Vaccine review: “Staphyloccocus aureus vaccines: Problems and prospects”

Vaccine 31 (2013) 2723–2730

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Review

Vaccine review: “Staphyloccocus aureus vaccines: Problems and prospects” Kathrin U. Jansen ∗ , Douglas Q. Girgenti, Ingrid L. Scully, Annaliesa S. Anderson Pfizer Inc, 401 N. Middletown Road, Pearl River, NY 10965, USA

a r t i c l e

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Article history: Received 4 February 2013 Received in revised form 28 March 2013 Accepted 1 April 2013 Available online 23 April 2013 Keywords: Staphylococcus S. aureus Vaccine Immune response Patient population

a b s t r a c t Staphylococcus aureus is a leading cause of both healthcare- and community-associated infections globally. S. aureus exhibits diverse clinical presentations, ranging from benign carriage and superficial skin and soft tissue infections to deep wound and organ/space infections, biofilm-related prosthesis infections, life-threatening bacteremia and sepsis. This broad clinical spectrum, together with the high incidence of these disease manifestations and magnitude of the diverse populations at risk, presents a high unmet medical need and a substantial burden to the healthcare system. With the increasing propensity of S. aureus to develop resistance to essentially all classes of antibiotics, alternative strategies, such as prophylactic vaccination to prevent S. aureus infections, are actively being pursued in healthcare settings. Within the last decade, the S. aureus vaccine field has witnessed two major vaccine failures in phase 3 clinical trials designed to prevent S. aureus infections in either patients undergoing cardiothoracic surgery or patients with end-stage renal disease undergoing hemodialysis. This review summarizes the potential underlying reasons why these two approaches may have failed, and proposes avenues that may provide successful vaccine approaches to prevent S. aureus disease in the future. © 2013 Elsevier Ltd. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2723 Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2727 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2727

1. Introduction When assessing the problem and prospect of developing a Staphylococcus aureus vaccine, it is important to carefully consider three areas that may influence success: the pathogen, the host and the requirements for a successful vaccine. S. aureus is a successful commensal bacterium that effectively colonizes both animal and human hosts [1]. Under normal circumstances and in healthy individuals, colonization per se usually is not problematic, and may actually be beneficial, in preventing severe S. aureus disease outcomes [2]. However, exposure of subjects (especially colonized subjects) to healthcare settings and procedures that breach the dermal barrier, the most effective human defense against this pathogen, can result in a higher incidence of S. aureus infections. It is important to realize that individuals in healthcare settings (compared to community settings) typically are ill and as such have an

∗ Corresponding author. Tel.: +1 845 602 5450; fax: +1 845 602 5727. E-mail addresses: Kathrin.Jansen@pfizer.com (K.U. Jansen), Douglas.girgenti@pfizer.com (D.Q. Girgenti), Ingrid.scully@pfizer.com (I.L. Scully), Annaliesa.Anderson@pfizer.com (A.S. Anderson). 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.04.002

increased probability of being immunocompromised as a result of their illness. Furthermore, hospitalized patients tend to be older, are more likely to have comorbidities such as obesity, diabetes mellitus, underlying cardiac and/or pulmonary disease. These patients may also require surgical management or intensive care [3–5]. All of these factors negatively impact immune responses and can increase the risk of infection. Individuals can also be immunologically compromised in certain healthcare-associated settings for reasons such as HIV infection, solid organ transplantation, end-stage renal disease, cancer, and/or treatment with immunosuppressive medications, conditions that are all known to increase the risk of S. aureus infection [3,6–9]. However, the precise immunopathological mechanisms that predispose a given individual to S. aureus disease are still unclear. Preclinical animal models have thus been developed to study S. aureus pathogenesis but these models are limited by the fact that S. aureus is exquisitely adapted to the human host. Therefore, no preclinical animal model of infection fully recapitulates the natural infectious process in humans, due to differences in host cell proteins, such as hemoglobin [10], and the requirement for high bacterial challenge doses [11] in the non human host. In addition to hospital settings and particularly in the U.S., S. aureus disease outbreaks in the community have occurred among

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elderly in institutional care facilities, inmates in correctional facilities, competitive sports participants, military recruits, childcare center attendees, college students and men who have sex with men [12–18]. Considering all the at risk populations, it becomes apparent that S. aureus is well adapted for survival in essentially all host niches that this successful pathogen can invade. Futhermore, the bacterium’s armament of virulence and pathogenesis factors is well-equipped to exploit the weaknesses of subjects at risk of disease [19]. From the perspective of the large and diverse reservoir of susceptible patients, the multiple disease manifestations exhibited by S. aureus, and the fact that S. aureus has co-evolved with its mammalian hosts as a commensal, S. aureus has developed a vast array of often redundant mechanisms to ensure its survival. A large number of reviews have summarized the exquisite ability of this pathogen to employ an array of virulence factors and survival mechanisms in the human host. These range from establishing and maintaining nasopharyngeal carriage [20,21], to invading the human host [22–24] and establishing infections through elaborating proteins and factors that scavenge essential nutrients [25–28], enable adhesion and tissue penetration [29–32], or facilitate the avoidance of attack by both the innate and adaptive immune system [33–38]. This complex and sophisticated adaptation of S. aureus to many different host niches needs to be considered when designing candidate vaccines against this pathogen. Thus the suggestion made by many in the field, including ourselves, is that a rational and logical approach to vaccine development must simultaneously address multiple virulence and bacterial defense mechanisms [19,39,40]. However, how many and which antigens should be targeted by a vaccine is a matter of some debate [41,42]. Another area of consideration in the development of an effective vaccine is an understanding and critical review of the protective immune responses that must be elicited by a vaccine to prevent S. aureus infection and disease. Over the last ten years, a large number of reviews and original papers have shed light as to which arms of the immune system need to be triggered and are critical for confering potential protection against this pathogen [38,43–53]. Vaccine-induced adaptive immunity, including both T cell and B cell responses, will likely be required for full protection. Antigenspecific T helper cells are critical for generating optimal antibody responses, and Th17 cells can enhance neutrophil function, which may augment bacterial clearance [48]. Indeed, individuals with AIDS or genetic defects in adaptive immune responses are at increased risk for S. aureus infection [54,14,55]. However, this area remains controversial, as our understanding of proposed protective immune mechanisms is often based on animal models (rather than thorough prospective studies in humans), with potentially limited applicability to the human situation, or generalizations that are based on simplistic approaches or assumptions. This review will not revisit the excellent work and numerous papers that have been published over the last few years in the areas described above, but will instead attempt to specifically highlight underlying issues associated with the unsuccessful vaccine approaches pursued to date. We propose that studying the three areas described below, namely critical anti-bacterial vaccine immunogenicity, bacterial pathogenesis with respect to vaccine development (vaccine antigen selection) and the choice of patient populations for evaluating vaccine efficacy, in a holistic rather than isolated fashion will have the best prospect of developing a successful prophylactic vaccine against S. aureus. 1) Anti-bacterial vaccine immunogenicity – Not all antibodies are created equal It is well established that functional human neutrophils are critical for preventing infection by Gram positive bacteria, including S. aureus. Neutrophils are crucial for the destruction

of S. aureus, through the elaboration of reactive oxygen species, release of toxic granule contents and DNA nets, and ultimately the uptake and killing of the pathogen [56,57]. This protective mechanism can be modeled by the opsonophagocytic activity assay (OPA) that measures the killing of S. aureus isolates in vitro [58]. There is ample evidence that humans with frank neutropenia or impaired neutrophil function due to congenital defects in neutrophil chemotaxis, the ability to generate a respiratory burst, or with defects in neutrophil granule biosynthesis, are all vulnerable to S. aureus infection and disease [59–63]. In addition, patients with innate imune system disorders affecting IL-1R or TLR signaling or patients with quantative or qualitative Th17 deficiencies have all been shown to be more susceptible to S. aureus infections [54,64,65]. Although the role of both neutrophils and the innate immune response in the protection against S. aureus infection is well accepted, there is considerable scepticism as to whether antistaphylococcal antibodies are protective [66]. This position is typically based on results emanating from the pursuit of a number of unsuccessful passive or active antibody immunotherapies against S. aureus infections and disease (Table 1). Upon closer examination, however, the conclusion that antibodies are not important for protection against S. aureus infection may be too simplistic for several reasons. First, one has to examine whether the antibody immunotherapies were based on either a prophylactic or a therapeutic approach. It may be quite difficult to observe antibody efficacy in therapeutic settings, where the infectious process is well underway and bacteria may have invaded cells or formed biofilms. Indeed, existing staphylococcal infections are difficult to treat with bacteriostatic and/or bactericidal antibiotics [67–76], even in the absence of resistance. Secondly, it is often quoted that human defects in the ability to make antibodies are not associated with an increased risk of acquiring S. aureus infections [1,77,78], yet such defects are associated with higher risk of infections by other Gram positive bacteria such as Streptococcus pneumoniae and Str. pyogenes (group A streptococci). However, unlike group A streptococci, where natural infection leads to protective immunity against strains with the same M protein type, colonization or natural infection with S. aureus rarely induces functional, opsonophagocytic antibodies in human subjects. This is in spite of the fact that the vast majority of human subjects do develop significant levels of non-functional binding antibodies to a plethora of S. aureus antigens [79,80]. Furthermore, even in the case of Str. pneumoniae, the levels of anti-capsular binding antibodies that correlate with protection in infants and young children [81] do not appear to be correlated with protection in older adults [82,83]. Therefore, it is not surprising that individuals with deficiencies in antibody production do not appear to be at an increased risk for infection with S. aureus, as even most individuals without these overt defects do not produce functional, anti-staphylococcal antibodies through natural exposure in quantities that kill the bacteria or neutralize its virulence factors [58,84]. Acknowledging these facts, the failure of Veronate, a pooled hyperimmune IgG preparation against S. aureus surface proteins (Table 1), was not surprising in hindsight, as the antibodies were not assessed for their functionality, and more importantly for their ability to elicit true opsonophagocytic killing responses. Also, not all antibodies are created equal. It is often stated that individuals become infected with S. aureus even in the presence of high levels of anti-staphylococcal antibodies, and therefore it is reasoned that antibodies are not playing a major role in protection. However, most studies in naturally exposed or even vaccinated humans have focused on measuring anti-staphylococcal binding antibodies using ELISA, rather than evaluating antibody responses in true functional assays, i.e. OPA where the bacteria

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Table 1 Overview of clinical trials where immunotherapeutics have been used to treat or prevent S. aureus disease. Manufacturer, product name

Current status

Prophylactic investigational vaccines PhIII complete NABIa , StaphVAX

Vaccine composition

Potential limitation(s)

Clinical trial reference(s)

Capsular polysaccharides 5 and 8 conjugated to Pseudomonas aerugunosa exotoxoid

• Did not reach primary endpionts • Manufacturing issues may have impacted vaccine efficacy • Single antigen approach • No efficacy seen • Humans make Abs through natural exposure that are not functional [84] • Neonates do not have a mature immune system • No efficacy seen • Lipoteichoic acid may not be accessible for antibody binding • Neonates do not have a mature immune system • TBD

NCT00071214 [139]; NCT00130260 [140]

• Single antigen • Unknown mechanism of action

NCT01447407

• TBD

NCT01011335 [144]

• TBD

NCT01160172 [145]

Inhibitexb (BMS), Veronate

PhIII complete

Enriched serum from unvaccinated subjects

Biosynexus, Pagibaximab

PhII/III complete

Anti lipoteichoic acid antibody

Pfizer, PF-06290510

PhII

NovaDigm Therapeutics, Inc, NDV-3 NABIa /GSK, protein components GSK, Unnamed

PhIb

ClfA MntC Capsular polysaccharides 5 and 8 conjugated to CRM197 Als3 from Candida albicans

PhI

Novartis, Unnamed

PhI

Vaccine Research International, SA75

PhI

NIAID, STEBVax Merck/Intercell, V710

PhI PhII/III complete; terminated

SEB IsdB

Sanofi SAR279356

PhII for PK; terminated

PNAG

NABIa , Altastaph

PhI; terminated

Immune serum from subjects vaccinated with StaphVAX

PhI complete

Therapeutic investigational vaccines PhII in SAB and CF Inhibitexb (BMS), Aurexis

Panton-Valentine Leukocidin toxoid Alpha toxin Tetravalent vaccine; components not disclosed, adjuvanted with GSK2392102 Tetravalent vaccine; components not disclosed but are all proteins, no adjuvant reported Whole cell vaccine

Anti-ClfA mAb

MedImmune LLC, MEDI4893 NABIa , Altastaph

PhI

Anti-␣ toxin mAb

PhI/II complete

Immune serum from subjects vaccinated with Staphvax

Kenta Biotech, KBSA301

PhI/II; enrollment suspended

Alpha toxin

Berne, Staphyban

Small investigational trial

Whole cell vaccine Alpha toxin toxoid

Novartis/Neutec Pharma, Aurograb

PhIII; terminated

F(ab) against ABC transporter YkpA Vancomycin

a b

• Protein antigens have not been reported to induce robust opsonophagocytic killing antibodies • Immunization with whole-cell S. aureus vaccines may not induce protective antibodies • Limited to SEB-expressing strains • No efficacy seen • Single antigen vaccine • Did not generate opsonophagocytic killing antibodies • Redundancy in iron-acquisition pathways • Biofilm target; antibodies and effector cells may not effectively penetrate pre-existing biofilm layer • Single antigen target • Immune serum from investigational vaccine

NCT00113191 [141]

NCT00646399 [142]

NCT01643941 [143]

[146]

NCT00974935 NCT00518687 [138]

NCT01389700 [147]

NCT00066989 [148]

• Some protection seen in SAB • Monoclonal antibodies are not as effective as pAbs • No direct killing activity, just prevents binding • Infection already established • Single antigen target • Single toxin target

NCT00198289 [149] (CF); NCT00198302 [150] (SAB)

• No efficacy seen [151] • Immune serum from investigational vaccine • Infection already established • Single antigen target • Secreted toxin, does not directly kill organism • Infection already established • Immunization with whole-cell S. aureus vaccines may not induce protective antibodies [84] • Infection already established • F(ab) only blocks transporter function • No Fc portion to facilitate uptake and killing • Single antigen target

NCT00063089 [152]

Nabi Biopharmaceuticals acquired Biota Holdings Limited on November 8, 2012, and has changed its name to Biota Pharmaceuticals, Inc. Inhibitex was acquired by Bristol Myers Squibb in 2012.

NCT01769417

NCT01589185 [153]

NCT00217841 [154]

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are demonstrated to be killed [58] or virulence factor neutralizing assays [85,79]. This is understandable, as functional assays are complex to routinely perform. They require extensive development and qualification time with tight control. Most are also often dependent on biological reagents (such as complement) and representative S. aureus clinical isolates, rather than laboratory strains, which are difficult to standardize and thus pose another hurdle for development. It has become increasingly evident over the last few years that antibodies generated to S. aureus surface proteins either do not induce antibodies with opsonophagocytic activity that kills S. aureus efficiently [84] or only do so at less than-optimal levels [86,87]. These points may help explain why Merck’s V710, a prophylactic monovalent vaccine composed of IsdB [88] developed to prevent S. aureus infections in patients undergoing cardiothoracic surgery, failed to show significant efficacy in preventing S. aureus infections (Table 1). A vaccine such as V710 does not appear to induce antibodies that efficiently destroy/kill live S. aureus bacteria, but instead has only been reported to facilitate the uptake of S. aureus cells into neutrophils. Unfortunately, none of the available clinical data of Merck’s V710 describe or document whether robust functional S. aureus killing responses were induced in the vaccine trials [89] or pre-clinically (Kim de dent 2010), with the exception of some data that individual mAbs recognizing IsdB (the vaccine’s single antigen target) did show functional killing activity [90,91]. Thus, it is unclear which protective mechanism could be postulated that would have predicted V710 efficacy. The focus on measuring and monitoring anti-staphylococcal binding antibodies, compared to true opsonophagocytic antibody responses, may also have contributed to the failure of StaphVAX, a vaccine based on the S. aureus polysaccharide capsular antigens CP5 and CP8. StaphVAX did show a 57% decrease (compared to control) in incidence of bacteremia in its initial phase 3 efficacy study in hemodialysis patients. This protective effect lasted up to 40 weeks postvaccination [92]. While data were published that attempted to correlate anti-CP5 or anti-CP8 binding antibodies with functional OPA activity, these correlations were weak and based on an insufficient number of patient samples [93]. Subsequently, in a larger phase 3 study of StaphVAX, no significant protection was observed, and whether functional antibodies were observed in this study was not disclosed. Issues with the consistency of manufacture, which may have impacted the ability to generate functional antibodies, were cited to be the main reason for the failure [94]. In contrast to the vaccine or immunotherapy approaches discussed above, or for those for which data are not yet disclosed (Table 1), the trivalent S. aureus vaccine under development by Pfizer has shown very robust functional antibody responses that kill clinical isolates in OPA [95] and neutralize an important S. aureus virulence factor [84]. Studies with Pfizer’s tri-antigen vaccine have further supported the concept that healthy human subjects generally do not have functional opsonophagocytic antibodies to S. aureus at baseline. However, the same subjects rapidly mounted functional responses after immunization with a tri-antigen vaccine, to levels that surpassed the low functional antibody levels observed in non-immunized subjects [58,95]. While this investigational multiantigen vaccine has not yet entered phase 3 development to assess efficacy, the fact that robust opsonophagocytic bacterial killing responses can be induced in humans through immunization with appropriate vaccine constructs, and with consideration of the failure to demonstrate such robust responses in previous S. aureus vaccine attempts, suggests that it is premature to discount the importance of anti-staphylococcal antibodies in protection against S. aureus, provided that such antibody responses are functional

and robust and that the host has a functioning neutrophil system. 2) S. aureus vaccine targets – One size hat does not fit all S. aureus is a complex and biologically well-adapted microorganism that causes a large number of different diseases in many different species, including humans. It is thus not surprising that S. aureus can express many different virulence factors [19,96,97,30] to adapt to, and survive in, different host niches. Furthermore, the expression of these virulence factors in a given subject or situation is temporally regulated and can differ from strain to strain [98]. In considering such biological complexity of the organism, vaccine approaches based on single S. aureus antigens are not likely to succeed, and in fact have already been proven to be unsuccessful, in both active and passive immunization approaches tested in humans (Table 1). To think that a “single hat (or antigen) can fit all” was naïve considering the diversity and complexity of S. aureus antigen expression as we understand it today. Indeed, Stranger-Jones et al. provided some experimental evidence in a mouse renal abscess model that immunization with multiple S. aureus antigens was more protective than vaccination with single antigens [99]. Not surprisingly, the S. aureus vaccine field has shifted its approach, and multiple antigen combination vaccines are under clinical study [39,100]. The important question of which antigens should be included remains, however, and is a focus of significant debate and discussion [42,101,102]. Because of the plasticity of S. aureus, determination of which antigens are expressed in vivo is critical. Equally important is the timing of such expression. With the fast in vivo replication and disease progression after initiation of S. aureus infection, knowledge of antigen expression early in the infectious cycle, and consistently across many S. aureus clinical isolates is crucial in the selection of vaccine antigens, to assure the immediate recognition and eradication of the organisms by the immune system. Furthermore, as noted above, inclusion of antigens in the vaccine that induce a functional, opsonophagocytic killing response is critical to assure the immediate destruction of the pathogen and to prevent the dissemination of the infection. The importance of including S. aureus toxins such as ␣-hemolysin in a vaccine is less clear, at least for prophylactic vaccines. Many prophylactic vaccines are designed to prevent the establishment of a productive infection, and to control the infection before the pathogen can expand and spread. Toxins are usually elaborated once an infection has been firmly established, or in situations of high bacterial burden, such as those achieved in preclinical animal models [103,104]. Under these circumstances, an effect of immunization with toxin-based vaccines may be observed, but it is unclear whether this protection is generalizable to human infection. 3) S. aureus vaccine populations – The devil is always in the detail In the past, S. aureus vaccine development appeared to be focused mainly on the pathogen and less on the host. Having experienced a number of S. aureus immunization strategy failures (both active and passive), the focus of the field has now shifted to understand in more detail the immune responses required to combat S. aureus infections [22,105,106]. These findings will not be discussed in this review. However, from a prophylactic vaccine perspective, an understanding of which underlying host factors may interfere with an effective S. aureus vaccine, and may have already contributed to the vaccine failures noted in Table 1, warrants additional thought. When considering potential patient populations that would benefit from prophylactic vaccination against S. aureus, the burden of disease as well as the immune status of the patients has to be considered. As a general rule, the healthier and more immunocompetent the patient, the lower the rate of invasive

K.U. Jansen et al. / Vaccine 31 (2013) 2723–2730 Table 2 US Incidence rates of S. aureus infections associated with surgery. Surgical subgroup

S. aureus infection rate (%)

MRSA rate (% of S. aureus infections)

Vascular Cardiothoracic General GYN/GU Neurosurgical Orthopedic Plastic

2.4 2.0 3.2 0.6 1.8 0.8 3.1

47.5 36.5 35.9 51.4 39.0 39.4 29.4

Adapted from Yu et al. [130].

S. aureus disease [107]. Conversely, the more immunologically compromised the patient and the greater overall degree of clinical morbidity, the greater the likelihood of invasive S. aureus infection [107]. An excellent representation of a generally healthier at risk population is the elective surgical population. This population is particularly attractive as a target for prophylactic vaccination, as elective surgery provides the opportunity to vaccinate prior to the known risk period for infection. Furthermore, most postoperative S. aureus infections occur during a relatively short and well-defined timeframe, such that a protective effect could be observed shortly after surgery. Even for surgical procedures with permanently implanted prostheses and devices, the majority of S. aureus infections occur within the first 90 postoperative days [108–112]. S. aureus infection is reported at rates up to 10% among the spectrum of operative procedures [113,108,114–118]. For the surgical patient it is the incision itself and the invasiveness of the surgery, which provides the critical risk factors, and without which the risk of infection would approximate that of the background population. Perioperative stressors such as the length of the operative procedure, tissue hypoxia and necrosis, hyperglycemia, blood loss and allogenic transfusion, in addition to the surgical patient’s overall degree of morbidity, further compound the risk of infection [119]. Numerous patient conditions which disrupt immune functions and/or the environment of the local surgical wound are reported to significantly increase postoperative infection risk [3–5,8,14,67,116,120–124]. Prominent among these are diabetes mellitus [125,126], obesity [127,128] and tobacco usage [129]. There is limited understanding of how immunologic defects attributed to these conditions could potentially affect the efficacy of a S. aureus vaccine. Prospective studies are required to help further define the impact of these risk factors on the immune response in relation to vaccination. In addition, it will be important for vaccine clinical studies in the surgical setting to record critical data such as tobacco usage, perioperative glucose levels, body mass index, and prior surgical history to assess the potential impact of individual patient variables on postoperative infection risk. In addition to patient factors, characteristics of the surgical procedure itself govern the greatest risk of postoperative infection. It is largely accepted that infection of the surgical wound most commonly occurs immediately following the incision, thus giving rise to initiatives which strategically focus on the timing and dosage of antibiotic prophylaxis administration [112]. The size and depth of the surgical site, wound characteristics (e.g. bleeding, necrosis, dead space, wound class), and duration and complexity of the procedure, result in a broad range of reported rates of postoperative S. aureus infection across surgical subspecialties and individual procedures as reported by Yu et al. [130] (Table 2). A further understanding of the individual contributions of “procedural risks” of the surgery in the context of S. aureus infection is clearly needed.

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With this rather complex picture for elective surgeries in otherwise immunocompetent individuals, the “host” factor becomes even more important when considering the patient populations in which previously studied S. aureus vaccines have failed. For example, subjects with end-stage renal disease do have very high S. aureus infection rates; a recent 12 year retrospective survey of haemodialysis patients from an Irish haemodialysis centre in a tertiary referral hospital estimated that the S. aureus bloodstream infection rate was 17.9 per 100 patient-years (range 9.7–36.8) [131]. Though this high infection rate is an attractive proposition for evaluating the efficacy of a S. aureus vaccine, it is frought with drawbacks; hemodialysis patients are immunocompromised and are undergoing dialysis at a rate that may deplete the antibodies that are generated to prevent the infection [132–134]. Similarly, the two passive vaccines that were tested for the prevention of S. aureus desease in neonates, Veronate and Pagibaximab, were limited by the ability of the infant’s immature immune system to utilize the antibodies that were supplied to them [135–137]. Likewise, the cardiothoracic surgical population that evaluated V710 proved to be a very ill population, as the number of serious adverse avents that were captured in the placebo population alone was substantial [138]. With such a high degree of morbidity in a trial population, the assessment of vaccine efficacy will be more complex than in a healthier population. Thus it would be best to avoid such a sick population, at least for initial pivotal vaccine efficacy trials. So how does one select an appropriate initial S. aureus vaccine efficacy population? There are no easy answers, as well-controlled prospective studies across a number of elective surgery populations addressing risk, co-morbidities, infection rates and outcomes, as well as which risk factors contribute to the infection, are largely not available. The challenge is to define populations that are healthy enough and immunocompetent enough to benefit from the vaccine, yet which still carry a significant disease burden. Conclusions – Looking ahead There is little debate that S. aureus infection and disease puts a great burden on patients as well as the healthcare system. In this review we have outlined some of the issues around developing vaccines for the prevention of S. aureus disease and how these issues could be addressed. We attempted to highlight important factors that may have been responsible for previous vaccine trial failures, including vaccine design (single compared to multiple vaccine targets), lack of eliciting an appropriate functional and opsonophagocytic killing response, and the choice of vaccine trial populations. However, we believe that these factors do not represent obstacles that should stand in the way of the successful development of an effective S. aureus vaccine, provided that they are evaluated and addressed together in a holistic fashion. Disclosures All authors are employees of Pfizer and as such are paid by Pfizer and may own Pfizer stock. The authours would like to achnowledge Jane Broughan and Ed Zito, both employees of Pfizer for helpful suggestions regarding this review. References [1] Lowy FD. How Staphylococcus aureus adapts to its host. N Engl J Med 2011;364:1987–90. [2] Wertheim HFL, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis 2005;5:751–62. [3] Anderson DJ, Chen LF, Schmader KE, Sexton DJ, Choi Y, Link K, et al. Poor functional status as a risk factor for surgical site infection due to

2728

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12] [13]

[14]

[15]

[16]

[17] [18]

[19]

[20] [21] [22] [23] [24]

[25] [26] [27] [28] [29]

[30] [31]

[32]

K.U. Jansen et al. / Vaccine 31 (2013) 2723–2730 methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol Off J Soc Hosp Epidemiol Am 2008;29:832–9. Harrington G, Russo P, Spelman D, Borrell S, Watson K, Barr W, et al. Surgical-site infection rates and risk factor analysis in coronary artery bypass graft surgery. Infect Control Hosp Epidemiol Off J Soc Hosp Epidemiol Am 2004;25:472–6. Kaye KS, Schmit K, Pieper C, Sloane R, Caughlan KF, Sexton DJ, et al. The effect of increasing age on the risk of surgical site infection. J Infect Dis 2005;191:1056–62. Miller MB, Weber DJ, Goodrich JS, Popowitch EB, Poe MD, Nyugen V, et al. Prevalence and risk factor analysis for methicillin-resistant Staphylococcus aureus nasal colonization in children attending child care centers. J Clin Microbiol 2011;49:1041–7. Kupfer M, Jatzwauk L, Monecke S, Mobius J, Weusten A. MRSA in a large German University Hospital: male gender is a significant risk factor for MRSA acquisition. GMS Krankenh Interdiszipl 2010;5. Junqueira BL, Connolly B, Abla O, Tomlinson G, Amaral JG. Severe neutropenia at time of port insertion is not a risk factor for catheter-associated infections in children with acute lymphoblastic leukemia. Cancer 2010;116: 4368–75. McAllister L, Gaynes RP, Rimland D, McGowan Jr JE. Hospitalization earlier than 1 year prior to admission as an additional risk factor for methicillinresistant Staphylococcus aureus colonization. Infect Control Hosp Epidemiol Off J Soc Hosp Epidemiol Am 2010;31:538–40. Pishchany G, McCoy AL, Torres VJ, Krause JC, Crowe Jr JE, Fabry ME, et al. Specificity for human hemoglobin enhances Staphylococcus aureus infection. Cell Host Microbe 2010;8:544–50. Veloso TR, Chaouch A, Roger T, Giddey M, Vouillamoz J, Majcherczyk P, et al. Use of a human-like low-grade bacteremia model of experimental endocarditis to study the role of Staphylococcus aureus adhesins and platelet aggregation in early endocarditis. Infect Immun 2013;81:697–703. Del Giudice P, Tattevin P, Etienne J. Community-acquired methicillinresistant Staphylococcus aureus. Rev Presse Med 2011 [ePub]. Furuya EY, Cook HA, Lee MH, Miller M, Larson E, Hyman S, et al. Community-associated methicillin-resistant Staphylococcus aureus prevalence: how common is it, A methodological comparison of prevalence ascertainment. Am J Infect Control 2007;35:359–66. Jacobson M, Gellermann H, Chambers H. Staphylococcus aureus bacteremia and recurrent staphylococcal infection in patients with acquired immunodeficiency syndrome and AIDS-related complex. Am J Med 1988;85:172–6. Kale-Pradhan P, Johnson LB. Treatment and recurrence management of staphylococcal infections: community-acquired MRSA. Exp Rev Anti-infect Therapy 2008;6:909–15. Karamatsu ML, Thorp AW, Brown L. Changes in communityassociated methicillin-resistant Staphylococcus aureus skin and soft tissue infections presenting to the pediatric emergency department: comparing 2003–2008. Pediat Emerg Care 2012;28:131–5, http://dx.doi.org/10.1097/PEC.0b013e318243fa36. Miller LG, Kaplan SL. Staphylococcus aureus: a community pathogen. Infect Dis Clin N Am 2009;23:35–52. Skov R, Christiansen K, Dancer SJ, Daum RS, Dryden M, Huang YC, et al. Update on the prevention and control of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA). Int J Antimicrob Agents 2012;39:193–200. Broughan J, Anderson R, Anderson AS. Strategies for and advances in the development of Staphylococcus aureus prophylactic vaccines. Exp Rev Vaccines 2011;10:695–708. Edwards AM, Massey RC, Clarke SR. Molecular mechanisms of Staphylococcus aureus nasopharyngeal colonization. Mol Oral Microbiol 2012;27:1–10. Peacock SJ, de Silva I, Lowy FD. What determines nasal carriage of Staphylococcus aureus. Trends Microbiol 2001;9:605–10. DeLeo FR, Diep BA, Otto M, Host Defense. Pathogenesis in Staphylococcus aureus infections. Infect Dis Clin N Am 2009;23:17–34. Is Lowy FD. Staphylococcus aureus an intracellular pathogen. Trends Microbiol 2000;8:341–3. Tong S, Chen L, Fowler V. Colonization, pathogenicity, host susceptibility, and therapeutics for Staphylococcus aureus: what is the clinical relevance. Semin Immunopathol 2012;34:185–200. Cassat JE, Skaar EP. Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity. Semin Immunopathol 2012;34:215–35. Kehres DG, Maguire ME. Emerging themes in manganese transport, biochemistry and pathogenesis in bacteria. FEMS Microbiol Rev 2003;27:263–90. Skaar EP. The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathog 2010;6:e1000949. Zaharik ML, Finlay BB. Mn2+ and bacterial pathogenesis. Front Biosci J Virt Library 2004;9:1035–42. McDevitt D, Nanavaty T, House-Pompeo K, Bell E, Turner N, McIntire L, et al. Characterization of the interaction between the Staphylococcus aureus clumping factor (ClfA) and fibrinogen. Eur J Biochem 1997;247: 416–24. Cheng AG, DeDent AC, Schneewind O, Missiakas D. A play in four acts: Staphylococcus aureus abscess formation. Trends Microbiol 2011;19:225–32. Chagnot C, Listrat A, Astruc T, Desvaux M. Bacterial adhesion to animal tissues: protein determinants for recognition of extracellular matrix components. Cell Microbiol 2012;14:1687–96. Heilmann C. Adhesion mechanisms of staphylococci. Adv Exp Med Biol 2011;715:105–23.

[33] Abdulahad WH, Stegeman CA, Kallenberg CG. Review article: the role of CD4(+) T cells in ANCA-associated systemic vasculitis. Nephrology 2009;14:26–32. [34] Fournier B, Philpott DJ. Recognition of Staphylococcus aureus by the innate immune system. Clin Microbiol Rev 2005;18:521–40. [35] Garzoni C, Kelley WL. Return of the Trojan horse: intracellular phenotype switching and immune evasion by Staphylococcus aureus. EMBO Mol Med 2011;3:115–7. [36] Kim HK, Thammavongsa V, Schneewind O, Missiakas D. Recurrent infections and immune evasion strategies of Staphylococcus aureus. Curr Opin Microbiol 2012;15:92–9. [37] Krishna S, Miller LS. Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin Immunopathol 2012;34:261–80. [38] Parker D, Prince A. Immunopathogenesis of Staphylococcus aureus pulmonary infection. Semin Immunopathol 2012;34:281–97. [39] Anderson AS, Miller AA, Donald RG, Scully IL, Nanra JS, Cooper D, et al. Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors. Hum Vaccines Immunother 2012;8. [40] Anderson AS, Scully IL, Timofeyeva Y, Murphy E, McNeil LK, Mininni T, et al. Staphylococcus aureus manganese transport protein C is a highly conserved cell surface protein that elicits protective immunity against S. aureus and Staphylococcus epidermidis. J Infect Dis 2012;205:1688–96. [41] Proctor RA. Challenges for a universal Staphylococcus aureus vaccine. Clin Infect Dis 2012;54:1179–86. [42] Daum RS, Progress Spellberg B. Toward a Staphylococcus aureus vaccine. Clin Infect Dis 2012;54:560–7. [43] Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the induction of skin allograft acceptance in mice. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 2011;11:936–46. [44] den Dunnen J, Vogelpoel LT, Wypych T, Muller FJ, de Boer L, Kuijpers TW, et al. IgG opsonization of bacteria promotes Th17 responses via synergy between TLRs and FcgammaRIIa in human dendritic cells. Blood 2012;120: 112–21. [45] Frank KM, Zhou T, Moreno-Vinasco L, Hollett B, Garcia JG, Bubeck Wardenburg J. Host response signature to Staphylococcus aureus alpha-hemolysin implicates pulmonary Th17 response. Infect Immun 2012;80:3161–9. [46] Gillrie MR, Zbytnuik L, McAvoy E, Kapadia R, Lee K, Waterhouse CC, et al. Divergent roles of Toll-like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo. Eur J Immunol 2010;40:1639–50. [47] Islander U, Andersson A, Lindberg E, Adlerberth I, Wold AE, Superantigenic Rudin A. Staphylococcus aureus stimulates production of interleukin-17 from memory but not naive T cells. Infect Immun 2010;78:381–6. [48] Joshi A, Pancari G, Cope L, Bowman E, Cua D, Proctor R, et al. Immunization with Staphylococcus aureus iron regulated surface determinant B (IsdB) confers protection via Th17/IL17 pathway in a murine sepsis model. Hum Vaccines Immunotherap 2012;8:0–10. [49] Kim MR, Hong SW, Choi EB, Lee WH, Kim YS, Jeon SG, et al. Staphylococcus aureus-derived extracellular vesicles induce neutrophilic pulmonary inflammation via both Th1 and Th17 cell responses. Allergy 2012;67:1271–81. [50] Niebuhr M, Gathmann M, Scharonow H, Mamerow D, Mommert S, Balaji H, et al. Staphylococcal alpha-toxin is a strong inducer of interleukin-17 in humans. Infect Immun 2011;79:1615–22. [51] Pancari G, Fan H, Smith S, Joshi A, Haimbach R, Clark D, et al. Characterization of the mechanism of protection mediated by CS-D7, a monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB). Front Cell Infect Microbiol 2012;2:36. [52] Prabhakara R, Harro JM, Leid JG, Harris M, Shirtliff ME. Murine immune response to a chronic Staphylococcus aureus biofilm infection. Infect Immun 2011;79:1789–96. [53] Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, et al. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 2012;484:514–8. [54] Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 2008;205:1551–7. [55] Monteil M, Hobbs J, Citron K. Selective immunodeficiency affecting staphylococcal response. Lancet 1987;2:880–3. [56] Mayer-Scholl A, Averhoff P, Zychlinsky A. How do neutrophils and pathogens interact. Curr Opin Microbiol 2004;7:62–6. [57] Wang F. The signaling mechanisms underlying cell polarity and chemotaxis. Cold Spring Harbor Perspect Biol 2009;1:a002980. [58] Nanra JS, Buitrago SM, Crawford S, Ng J, Fink PS, Hawkins J, et al. Capsular polysaccharides are an important immune evasion mechanism for Staphylococcus aureus. Hum Vaccines Immunotherap 2012;9. [59] Bodey G, Buckley M, Sathe YS, Freireich E. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328–40. [60] Quie PG, White JG, Holmes B, Good RA. In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Invest 1967;46:668–79. [61] Johnston RB, Keele BB, Misra HP, Lehmeyer JE, Webb LS, Baehner RL, et al. The role of superoxide anion generation in phagocytic bactericidal activity, Studies with normal and chronic granulomatous disease leukocytes. J Clin Invest 1975;55:1357–72.

K.U. Jansen et al. / Vaccine 31 (2013) 2723–2730 [62] Curnutte J. Hematology of infancy and childhood. Philadelphia, PA: Saunders; 1993. [63] Handin RL. Harrison’s principles of internal medicine. 14th ed. Texas: McGraw-Hill; 1998. [64] Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 2000;68:6398–401. [65] Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 2003;299:2076–9. [66] Proctor RA. Is there a future for a Staphylococcus aureus vaccine. Vaccine 2012;30:2921–7. [67] Akins PT, Belko J, Banerjee A, Guppy K, Herbert D, Slipchenko T, et al. Perioperative management of neurosurgical patients with methicillin-resistant Staphylococcus aureus. J Neurosurg 2010;112:354–61. [68] Bassetti M, Melica G, Cenderello G, Rosso R, Di Biagio A, Bassetti D. Grampositive bacterial resistance, a challenge for the next millennium. Panminerva Med 2002;44:179–84. [69] Cameron DR, Howden BP, Peleg AY. The interface between antibiotic resistance and virulence in Staphylococcus aureus and its impact upon clinical outcomes. Clin Infect Dis Off Pub Infect Dis Soc Am 2011;53:576–82. [70] Chao D, Nanda A. Spinal epidural abscess: a diagnostic challenge. Am Family Phys 2002;65:1341–6. [71] Concia E, Prandini N, Massari L, Ghisellini F, Consoli V, Menichetti F, et al. Osteomyelitis: clinical update for practical guidelines. Nucl Med Commun 2006;27:645–60. [72] Cornaglia G, Rossolini GM. Forthcoming therapeutic perspectives for infections due to multidrug-resistant Gram-positive pathogens. Clin Microbiol Infect Off Pub Eur Soc Clin Microbiol Infect Dis 2009;15:218–23. [73] Deasy J. The antibiotic challenge: changing clinical management of infections. JAAPA 2009;22:22–6. [74] Harbarth S. Control of endemic methicillin-resistant Staphylococcus aureus – recent advances and future challenges. Clin Microbiol Infect Off Pub Eur Soc Clin Microbiol Infect Dis 2006;12:1154–62. [75] Hiramatsu K. Vancomycin resistance in staphylococci. Drug Resist Updates Rev Comment Antimicrob Anticancer Chemother 1998;1:135–50. [76] Jorge LS, Chueire AG, Rossit AR. Osteomyelitis: a current challenge. Braz J Infect Dis Off Pub Braz Soc Infect Dis 2010;14:310–5. [77] Aboelela SW, Saiman L, Stone P, Lowy FD, Quiros D, Larson E. Effectiveness of barrier precautions and surveillance cultures to control transmission of multidrug-resistant organisms: a systematic review of the literature. Am J Infect Control 2006;34:484–94. [78] Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998;339:520–32. [79] Hawkins J, Kodali S, Matsuka YV, McNeil LK, Mininni T, Scully IL, et al. A recombinant clumping factor A-containing vaccine induces functional antibodies to Staphylococcus aureus that are not observed after natural exposure. Clin Vaccine Immunol 2012;19:1641–50. [80] Dale JB. Current status of group A streptococcal vaccine development. Adv Exp Med Biol 2008;609:53–63. [81] Jodar L, Butler J, Carlone G, Dagan R, Goldblatt D, Kayhty H, et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine 2003;21:3265–72. [82] Romero-Steiner S, Musher DM, Cetron MS, Pais LB, Groover JE, Fiore AE, et al. Reduction in functional antibody activity against Streptococcus pneumoniae in vaccinated elderly individuals highly correlates with decreased IgG antibody avidity. Clin Infect Dis Off Pub Infect Dis Soc Am 1999;29:281–8. [83] Musher DM, Groover JE, Rowland JM, Watson DA, Struewing JB, Baughn RE, et al. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin Infect Dis Off Pub Infect Dis Soc Am 1993;17:66–73. [84] Hawkins J, Kodali S, Matsuka YV, McNeil LK, Mininni T, Scully IL, et al. A recombinant clumping factor A-containing vaccine induces functional antibodies to Staphylococcus aureus that are not observed after natural exposure. CVI 2012;19:1641–50. [85] Tkaczyk C, Hua L, Varkey R, Shi Y, Dettinger L, Woods R, et al. Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency. CVI 2012;19:377–85. [86] Mishra RP, Mariotti P, Fiaschi L, Nosari S, Maccari S, Liberatori S, et al. Staphylococcus aureus FhuD2 is involved in the early phase of staphylococcal dissemination and generates protective immunity in mice. J Infect Dis 2012;206:1041–9. [87] Kim HK, DeDent A, Cheng AG, McAdow M, Bagnoli F, Missiakas DM, et al. IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge. Vaccine 2010;28:6382–92. [88] Harro C, Betts R, Orenstein W, Kwak EJ, Greenberg HE, Onorato MT, et al. Safety and immunogenicity of a novel Staphylococcus aureus vaccine: results from the first study of the vaccine dose range in humans. CVI 2010;17: 1868–74. [89] Fowler VG AK, Moreira E, Moustafa M, Isgro F, Boucher H, FIDSA, et al. Efficacy and safety of an investigational Staphylococcus aureus vaccine in preventing bacteremia and deep sternal wound infections after cardiothoracic surgery. IDWeek. San Diego, CA; 2012. [90] Brown M, Kowalski R, Zorman J, Wang XM, Towne V, Zhao Q, et al. Selection and characterization of murine monoclonal antibodies to Staphylococcus aureus iron-regulated surface determinant B with functional activity in vitro and in vivo. CVI 2009;16:1095–104.

2729

[91] Ebert T, Smith S, Pancari G, Clark D, Hampton R, Secore S, et al. A fully human monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) with functional activity in vitro and in vivo. Hum Antibodies 2010;19:113–28. [92] Shinefield H, Black S, Fattom A, Horwith G, Rasgon S, Ordonez J, et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N Engl J Med 2002;346:491–6. [93] Fattom AI, Horwith G, Fuller S, Propst M, Naso R. Development of StaphVAX, a polysaccharide conjugate vaccine against S. aureus infection: from the lab bench to phase III clinical trials. Vaccine 2004;22:880–7. [94] Matalon AM, M.; Buerkert, J.; Block, G; Hohenboken, M.; Fattom, A.; Horwirth, G., Rasmussen, H., Damasco, S.; Boutriau, D. Efficacy profile of a bivalent Staphylococcus aureus glycoconjugate investigational vaccine in adults on haemodialysis: Phase III randomized study. International symposium on staphylococcal infections. Lyon, France; 2012. p. 9–114. [95] Richmond PNM, Marshall H, Shakib S, Hodsman P, Jiang Q, Cooper D, et al. Safety, Tolerability, and Immunogenicity of a novel 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults: results of a randomized, placebo controlled Phase 1 first-in-human study. IDWeek. San Diego, CA; 2012. [96] Anwar S, Prince LR, Foster SJ, Whyte MK, Sabroe I. The rise and rise of Staphylococcus aureus: laughing in the face of granulocytes. Clin Exp Immunol 2009;157:216–24. [97] Clarke SR, Foster SJ. Surface adhesins of Staphylococcus aureus. Adv Microb Phys 2006;51:187–224. [98] Anderson AS, Scully IL, Timofeyeva Y, Murphy E, McNeil LK, Mininni T, et al. The Staphylococcus aureus transporter MntC is a highly conserved cell surface protein that elicits protective immunity against both S. aureus and Staphylococcus epidermidis. J Infect Dis 2012. [99] Stranger-Jones YK, Bae T, Schneewind O. Vaccine assembly from surface proteins of Staphylococcus aureus. Proc Natl Acad Sci 2006;103:16942–7. [100] Bagnoli F, Bertholet S, Grandi G. Inferring reasons for the failure of Staphylococcus aureus vaccines in clinical trials. Front Cell Infect Microbiol 2012;2:16. [101] Dunman PM, Nesin M. Passive immunization as prophylaxis: when and where will this work. Curr Opin Pharmacol 2003;3:486–96. [102] Projan SJ, Nesin M, Dunman PM. Staphylococcal vaccines and immunotherapy: to dream the impossible dream. Curr Opin Pharmacol 2006;6:473–9. [103] Menzies BE, Kernodle DS. Passive immunization with antiserum to a nontoxic alpha-toxin mutant from Staphylococcus aureus is protective in a murine model. Infect Immun 1996;64:1839–41. [104] Bubeck Wardenburg J, Schneewind O. Vaccine protection against Staphylococcus aureus pneumonia. J Exp Med 2008;205:287–94. [105] Proctor RA. Challenges for a universal Staphylococcus aureus vaccine. Clin Infect Dis Off Pub Infect Dis Soc Am 2012;54:1179–86. [106] Tseng CW, Kyme PA, Arruda A, Ramanujan VK, Tawackoli W, Liu GY. Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus. PLoS One 2012;7:e41454. [107] Fagan RL, Bulens F, Mu S, Nadle Y, Bamberg J, Petit W, et al. Estimates of Invasive Methicillin-Resistant Staphylococcus aureus Infection Rates by Specific Population Groups. ID Week. San Diego; 2012. [108] Korinek AM, Golmard JL, Elcheick A, Bismuth R, van Effenterre R, Coriat P, et al. Risk factors for neurosurgical site infections after craniotomy: a critical reappraisal of antibiotic prophylaxis on 4578 patients. Brit J Neurosurg 2005;19:155–62. [109] Nery PB, Fernandes R, Nair GM, Sumner GL, Ribas CS, Menon SM, et al. Device-related infection among patients with pacemakers and implantable defibrillators: incidence, risk factors, and consequences. J Cardiovas Electrophysiol 2010;21:786–90. [110] Ridgeway S, Wilson J, Charlet A, Kafatos G, Pearson A, Coello R. Infection of the surgical site after arthroplasty of the hip. J Bone Joint Surg Brit Vol 2005;87:844–50. [111] Rao SB, Vasquez G, Harrop J, Maltenfort M, Stein N, Kaliyadan G, et al. Risk factors for surgical site infections following spinal fusion procedures: a case–control study. Clin Infect Dis Off Pub Infect Dis Soc Am 2011;53: 686–92. [112] Bratzler DW, Houck PM, Surgical Infection Prevention Guidelines Writers W, American Academy of Orthopaedic S, American Association of Critical Care N, American Association of Nurse A, et al. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis Off Pub Infect Dis Soc Am 2004;38:1706–15. [113] Sands K, Vineyard G, Platt R. Surgical site infections occurring after hospital discharge. J Infect Dis 1996;173:963–70. [114] Wloch C, Wilson J, Lamagni T, Harrington P, Charlett A, Sheridan E. Risk factors for surgical site infection following caesarean section in England: results from a multicentre cohort study. BJOG 2012;119:1324–33. [115] Bleasdale SC, Trick WE, Gonzalez IM, Lyles RD, Hayden MK, Weinstein RA. Effectiveness of chlorhexidine bathing to reduce catheter-associated bloodstream infections in medical intensive care unit patients. Arch Intern Med 2007;167:2073–9. [116] Fakih MG, Sharma M, Khatib R, Berriel-Cass D, Meisner S, Harrington S, et al. Increase in the rate of sternal surgical site infection after coronary artery bypass graft: a marker of higher severity of illness. Infect Control Hosp Epidemiol Off J Soc Hosp Epidemiol Am 2007;28:655–60. [117] Taylor G, Herrick T, Mah M. Wound infections after hysterectomy: opportunities for practice improvement. Am J Infect Control 1998;26:254–7. [118] Khan UD. Breast augmentation, antibiotic prophylaxis, and infection: comparative analysis of 1628 primary augmentation mammoplasties assessing

2730

[119]

[120]

[121]

[122] [123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132] [133] [134] [135] [136]

K.U. Jansen et al. / Vaccine 31 (2013) 2723–2730 the role and efficacy of antibiotics prophylaxis duration. Aesthet Plast Surg 2010;34:42–7. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol Off J Soc Hosp Epidemiol Am 1999;20:250–78 [quiz 79–80]. Belsky DS, Teates CD, Hartman ML. Case report: diabetes mellitus as a predisposing factor in the development of pyomyositis. Am J Med Sci 1994;308:251–4. Hamel M, Zoutman D, O’Callaghan C. Exposure to hospital roommates as a risk factor for health care-associated infection. Am J Infect Control 2010;38:173–81. Hsu RB, Chen RJ, Wang SS, Chu SH. Infected aortic aneurysms: clinical outcome and risk factor analysis. J Vasc Surg 2004;40:30–5. Jensen AG, Wachmann CH, Poulsen KB, Espersen F, Scheibel J, Skinhoj P, et al. Risk factors for hospital-acquired Staphylococcus aureus bacteremia. Arch Intern Med 1999;159:1437–44. Kim ES, Kim HB, Song KH, Kim YK, Kim HH, Jin HY, et al. Prospective nationwide surveillance of surgical site infections after gastric surgery and risk factor analysis in the Korean Nosocomial Infections Surveillance System (KONIS). Infect Control Hosp Epidemiol Off J Soc Hosp Epidemiol Am 2012;33: 572–80. Spelman DW, Russo P, Harrington G, Davis BB, Rabinov M, Smith JA, et al. Risk factors for surgical wound infection and bacteraemia following coronary artery bypass surgery. Austr NZ J Surg 2000;70:47–51. Centofanti P, Savia F, La Torre M, Ceresa F, Sansone F, Veglio V, et al. A prospective study of prevalence of 60-days postoperative wound infections after cardiac surgery, an updated risk factor analysis. J Cardiovasc Surg 2007;48:641–6. Dodds Ashley ES, Carroll DN, Engemann JJ, Harris AD, Fowler Jr VG, Sexton DJ, et al. Risk factors for postoperative mediastinitis due to methicillinresistant Staphylococcus aureus. Clin Infect Dis Off Pub Infect Dis Soc Am 2004;38:1555–60. Fang S, Skeete D, Cullen JJ. Preoperative risk factors for postoperative Staphylococcus aureus nosocomial infections. Surg Technol Int 2004;13: 35–8. Sorensen LT, Horby J, Friis E, Pilsgaard B, Jorgensen T. Smoking as a risk factor for wound healing and infection in breast cancer surgery. Eur J Surg Oncol J Eur Soc Surg Oncol Brit Assoc Surg Oncol 2002;28:815–20. Yu H, Mardekian J, Strutton D, Girgenti D. Characterizing Staphylococcus aureus infections following elective surgeries in US hospitals. International conference on antimicrobial agents and chemotherapeutics. San Francisco, CA; 2012. Fitzgerald SF, O’Gorman J, Morris-Downes MM, Crowley RK, Donlon S, Bajwa R, et al. A 12-year review of Staphylococcus aureus bloodstream infections in haemodialysis patients: more work to be done. J Hosp Infect 2011;79: 218–21. Descamps-Latscha B, Chatenoud L. T cells and B cells in chronic renal failure. Semin Nephrol 1996;16:183–91. Schollmeyer P, Bozkurt F. The immune status of the uremic patient: hemodialysis vs CAPD. Clin Nephrol 1988;30(Suppl. 1):S37–40. Kay NE, Raij LR. Immune abnormalities in renal failure and hemodialysis. Blood Purif 1986;4:120–9. Kotiranta-Ainamo A, Rautonen J, Rautonen N. Imbalanced cytokine secretion in newborns. Biol Neonate 2004;85:55–60. Chelvarajan RL, Collins SM, Doubinskaia IE, Goes S, Van Willigen J, Flanagan D, et al. Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens. J Leukocyte Biol 2004;75:982–94.

[137] Marodi L. Innate cellular immune responses in newborns. Clin Immunol 2006;118:137–44. [138] Merck. Efficacy, Immunogenicity, and safety of a single dose of V710 in adult patients scheduled for cardiothoracic surgery (V710-003 AM2). ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2012. [139] NabiBiopharmaceuticals. Study to evaluate the effectiveness of StaphVAX in adults on hemodialysis. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2006. [140] NabiBiopharmaceuticals. StaphVAX in cardiovascular surgery patients. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2007. [141] Bristol-Myers Squibb. Safety and efficacy of Veronate® versus placebo in preventing nosocomial staphylococcal sepsis in premature infants. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2006. [142] Biosynexus Incorporated. Safety and efficacy of pagibaximab injection in very low birth weight neonates for prevention of staphylococcal sepsis. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2011. [143] Pfizer evaluation of a single vaccination of one of three ascending dose levels of a 4-antigen staphylococcus aureus vaccine (SA4Ag) and a single dose level of a 3-antigen staphylococcus aureus vaccine (SA3Ag) in healthy adults aged 65 to <86 years. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2012. [144] Uniformed Services University of the Health Sciences. Staphylococcus aureus toxoids phase 1–2 vaccine trial. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2012. [145] GlaxoSmithKline. A study to evaluate the safety, reactogenicity and immunogenicity of GSK biologicals’ staphylococcal investigational vaccine in healthy adults. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2012. [146] Vaccine Research International Plc. Phase I trial. Birmingham, UK. Vaccine Research International Plc; 2013. [147] Sanofi. Pharmacokinetics, Pharmacodynamics and safety evaluation of SAR279356 in intensive care unit mechanically ventilated patients. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2013. [148] NabiBiopharmaceuticals. Safety study of an intravenous staphylococcus aureus immune globulin (human), [altastaph] in low-birth-weight-neonates. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2012. [149] Inhibitex Aurexis® in cystic fibrosis subjects chronically colonized with Staphylococcus aureus in their lungs. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2006. [150] Inhibitex clinical trial comparing safety and pharmacokinetics of standard antibiotic therapy, plus Aurexis® or placebo, for treatment of Staphylococcus aureus bacteremia (SAB). ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2005. [151] Rupp ME, Holley Jr HP, Lutz J, Dicpinigaitis PV, Woods CW, Levine DP, et al. Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2007;51:4249–54. [152] NabiBiopharmaceuticals. Safety and behavior of S. Aureus immune globulin intravenous (human), [altastaph] in patients with S. aureus bacteremia and continuing fever. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2012. [153] Kenta Biotech Ltd. Safety, pharmacokinetics and efficacy of KBSA301 in severe pneumonia (S. aureus). ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2013. [154] NeuTec Pharma. Aurograb and vancomycin in MRSA infection. ClinicalTrialsgov. Bethesda, MD: National Library of Medicine (US); 2006.