aureusvaccine has been based on the notion that the neutralization of virulence factors elaborated by the bacterium could ameliorate or prevent disease. order to generate immune synergy againstS. aureusinfections. A single-antigen vaccine may achieve this immune synergy. However, multivalent antigens may be more likely to induce both humoral and T cell immunity and to induce protection against a broader array ofS. aureusisolates. A number of candidate vaccines are in development, raising the promise that effective vaccines againstS. aureuswill become available in the not-so-distant future. Possible development programs for such vaccines are discussed. Keywords:S. aureus, Vaccine, Development, Immunology == Introduction == Staphylococcus aureusis a Rabbit Polyclonal to TAIP-12 ubiquitous pathogen. It is the most common cause of culture-confirmed skin and soft tissue infections (SSTIs) [14] and endocarditis [5], and is the second most common cause of bacteremia [6,7].S. aureusis also a predominant cause of a variety of nosocomial infections, including ventilator-associated pneumonia, intravenous catheter-associated infections, postsurgical wound infections, as well as invasive infections in neutropenic patients and in patients undergoing solid organ or hematopoeitic stem cell transplants [8]. Invasive infections caused byS. aureuscontinue to increase in frequency [9,10]. Population-based estimates of the incidence ofS. aureusinfections have ranged from a low of approximately 30 per 100,000 [11,12] for analyses restricted to invasive (beyond skin) disease to up to 600 per 100,000 based on extrapolation from a surveillance study in the USA [13]. In a separate study from Europe, the incidence BX-795 of just bacteremia caused byS. aureuswas reported to be 30 per 100,000 [14]. Given that >90% of infections caused byS. aureusare skin infections [15], incidences ofS. aureusbacteremia of ~30 per 100,000 support the estimate of approximately 600 per 100,000 total incidence ofS. aureusdisease reported by the CDC. Therefore, there may be 1.8 million cases ofS. aureusinfection (including skin infection) per year in the USA alone, which obviously provides a potentially massive market to stimulate interest in vaccine development. Community-associatedS. aureusinfections were formerly nearly uniformly susceptible to penicillinase-resistant beta lactams (i.e., BX-795 methicillin, oxacillin, etc.). However, over the past decade, a number of community-based outbreaks of methicillin-resistantS. aureus(MRSA) infections have emerged, initially in pediatric populations [1618]. Community outbreaks of MRSA infections also have been seen in adults in multiple locales in the USA and across the globe, and in many places, MRSA has become the predominantS. aureusstrain causing community-acquired infections [15,1923]. The rise in MRSA incidence underscores the need to develop new strategies to prevent invasiveS. aureusinfections. Given its high incidence of causing life-threatening, drug-resistant infections, a vaccine to preventS. aureusinfections would have an enormous and beneficial impact on global and US health. The purpose of this review was to broadly discuss challenges to and the promise of developingS. aureusactive vaccines. Issues ranging from fundamental immunology, to antigen targets, to practical considerations for development programs are discussed. == Fundamental immune underpinnings of aS. aureusvaccine == == What type of immune response should be stimulated? == When rationally designing a vaccine against a specific disease, it is desirable to understand what mode of immunity, when induced, will serve to protect the host from the target infection. Vaccines which induce the protective mode of immunity can then be developed. There are two types of studies which can elucidate the nature of protective immunity against specific diseases. For example, natural infection may induce a specific type of memory immune response which protects against subsequent reinfection. Identification of the nature of that protective memory response in patients with previous natural infection can be used to elucidate what type of immune response to focus on when vaccinating immunologically naive patients. A second means to elucidate the nature of protective immunity against a specific disease is definition of the nature of immune BX-795 defects which specifically predispose to the disease. These two types of datadescription of the type of immunity that is protective after natural infection and description of specific immune defects that predispose to infectionprovide complementary information. Specifically, protective immunity after natural infection elucidates immunity that is sufficient to.