Professional Documents
Culture Documents
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
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
2724
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
2725
Table 1
Overview of clinical trials where immunotherapeutics have been used to treat or prevent S. aureus disease.
Manufacturer, product
name
Current status
Vaccine composition
Potential limitation(s)
NCT00071214 [139];
NCT00130260 [140]
Single antigen
Unknown mechanism of action
NCT01447407
TBD
NCT01011335 [144]
TBD
NCT01160172 [145]
Inhibitexb (BMS),
Veronate
PhIII complete
Biosynexus,
Pagibaximab
PhII/III complete
Pzer, PF-06290510
PhII
NovaDigm
Therapeutics, Inc,
NDV-3
NABIa /GSK, protein
components
GSK, Unnamed
PhIb
PhI
Novartis, Unnamed
PhI
Vaccine Research
International, SA75
PhI
NIAID, STEBVax
Merck/Intercell, V710
PhI
PhII/III complete;
terminated
SEB
IsdB
Sano SAR279356
PNAG
NABIa , Altastaph
PhI; terminated
PhI complete
Anti-ClfA mAb
MedImmune LLC,
MEDI4893
NABIa , Altastaph
PhI
PhI/II complete
Kenta Biotech,
KBSA301
PhI/II; enrollment
suspended
Alpha toxin
Berne, Staphyban
Novartis/Neutec
Pharma, Aurograb
PhIII; terminated
a
b
NCT00113191 [141]
NCT00646399 [142]
NCT01643941 [143]
[146]
NCT00974935
NCT00518687 [138]
NCT01389700 [147]
NCT00066989 [148]
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]
2726
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
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
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
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