SURGICAL INFECTIONS

Volume 19, Number 8, 2018

ª Mary Ann Liebert, Inc.
DOI: 10.1089/sur.2018.263

Immunization Against Staphylococcus aureus Infections

Philip S. Barie,1,2 Mayur Narayan,1 and Robert G. Sawyer3

Abstract
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Background: Infections caused by Staphylococcus aureus continue to plague surgical patients, whether as
surgical site infections or other nosocomial infections that complicate surgical care. The only meaningful
methods available to decrease the risk of developing such infections are topical skin antisepsis (pre-operative
skin preparation) and peri-operative antibiotic prophylaxis, neither of which offer a panacea. Alternatives to the
latter are sought so as to minimize antibiotic selection pressure as a factor in the increasing problem of
antimicrobial drug resistance. This review considers the possibility that immunization against S. aureus may
offer a viable alternative for prophylaxis.
Methods: Review and synthesis of pertinent English-language medical literature.
Results: Vaccination against viral pathogens has been in successful clinical use for more than two centuries and
was instrumental in the eradication of smallpox and the near-elimination of diseases such as poliomyelitis.
Vaccinations against a limited number of bacterial pathogens (e.g., Bordetella pertussis, Clostridium tetanii,
Corynebacterium diphtheriae, Haemophilus influenzae type b, Neisseria meningiditis, Streptococcus pneumo-
niae) have also been introduced with success, whereas others against bacteria are in development (C. difficile,
Pseudomonas aeruginosa, S. aureus). Vaccination against S. aureus infection is in current veterinary use (e.g.,
to prevent mastitis among dairy cattle) but has not been successful to date in human beings despite multiple
attempts, although development continues.
Conclusions: Because of its complex microbiology, including multiple virulence factors and the ability to
evade host immune surveillance, S. aureus presents numerous antigenic targets for vaccine development.
Failure of two prior single-antigen vaccines in clinical trials has led to the consensus that future vaccine
candidates must be directed against multiple antigens. Two distinct four-antigen vaccines are in clinical trials,
but efficacy is yet to be determined.

Keywords: immunization; infection prevention; Staphylococcus aureus; surgical prophylaxis; vaccination

V accination is the administration of antigenic material

(the vaccine) to stimulate an individual’s immune sys-
tem to develop adaptive immunity to a pathogen, so as to
prevent or ameliorate infectious disease(s). Historically and
to the present day, vaccination has been directed clinically
against viral pathogens with great success, but more recently
vaccines against bacterial pathogens have become suc-
cessful (e.g., Bordetella pertussis, Clostridium tetanii, Cor-
ynebacterium diphtheriae, Haemophilus influenzae type b,
Neisseria meningiditis, Streptococcus pneumoniae), many of
which are utilized regularly in acute care surgery practice.
Interest in immunization (used herein synonymously with
vaccination) against bacterial pathogens would be stimulated
if a vaccine were to be developed against hospital-acquired
pathogens that, as established infections, carry substantial
morbidity and some risk of death. By contrast, inoculation
refers to the induction of active adaptive immunity, which
uses un-attenuated live pathogens, whereas passive immunity
is the hoped-for result of administration of immunoglobulin
or, experimentally, a monoclonal antibody or antibiotic–
antibody conjugates.
Vaccination is the most effective method of preventing
viral diseases, and in some circumstances the prevention may
extend to diseases consequent to chronic infection (e.g.,
hepatitis B vaccination and reduced incidence of hepatocel-
lular carcinoma [1,2]; human papilloma virus vaccination
uptake is not yet sufficiently prevalent to assess the effect on
cervical or oropharyngeal carcinoma incidence [3,4]. When a

Departments of 1Surgery and 2Medicine, Weill Cornell Medicine, New York, New York.
3
Department of Surgery, Western Michigan University, Kalamazoo, Michigan.

750
 IMMUNIZATION AGAINST STAPHYLOCOCCUS AUREUS
sufficiently large percentage of a population has been vac-
cinated, herd immunity results. Widespread immunity as a
result of vaccination is largely responsible for the worldwide
eradication of smallpox and the marked reduction of diseases
such as poliomyelitis, measles, and tetanus (arguably the
most successful example of vaccination against a bacterial
pathogen-C. tetanii) from much of the world.
Historic Perspective
Smallpox was likely the first disease subjected to prevention
by inoculation [5] and was the first disease for which a vaccine
was produced. The smallpox vaccine was ‘‘invented’’ in 1796
by the British physician Edward Jenner and although at least
six people had used the same principles years earlier, he was
the first to publish evidence that it was effective and to provide
advice on its production [6]. The terms ‘‘vaccine’’ and ‘‘vac-
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cination’’ are derived from Variolae vaccinae (smallpox of the
cow), the term devised by Jenner to denote cowpox. The im-
munization was called vaccination because it was derived from
a virus affecting cows (Latin: vacca ‘cow’) [5,6]. Smallpox
was a contagious and deadly disease, causing the deaths of
20%–60% of infected adults and more than 80% of infected
children [7]. When smallpox was finally eradicated in 1979, it
had already killed an estimated 300–500 million people [8] in
the twentieth century.
In common parlance, vaccination and immunization have a
similar meaning. This distinguishes them from inoculation,
which uses un-attenuated live pathogens, although in com-
mon usage any of the terms can refer to an immunization.
Vaccination efforts have been met with some controversy on
scientific, ethical, political, medical safety, and religious
grounds, all largely unfounded. Early success of vaccination
brought widespread acceptance, and mass vaccination cam-
paigns have reduced greatly the incidence of many diseases
in numerous geographic regions.
Principles of Vaccination
Until relatively recently, vaccine development has been
empirical, with limited understanding of how the immune
system is activated to elicit adaptive immunity, but, advances
in immunology, microbiology, genetics, and molecular bi-
ology have led to burgeoning understanding of the interac-
tions of microorganisms with the human immune system [9].
Modern vaccine development builds on precise knowledge of
the microbiology of pathogens, their interaction with the
immune system, and their capacity to counteract and evade
innate and adaptive immune mechanisms, using technologies
to produce highly purified antigens that provide a lower re-
actogenicity (the propensity of a vaccine to produce common,
expected adverse reactions (e.g., fever, soreness at injection
site, bruising, erythema, induration, and edema). However, it
is unclear whether a higher degree of reactogenicity to a
vaccine correlates with more severe adverse events; the U.S.
Food and Drug Administration (FDA) has been unable to
make such an association.
Attempts to improve vaccine antigen purity may result in
impaired vaccine immunogenicity (the ability of a particular
antigen or epitope [or antigenic determinant]; the part of an
antigen molecule to which an antibody attaches itself to
provoke an immune response). Distinction is made between
wanted (i.e., successful vaccination) and unwanted immu-
751
nogenicity (i.e., drug allergy). Some such disadvantages re-
lated to highly purified or genetically engineered vaccines
can be overcome by innovative technologies, such as live
vector vaccines, and DNA or RNA vaccines. Moreover, re-
cent years have witnessed the development of novel adjuvant
(in immunology, a substance used to enhance antigenicity,
e.g., a suspension of minerals [alum, aluminum hydroxide, or
phosphate] on which antigen is adsorbed) formulations that
specifically focus on the augmentation or regulation of the
interplay between innate and adaptive immune systems and
the function of antigen-presenting cells. Finally, vaccine
design has become more tailored, which in turn enhances the
potential of extending its application to complex microbial
pathogens hitherto not accessible. This review provides an
overview of the key considerations and processes involved in
vaccine development against S. aureus.
Staphylococcus aureus as a Human Pathogen
Staphylococcus aureus is ubiquitous and a virulent human
and animal pathogen that may afflict healthy individuals or
those with compromised immunity, outpatients, or those
hospitalized. More than two million people become infected
with S. aureus each year in the United States, with more than
100,000 deaths annually [10]. A multiplicity of infections has
been observed, because the pathogen can infect almost any
tissue imaginable. Surgical infections of interest caused by
S. aureus include community-acquired infections, especially
of skin and soft tissue; surgical site infections (in which it is
the most common pathogen); and post-operative nosocomial
infections [11].
Identification of the patient at risk is a crucial first step in
prevention. Population-based studies have identified male
gender and both extremes of age as risk factors for the ac-
quisition of staphylococci. Dialysis dependence, diabetes
mellitus, cancer, human immunodeficiency virus infection,
intravenous drug use, alcohol abuse, recent surgery, critical
illness, and staphylococcal nasal carriage have been identi-
fied as independent risk factors [12,13]. Individuals who are
persistent nasal carriers (the primary locus, although other
sites are possible) of S. aureus may represent as much as 30%
of healthy people [14]. Most persistent carriers (as many
as 90%) harbor a single strain of methicillin-susceptible
S. aureus (MSSA), although methicillin-resistant S. aureus
(MRSA) nasal carriage is recognized now in up to 10% of
carriers). Patients who are persistent carriers are at higher risk
of acquiring S. aureus infection. In addition to decolonization
of staphylococcal carriers [15,16], other tactics being investi-
gated include phage therapy, molecules aimed at blocking
regulation of virulence determinants and surface adhesins,
and vaccination.
Mechanisms of virulence and immune evasion
The high prevalence and threat of S. aureus infections in
surgical patients has led to vigorous efforts to develop spe-
cific preventive and therapeutic measures directed against
this pathogen, by enhanced infection control practices, use of
topical antiseptics, and narrow-spectrum systemic antibac-
terial agents [17,18]. Prevention remains elusive despite
these efforts.
Staphylococcus aureus manifests a broad array of viru-
lence factors to account for its pathogenicity, and new
 752
virulence characteristics continue to be acquired. Staphylo-
coccus aureus is able to evade immune surveillance mecha-
nisms as well. The genome of S. aureus consists of 75% core
genes that appear in all species and 25% accessory genes that
vary among strains [19]. Within the accessory component of
the genome are mobile genetic elements that are transferable
among S. aureus strains. Accessory components may consist
of pathogenicity islands, prophages (from bacteriophages),
staphylococcal cassette chromosomes (SCC), genetic is-
lands, and plasmids [20]. Structural elements, metabolic
regulators, and virulence factors of S. aureus may be common
to all species (e.g., coagulases), or they may be highly spe-
cific for each strain (especially in the case of virulence fac-
tors). The exchange of mobile genetic units among strains of
S. aureus and the acquisition of genetic material from other
bacterial species (e.g., Enterococcus), results in fluid patterns
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of virulence and resistance.
Microbial virulence factors of S. aureus generally have been
grouped into bacterial structural factors, secreted bacterial
products and enzymes, and resistance mechanisms to antimi-
crobial agents [21]. Structural elements of the bacterial cell
include a polysaccharide capsule that resists phagocytosis and
the peptidoglycan cell wall that anchors a number of surface
adhesion proteins, allowing microbial binding to the extra-
cellular matrix of targeted host tissues [22]. The surface ad-
hesion proteins of the cell wall are referred to collectively as
microbial surface components recognizing adhesive matrix
molecules (MSCRAMMs) [11,22–24]. The MSCRAMMs are
identified in many species of gram-positive organisms, of
which several are unique to S. aureus.
Products secreted by S. aureus include those that enhance
microbial adherence to host tissues, exotoxins that are di-
rectly toxic to host cells, and enzymes that degrade and digest
the extracellular matrix. Secretable expanded repertoire ad-
hesive molecules (SERAMs) are a group of secreted proteins
that have duplicative functions of the MSCRAMMs identi-
fied above, except that they are secreted proteins, not part of
the staphylococcal cell wall [25]. The SERAMs of considerable
interest for S. aureus are coagulase (of which there are actually
two, staphylocoagulase and von Willebrand factor binding
protein), which target prothrombin and fibrinogen. The result of
the action of coagulases is generation of a staphylococcal–
fibrin matrix and creation of a local environment that facilitates
microbial adherence to tissue and a protected environment
against host defense mechanisms and antimicrobial therapy
[26]. Coagulases have effects that are analogous to clumping
factor of the MSCRAMMs, but they are freely secreted and
unique proteins [27].
Three exotoxin families predominate in the pathogenesis of
S. aureus infections and allergic responses, namely pore-
forming toxins, exfoliative toxins, and superantigens. Exotoxins
are those secreted products that are cytotoxic to host cells [28–
30], whereas superantigens are secreted products that provoke
an exuberant inflammatory response by the host [31,32]. In-
dividual cytotoxins have different cell targets but generally
function similarly by damaging the cell membrane, creating
pores, and leading to extravasation of cellular contents.
Expression of virulence
Staphylococcus aureus secretes numerous virulence fac-
tors, including the aforementioned toxins capable of mem-
BARIE ET AL.
brane pore formation and cytolysis. These virulence factors
include bi-component leukocidins [29], heptameric beta-
barrel–forming alpha-toxin (Hla), and phenol-soluble mod-
ulins (PSMs) [33]. An array of cell wall-anchored (CWA)
proteins, which number more than 25 and have substantial
functional redundancy, bind to cell wall peptidoglycans [34].
Clumping factor A (ClfA) is the major fibrinogen-binding
protein of S. aureus. Clumping factor A causes platelet ag-
gregation and clumping of bacteria on plasma, and is a major
factor relating to pathogen survival and dissemination in
blood. By contrast, S. aureus attachment to nasal epithelial
cells is facilitated by the staphylococcal surface adhesin
clumping factor B (ClfB) [34]. Fibronectin-binding proteins
(FnBPs) A and B enable S. aureus to adhere to and invade a
host of cell types, including epithelia, fibroblasts, and oste-
oblasts [35]. Protein A (SpA) is a conserved, multi-functional
surface protein that has a number of immunosuppressive
traits, including induced apoptosis of B-lymphocytes thereby
suppressing the host antibody response, and is arguably the
most important mechanism of immune evasion in S. aureus
[34] (see below). Iron-regulated surface proteins (Isd) A and
B are part of the heme uptake system (iron is a necessary
nutrient for bacteria) [34]. The Isd proteins play a role in
bacterial adherence to epithelial cells and IsdA on the bac-
terial surface causes the bacteria to become more hydrophilic
and negatively charged, facilitating cellular attachment.
Immune evasion
When innate immune mechanisms are insufficient to clear
a bacterial infection, adaptive immune mechanisms are ac-
tivated [33–35]. The adaptive immune response to S. aureus
requires an integrated response involving T-helper type 1
(TH1), TH17, and humoral antibody (IgG) responses, gener-
ating the production of interleukin (IL)-1 and IL-17A to
promote abscess formation, which in turn is required for the
clearance of bacteria via phagocytosis and oxidative burst.
Staphylococcal infections in human beings are known to
elicit only modest, transitory antibody responses [36,37], two
tangible manifestations of which are the nasal carrier state
(see above) and recurrent acute infections but also begging
the question as to whether active immunization against
staphylococcal infections will be of benefit. Staphylococci
can exist as human commensal flora because several mech-
anisms to ‘‘evade’’ detection by immune surveillance mech-
anisms (e.g., complement deposition, neutrophil killing)
have evolved [36]. Elaborated enterotoxins act as potent
T-lymphocyte superantigens, which bind major histocom-
patibility complex class II (MHC-II) determinants on the
surface of antigen-presenting cells, but the multiplicity of
these many toxins, both in number and functional redundancy
of staphylococcal enterotoxins and toxic shock syndrome
toxins (TSSTs), has prevented development of a superantigen
vaccine (see below).
Also during infection, S. aureus produces adenosine
(via adenosine synthase A-AdsA) from high-energy phos-
phates [38], which may be the most potent immunosup-
pressive signaling molecule. Adenosine receptor-mediated
signaling impedes phagocytosis by neutrophils (staphylo-
cocci that express wild-type AdsA are capable of surviving
neutrophil phagocytosis) and may degrade adaptive host
immune responses by impairing antigen presentation to
 IMMUNIZATION AGAINST STAPHYLOCOCCUS AUREUS
macrophages and dendritic cells. The B-cell superantigens
staphylococcal protein A (SpA) [39] and S. aureus binder of
immunoglobulin (Sbi) [40] (both of which harbor multiple
immunoglobin-binding domains) inhibit opsonophagocytic
clearance of the pathogen, and may inhibit normal B-
lymphocyte functioning, possibly by induction of clonal ex-
pansion leading to B-call apoptosis, or by inhibiting receptor
interaction of complement factor C3. The SpA protein me-
diates binding of IgG in an incorrect orientation on the bac-
terial surface, leading to decreased neutrophil binding and
consequent evasion of phagocytosis.
Staphylococcus aureus as a Target for Passive
Immunization
Passive immunization against S. aureus has been unsuc-
cessful to date [41]. No efficacy was seen from infusion of
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enriched human serum (IgG infusion) from unvaccinated
subjects [42, cited in Janssen et al. (41)]. Neither was efficacy
demonstrated from either of two trials of immune serum col-
lected from subjects who received a capsular polysaccharide
(CP) CP5/CP8/Pseudomonas exotoxin conjugate vaccine
[43,44 (cited in Janssen et al. (41),45]. More recently, a phase 2
trial failed to prevent S. aureus ventilator-associated pneumonia
after pre-treatment of patients with heavy airway colonization
by S. aureus with an anti-staphylococcal monoclonal antibody
(ASN100) [46]. ASN100 is a combination of two monoclonal
antibodies (ASN-1 and ASN-2) that together neutralize six S.
aureus cytotoxins. ASN-1 neutralizes a-hemolysin and four of
the five leukocidins (HlgAB, HlgCB, LukED, and LukSF, the
latter also known as Panton-Valentine leukocidin or PVL).
ASN-2 neutralizes the fifth leukocidin, LukGH (also known as
LukAB). LukGH, a potent immune evasion factor of S. aureus,
is expressed by the majority of all clinical isolates and con-
tributes substantially to S. aureus-mediated phagocyte killing.
Attempts continue to develop effective passive anti-
staphylococcal immunity. Although S. aureus is an extra-
cellular bacterium, it can evade host defenses by adapting as
an intracellular organism, where it can evade the action of
antibodies but also antibacterial agents and in so doing, serve
as a nidus for dissemination. A novel antibody–antibiotic
conjugate is being developed, designed to be activated spe-
cifically inside phagocytes that have engulfed S. aureus
[47,48]. The antibody is directed against cell wall component
teichoic acid (against which approximately one-third of in-
Table 1. Anti-Staphylococcal Vaccines in Clinical Development
Vaccine designation Developer
SA4Ag Pfizer
Unknown GSK
NOV-3A NovaDigm
4C-Staph GSK (Novartis)
STEBVax IBT/NIAID
Unknown Nabi
Unknown GSK
Data derived from Mohamed et al. [53] and Bagnoli et al. [54].
Als = Candida albicans agglutinin-like sequence protein (has three dimensional structural similarity to clumping factor [Clf] A);
AT = alpha-toxin; CP = capsular polysaccharide; Csa = conserved staphylococcal antigen; EsxAB = fusion protein of secreted proteins ess
extracellular A and B; FhuD2 = ferric hydoxamate uptake lipoprotein D2, involved in iron-hydroxamate uptake; GSK = GlaxoSmithKline,
Middlesex, United Kingdom; Mnt = manganese transporter protein; NIAID = National Institute for Arthritis and Infectious Diseases;
PVL = Panton-Valentine leukocidin; SEB = staphylococcal enterotoxin B.
753
nate anti-staphylococcal antibodies are directed) [47],
whereas the antibiotic chosen was the rifamycin derivative
rifalogue, which is bactericidal in the acidic milieu of the
phagolysosome and active against non-replicating bacteria
and antibiotic-tolerant persister cells. The antibody recog-
nizes cell-free S. aureus, leading to opsonization and
phagocytosis. Once intracellular, rifalogue is cleaved by ca-
thepsins and exerts its effect. Preliminary work showed that
the conjugate is ineffective against planktonic S. aureus and
that the conjugate does not penetrate mammalian cells be-
cause of the size of the antibody.
Staphylococcus aureus as a Target for Active
Immunization
Prevention of S. aureus infection by an effective vaccine
would save lives and cost, be antibiotic sparing, and hinder the
development of antibiotic resistance [49,50]. If an effective
vaccine could be targeted for prevention when the risk of be-
coming infected is highest (e.g., in the short-term aftermath of
surgery or some other invasive procedure), success might be
achieved, because the need to provide immunity would exist
for just a limited time. An ideal vaccine would have three main
attributes: Induction of antibodies to neutralize toxins causing
inflammation and tissue necrosis; induction of antibodies
against CWA proteins believed to be important in the initial
attachment of bacteria to host ligands; and the ability to induce
a robust cytokine-mediated response to promote neutrophil
recruitment and effective bacterial clearance. A successful anti-
staphylococcal vaccine would not have to prevent infection by
MRSA specifically, because putative vaccine targets could be
independent of elements responsible for antibiotic resistance.
Development of a vaccine directed against several strains
will require biologic finesse. Although anti-staphylococcal
vaccines have been raised against a variety of targets, mul-
tiple efforts thus far have failed to demonstrate efficacy, in-
cluding in phase 3 trials. In a double-blind trial involving
patients with end-stage renal disease who were undergoing
hemodialysis, Shinefield et al. [51] evaluated the safety,
immunogenicity, and efficacy of a vaccine with S. aureus CP5
and CP8 capsular polysaccharides conjugated to nontoxic
recombinant Pseudomonas aeruginosa exotoxin A. A total of
1,804 adult patients (73 hemodialysis centers) were assigned
randomly to receive a single intramuscular injection of either
vaccine or saline. Immunoglobulin G (IgG) antibodies to both
Antigenic targets Trial phase
CP5, CP8, ClfA, MntC 2b (ongoing)
CP5, CP8, AT, ClfA 1 (completed)
Als3p 1 (completed)
FhuD2m Csa1A, EsxAB 1 (completed)
SEB 1 (completed)
AT/PVL 2 (completed)
CP5, CP8, AT Pre-clinical
 754
capsular polysaccharides were measured, and episodes of
S. aureus bacteremia (primary end point, assessed at one year)
were recorded. The capsular polysaccharides elicited an anti-
body response of at least 80 mcg/mL (the estimated minimal
level conferring protection) in 80% of patients for CP5 and in
75% of patients for CP8. Between weeks 3 and 40 after vac-
cination, S. aureus bacteremia developed in 11 of 892 evalu-
able patients in the vaccine group, compared with 26 of 906
patients in the control group (vaccine efficacy [VE] estimate
57%; 95% confidence interval (CI), 10%–81%; p = 0.02).
However, the efficacy during weeks 3 to 54 was only 26%
(p = 0.23). Reactions to the vaccine were generally mild-to-
moderate, and most resolved within two days. The authors
concluded that the vaccine conferred partial immunity against
S. aureus bacteremia for approximately 40 wks, after which
protection waned as antibody concentrations decreased.
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In view of the failure of that trial, a second study in he-
modialysis patients evaluated the VE of two vaccine doses
(rather than the single dose in the prior study) [52]. In a
double-blind trial, 3,359 patients were randomly assigned
(1:1) to receive vaccine or placebo at week 0 and 35. The VE
in preventing S. aureus bacteremia was assessed between 3
and 35 wks and 3 and 60 wks post-dose 1. Serious adverse
events (SAEs) were recorded for 42 d post-vaccination and
deaths until study end. No substantial difference in the inci-
dence of S. aureus bacteremia was observed between weeks
3–35 post-dose 1 (VE -23%, 95% CI: -98%–23%, p = 0.39)
or at 3–60 wks post-dose 1 (VE -8%, 95% CI: -57%–26%,
p = 0.70). Serious adverse events were reported by 24% and
25% of vaccine and placebo recipients, respectively. These
data did not show a protective effect of either one or two
vaccine doses against S. aureus bacteremia in hemodialysis
patients despite a robust immune response and an acceptable
safety profile. The authors suggested a need to expand the
antigen composition of the vaccine among possible explana-
tions for the failure of the trial.
Several additional anti-staphylococcal vaccines have
reached clinical development, using various antigenic tar-
gets (Table 1) [53,54]. Immunization against several anti-
genic targets has heretofore been unsuccessful (e.g.,
lipotechoic acid, alpha-toxin), as have single-antigen im-
munization approaches against plausible biologic (protein)
targets. Pfizer (Pearl River, NY) is developing a four-antigen
(SA4Ag) vaccine that targets CP5 and CP8 (both conjugated
to a mutant non-toxic diphtheria toxin carrier protein
[CRM197]), a mutated recombinant ClfA protein (rmClfA),
and a recombinant form of the manganese transporter A
protein (MntC), an essential metabolic regulator (manga-
nese is essential for detoxification of the neutrophil respi-
ratory burst) (Table 1). These targeted virulence factors have
the shared attribute that they are deployed early (experi-
mentally, within one to six hours) during infection and elicit
robust functional antibody responses. In a preliminary safety
and efficacy trial [55], 100 participants were vaccinated with a
single dose of SA4Ag. SA4Ag was well tolerated, with a
satisfactory safety profile. On day 29, antibody titers had in-
creased 69.2-fold (for CP5) and 28.9-fold (for CP8) and 19.6-
fold (for MntC) and 12.3-fold (for ClfA), respectively. The
majority of participants achieved the pre-defined biologically
relevant thresholds: CP5, 100%; CP8, 97.9%, ClfA, 87.8%;
and MntC, 96.9%. In phase 2/2a studies conducted in healthy
adults aged 18–64 yrs [56] and 65–85 yrs [57], SA4Ag elicited
BARIE ET AL.
rapid, robust immune responses to each of the antigens, sus-
tained for at least 12 mos. Meta-analysis of these trials [58]
confirmed the robust safety profile.
Arguably the most promising approach for anti-
staphylococcal vaccination would be to vaccinate prior to
the at-risk period (e.g., prior to elective surgery). Not only
would soft tissue infections be targeted (e.g., surgical site
infection), but a vaccine-induced antibody response would
provide antibodies as well as human matrix proteins access
to surgical implants (e.g., prosthetic joints, surgical mesh),
and so potentially would, in theory, preclude bacterial ad-
hesion to the implant, biofilm formation, and subsequent
dissemination. Eventually, any type of elective operation
that is plagued by staphylococcal infection could be a can-
didate for pre-operative vaccination, but an ongoing trial
(Staphylococcus aureus Surgical Inpatient Vaccine Efficacy
[STRIVE]) is targeting the vaccination of patients under-
going spine surgery with multi-level instrumentation from
10 to 60 d prior to surgery [59]. Future studies might target
infra-inguinal vascular surgery with insertion of a prosthetic
graft, open incisional hernia repair with insertion of mesh,
or other high-risk (for staphylococcal infection) elective
operations.
Author Disclosure Statement
Doctor Barie is a consultant for and has received honoraria
from Arsanis, Inc. and Pfizer, Inc. Doctor Narayan has
nothing to disclose. Doctor Sawyer is a consultant for and has
received honoraria from Pfizer, Inc.
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Address correspondence to:
Dr. Philip S. Barie
Department of Surgery, P713A
New York-Presbyterian Hospital/
Weill Cornell Medical Center
525 East 68th Street
New York, NY 10065
E-mail: pbarie@med.cornell.edu