vaccine was highly immunogenic in mice when it was formulated with amorphous aluminum hydroxyphosphate sulfate adjuvant, and the resulting antibody responses were associated with reproducible and significant protection in animal models of infection. The specificity of the protective immune responses in mice was demonstrated by using an S. aureus strain deficient for IsdB and HarA, a protein with a high level of identity to IsdB. We also demonstrated that IsdB is highly immunogenic in rhesus macaques, inducing a more-than-fivefold increase in antibody titers after a single immunization. Based on the data presented here, IsdB has excellent prospects for use as a vaccine against S. aureus disease in humans.Staphylococcus aureus is a gram-positive bacterium that is notable for the frequency and severity of infections that it causes in hospitalized patients. These infections range from localized skin infections to bacteremia and septic shock. In the past 20 years there has been a dramatic increase in the incidence of nosocomial staphylococcal infections; this increase parallels the increased use of intravascular devices and invasive procedures. S. aureus has been identified as one of the three most frequent nosocomial pathogens and is responsible for approximately 25% of the 2 million nosocomial infections reported in the United States each year (38, 39). A second trend has been the increase in the incidence of methicillin-resistant S. aureus, largely due to selective antibiotic pressure. Resistant strains were initially identified in tertiary care hospitals but have been increasingly reported among infections in the community (25, 30). Resistance to methicillin is often accompanied by resistance to other antibiotics; a CDC survey showed that the proportion of methicillin-resistant isolates which were susceptible only to vancomycin rose from 22.8% to 56. 2% from 1987 to 1997 (18). More recently, S. aureus strains with intermediate susceptibility or resistance to vancomycin have been reported (11,24,36). Infections caused by multidrug-resistant S. aureus limit therapeutic options, and they may be associated with higher mortality and higher costs than infections caused by susceptible staphylococci. There is clearly a need for new treatment and prevention strategies.In an immunological survey of S. aureus su...

Naturally occurring IgG antibody levels to theStaphylococcus aureusprotein IsdB in humans

“…Of the 50 hospital controls, 39 had sera from multiple time-points (median number of samples: 4, range: 2 to 8), and the mean time for final follow-up was 11.6 days post-diagnosis (range: 2 to 34 days). The mean time of followup was slightly longer for the hospital S. aureus cases compared deleted strain, 9,16 confirming the specificity of the vaccine. An observed rise in anti-IsdB titers induced by IsdB formulated on Merck aluminum adjuvant (MAA) correlated with protection against lethal S. aureus challenge, 9 indicating that antibody titers may be used as a nominal biomarker for vaccine efficacy.…”

“…9 The potential use of this antigen as a component of a vaccine for prevention of S. aureus disease has been previously described. 9,15 However, as a stand-alone vaccine (V710), protection was not observed in a clinical efficacy trial among cardiac surgery patients, 21 despite a significant increase in IsdB antibody titers in the V710 vaccinated patients. Although the IsdB specific with the hospital controls (p = 0.05).…”

“…8 The IsdB antigen is highly conserved and expressed on all isolates examined to date. 9 Due to upregulation in iron-limited environments, 9,10 IsdB is theoretically available for immune recognition during infection in the human host, where iron is highly sequestered. 8,11,12 Expression of IsdB was highly upregulated by essentially 100% of strain Becker grown under in vivo conditions in rats.…”

“…8,11,12 Expression of IsdB was highly upregulated by essentially 100% of strain Becker grown under in vivo conditions in rats. 10 Multiple reports have demonstrated IsdB to be a potential vaccine candidate for the prevention of S. aureus infection 9,[13][14][15][16] in rodent challenge models. Importantly, enhanced protection from lethal sepsis in rodent models was mediated by both IsdB-specific CD4+ T cells, 16 and IsdB-specific mAb.…”

“…Importantly, enhanced protection from lethal sepsis in rodent models was mediated by both IsdB-specific CD4+ T cells, 16 and IsdB-specific mAb. 10,13,[17][18][19] The protection afforded by vaccination with IsdB in rodents was lost if the animals were challenged with an IsdB fluid (9), surgical tissue (22), synovial fluid (17), sputum (9), or other sites (5) during routine clinical care. Of the 52 S. aureus isolates, 51 were spa typed; a single isolate failed to grow sufficiently in culture for spa determination.…”