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Vaccine 31 (2013) 27232730

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Review

Vaccine review: Staphyloccocus aureus vaccines: Problems and prospects


Kathrin U. Jansen , Douglas Q. Girgenti, Ingrid L. Scully, Annaliesa S. Anderson
Pzer Inc, 401 N. Middletown Road, Pearl River, NY 10965, USA

a r t i c l e

i n f o

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 supercial skin
and soft tissue infections to deep wound and organ/space infections, biolm-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 eld 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 inuence 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 benecial, 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@pzer.com (K.U. Jansen),
Douglas.girgenti@pzer.com (D.Q. Girgenti), Ingrid.scully@pzer.com (I.L. Scully),
Annaliesa.Anderson@pzer.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 [35]. 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 [3,69]. 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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K.U. Jansen et al. / Vaccine 31 (2013) 27232730

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 [1218]. 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 bacteriums 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
[2224] and establishing infections through elaborating proteins
and factors that scavenge essential nutrients [2528], enable adhesion and tissue penetration [2932], or facilitate the avoidance of
attack by both the innate and adaptive immune system [3338].
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 eld, 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 [38,4353].
Vaccine-induced adaptive immunity, including both T cell and B
cell responses, will likely be required for full protection. Antigenspecic 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 specically
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 efcacy, 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 [5963]. In addition,
patients with innate imune system disorders affecting IL-1R or
TLR signaling or patients with quantative or qualitative Th17
deciencies 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 difcult to observe antibody efcacy in therapeutic settings, where
the infectious process is well underway and bacteria may have
invaded cells or formed biolms. Indeed, existing staphylococcal
infections are difcult to treat with bacteriostatic and/or bactericidal antibiotics [6776], 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 signicant 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 deciencies 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

K.U. Jansen et al. / Vaccine 31 (2013) 27232730

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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 efcacy
Single antigen approach
No efcacy seen
Humans make Abs through natural
exposure that are not functional [84]
Neonates do not have a mature
immune system
No efcacy 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

Pzer, 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

Sano 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 efcacy seen
Single antigen vaccine
Did not generate opsonophagocytic
killing antibodies
Redundancy in iron-acquisition
pathways
Biolm target; antibodies and
effector cells may not effectively
penetrate pre-existing biolm 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 efcacy 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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K.U. Jansen et al. / Vaccine 31 (2013) 27232730

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 qualication 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 difcult 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 efciently [84] or only do so at less than-optimal levels
[86,87]. These points may help explain why Mercks V710, a prophylactic monovalent vaccine composed of IsdB [88] developed
to prevent S. aureus infections in patients undergoing cardiothoracic surgery, failed to show signicant efcacy in preventing
S. aureus infections (Table 1). A vaccine such as V710 does not
appear to induce antibodies that efciently 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 Mercks 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 vaccines 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 efcacy.
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 efcacy 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 insufcient number of
patient samples [93]. Subsequently, in a larger phase 3 study of
StaphVAX, no signicant 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
Pzer 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 Pzers 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 efcacy, 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 t 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 t all was nave 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 eld 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 signicant 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 rmly 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 eld has now
shifted to understand in more detail the immune responses
required to combat S. aureus infections [22,105,106]. These ndings 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
benet 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) 27232730


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-dened 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 rst 90 postoperative days [108112].
S. aureus infection is reported at rates up to 10% among the
spectrum of operative procedures [113,108,114118]. 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 patients 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 signicantly increase
postoperative infection risk [35,8,14,67,116,120124]. 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 efcacy of a S. aureus
vaccine. Prospective studies are required to help further dene
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.

2727

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 9.736.8) [131]. Though this high infection
rate is an attractive proposition for evaluating the efcacy 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 [132134]. 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 infants immature immune system to utilize the
antibodies that were supplied to them [135137]. 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 efcacy 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 efcacy
trials.
So how does one select an appropriate initial S. aureus
vaccine efcacy 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
dene populations that are healthy enough and immunocompetent enough to benet from the vaccine, yet which still carry
a signicant 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 Pzer and as such are paid by Pzer
and may own Pzer stock. The authours would like to achnowledge
Jane Broughan and Ed Zito, both employees of Pzer for helpful
suggestions regarding this review.
References
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