Elsevier

Vaccine

Volume 31, Issue 25, 7 June 2013, Pages 2723-2730
Vaccine

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

https://doi.org/10.1016/j.vaccine.2013.04.002Get rights and content

Highlights

  • Staphylococcus aureus causes serious, life-threatening infections.

  • Increasing antibiotic resistance has driven the search for alternate therapies.

  • No S. aureus vaccine approach has been successful thus far.

  • Approaches to solve issues surrounding S. aureus vaccine development are presented.

Abstract

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.

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 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], [4], [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], [7], [8], [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 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], [13], [14], [15], [16], [17], [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], [23], [24] and establishing infections through elaborating proteins and factors that scavenge essential nutrients [25], [26], [27], [28], enable adhesion and tissue penetration [29], [30], [31], [32], or facilitate the avoidance of attack by both the innate and adaptive immune system [33], [34], [35], [36], [37], [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], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]. Vaccine-induced adaptive immunity, including both T cell and B cell responses, will likely be required for full protection. Antigen-specific 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], [60], [61], [62], [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 anti-staphylococcal 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], [68], [69], [70], [71], [72], [73], [74], [75], [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 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 α-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 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], [109], [110], [111], [112].

    S. aureus infection is reported at rates up to 10% among the spectrum of operative procedures [113], [108], [114], [115], [116], [117], [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], [4], [5], [8], [14], [67], [116], [120], [121], [122], [123], [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.

    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], [133], [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], [136], [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.

Section snippets

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.

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