1130 Journal of Dental Education Volume 67, Number 10

Transfer of Advances in Science into Dental Education

Caries Vaccines for the Twenty-First Century
Daniel J. Smith, Ph.D.
Abstract: Can infection with the dental caries pathogen, Streptococcus mutans, be intercepted or modified immunologically?
Resolving this question requires answers to many questions: What are the pathways by which this cariogenic streptococcus enters
and accumulates in the dental biofilm? Can bacterial components associated with virulence induce immune responses? What is
the level of maturity of immune pathways in the oral cavity of the young child at the time of infection? Can immune strategies
deal effectively with chronic S. mutans infections? Are these vaccines safe? Many such questions have been answered. For
example, preclinical application of modern methods of mucosal vaccine design and delivery has routinely resulted in protection
from dental caries caused by S. mutans infection, using antigens involved in the sucrose-independent or sucrose-dependent
mechanisms of infection by these cariogenic streptococci. Passive administration of antibody to functional epitopes of S. mutans
virulence antigens has also provided a degree of protection in preclinical studies and small-scale human investigations. The
caries-protective capacity of active immunization with dental caries vaccines now awaits proof of principle in pediatric clinical
trials.
Dr. Smith is Senior Staff Member, Department of Immunology, The Forsyth Institute. Direct correspondence and requests for
reprints to him at Department of Immunology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115; 617-456-7720 phone;
617-456-0742 fax; dsmith@forsyth.org. His research was performed through the generous support of the National Institute of
Dental and Craniofacial Research (DE-01653, DE-04733, DE/AI-12324). This article was adapted from his review that appeared
in Critical Reviews in Oral Biology and Medicine 2002;13:335-49.
Key words: dental caries, SIgA, vaccine, mucosal immunization, Streptococcus mutans, glucosyltransferase, antigen I/II, glucan
binding protein
Submitted for publication 8/4/03; accepted 8/20/03
I
s dental caries conquered? Walk into a day care
center in Brazil, and chances are that at least 25
percent of the children over three years of age
will have active disease. Go to China where epide-
miologists report that three-quarters of five-year-old
children experience significant dental decay. Stay at
home in the United States, and find that being a young
kid on the wrong side of the poverty line brings with
it the likelihood of untreated decay. Elders are show-
ing up with disease on their root surfaces. In the
United States, we spend $70 billion annually in den-
tal services, a significant portion of which pays for
dental caries treatment or conditions resulting from
tooth decay. Clearly, we have a long way to go be-
fore we can declare victory over this disease.
We have made great strides in understanding
dental caries etiology. Infection as a key component
was uncovered more than 110 years ago by Miller
who made the link among microorganisms, dietary
carbohydrates, and dental disease.
1
Early in the last
century Clarke isolated the bacterium, Streptococ-
cus mutans (Figure 1), upon which modern dental
research has cast its brightest light. In the latter half
of the twentieth century, research efforts at NIH and
in Scandinavia confirmed the cariogenic properties
of this organism, demonstrated its transmissibility,
and described its worldwide distribution. Later, oth-
ers identified many of its virulence characteristics
and unraveled its biochemistry. Ultimately, the com-
plete genome sequence of S. mutans was reported in
2002.
2
Although molecular biological and cultural
techniques have also incriminated other bacteria in
the process and extension of dental caries in various
dental habitats, S. mutans continues to be Public
Enemy #1, especially for early childhood dental dis-
ease.
3
How to treat this disease? Use of fluoride in its
many forms, use of sugarless products and sealants,
and increased access to dental care are among the
approaches that have had a significant impact on the
amount of disease of the young and economically
advantaged. Many of these approaches can be
broadly effective. However, economic, behavioral,
or cultural barriers to their use have continued the
epidemic of dental disease in the mouths of many
children in our global village.
Vaccine strategies have been invoked often to
diminish or prevent the impact of infectious disease,
especially among the young. Vaccines are particu-
larly well suited for public health applications, espe-
October 2003 Journal of Dental Education 1131
cially in environments that do not lend themselves
to regular health care. Given a general appreciation
for the infectious component of dental caries, injected
vaccines containing lactobacilli were administered
with limited success in the 1940s. However, at that
time the molecular pathogenesis of S. mutans was
unknown, nor was there an understanding of the
immune mechanisms that operate in the oral cavity.
Most virulence characteristics were unclear, with the
exception of the ability of cariogenic bacteria to pro-
duce enamel-dissolving acid. Today we have an-
swered many of these questions, permitting us to
more knowledgeably explore the potential for vac-
cine therapy for dental caries associated with S.
mutans.
Acquisition of Mutans
Streptococci
The modern era of vaccine therapy began in
the late 1960s with William Bowens use of S. mutans
to intravenously immunize irus monkeys.
4
At that
time, it was known that most people carried S. mutans
in their dental plaque. It became clear from animal
studies, however, that once these organisms colonized
dental plaque, they were extremely difficult to dis-
lodge. Thus, most (but not all) of the experimental
dental caries vaccine approaches attempted to modify
initial infection with S. mutans. Translating this ap-
proach to humans required that we know when chil-
dren first become infected with S. mutans and from
whom their infection came.
Studies of the natural history of oral strepto-
coccal acquisition by infants revealed that, under
normal circumstances of diet and challenge, children
become permanently colonized with mutans strep-
tococci between the middle of the second year and
the end of the third year of life. Page Caufield et al.
5
referred to this period as the window of infectiv-
ity. Several groups found that the primary source of
infection was maternal, although recent evidence sug-
gests that nonfamilial transfer can occur when envi-
ronmental conditions strongly favor colonization.
The window may open even earlier if maternal S.
mutans infection levels are high, coupled with fre-
quent exposure to dietary sucrose. More sensitive
techniques for microbial detection, e.g., DNA probe
technology, have also suggested that low levels of
mutans streptococci may be found in the oral cavity
during the first year of life, especially in caries-prone
populations.
6
However, mutans streptococci in such
children are not colonizing their preferred ecologi-
cal habitat at this early age. Thus, the data suggest
that a window of vaccine opportunity could exist
between twelve and eighteen months for most popu-
lations.
Figure 1. Scanning electron micrograph of Streptococcus mutans
Image courtesy of Drs. Renata Mattos-Graner and Ziedonis Skobe.
1132 Journal of Dental Education Volume 67, Number 10
Despite the influence of maternal dose, chil-
dren who do not become infected by approximately
three years of age appear to remain uninfected, or
minimally colonized for several years, possibly un-
til new opportunities for colonization occur upon
eruption of the secondary dentition. This suggests
that a longer-term benefit may ensue if mutans strep-
tococcal colonization could be impeded in early
childhood by measures such as immunization.
Molecular Pathogenesis
Thirty years ago British and American scien-
tists demonstrated that experimental protection could
be achieved by immunization with mutans strepto-
cocci (reviewed by Michalek and Childers
7
). Atten-
tion then focused on immunologically intercepting
properties of these organisms that led to disease. The
molecular pathogenesis of mutans streptococci in-
volves several phases, each of which offers targets
for immunological intervention (Figure 2). These
acidogenic streptococci require the hard surfaces
furnished by teeth for sustained colonization and ac-
cumulation. To colonize the oral cavity, these strep-
tococci must first bind to pre-existing receptors
within dental biofilms. Initial attachment to the tooth
occurs by the interaction of bacterial proteins with
host-derived components in the dental pellicle cov-
ering the tooth surface. These bacterial adhesins, first
described by Russell and Lehner
8
and often referred
to as antigen I/II in Streptococcus mutans, bind acidic,
mucin-like glycoproteins found in parotid and sub-
mandibular saliva. These components are found in
salivary pellicles that coat both the tooth surface and
early colonizing bacteria such as Streptococcus san-
guis and Actinomyces species.
The ultimate pathogenicity of mutans strepto-
cocci occurs through erosion of the hydroxyapatite-
like mineral in dental enamel by lactic acid, a meta-
bolic end product of bacterial growth. However,
significantly destructive concentrations of this acid
require the substantial accumulation of these
acidogenic streptococci in dental plaque. This accu-
mulation process is initiated by the activity of extra-
cellular glucosyltransferases (GTF) of which several
are constitutively secreted by mutans streptococci.
9,10
In the presence of dietary sucrose, GTFs synthesize
several forms of high molecular weight branched
extracellular glucans. GTFs that synthesize insoluble
forms of glucan (S. mutans GTF-B and GTF-C) have
been most closely associated with pathogenicity.
These glucose polymers provide scaffolding for the
aggregation of mutans and other oral streptococci
through interaction with bacterial cell-associated
glucan-binding proteins. Furthermore, glucans
modify the porosity of the dental biofilm, thus in-
creasing the availability of nutrients for continued
bacterial metabolism. Several glucan-binding proteins
have been described in mutans streptococci.
11-14
Al-
though each of these glucan-binding proteins (GBPs)
has the ability to bind to certain forms of glucan and
some have been shown to be cell-associated, their
unique contributions to in vivo plaque development
are as yet unclear. GTFs also contain glucan-bind-
ing domains. The interactions of glucans with cell-
associated glucan-binding domains of GTFs and
GBPs combine to cause extensive accumulation of
mutans streptococci in the dental biofilm (Figure 2).
Since GTFs and GBPs are also secreted into the ex-
tracellular environment, their specific or nonspecific
incorporation into the salivary pellicle would also
provide binding sites for mutans streptococci.
Theoretically, the next phase of pathogenesis
results from the metabolic activities of these masses
of accumulated mutans streptococci (and possibly
of other accumulation-associated microorganisms).
Mutans streptococci are the most prolific producers
of lactic acid in these accumulations although other
low pH bacteria may also contribute.
15
Dental car-
ies ultimately ensues because the resulting increase
in lactic acid concentration cannot be sufficiently
buffered to prevent enamel dissolution.
Thus, several stages in the molecular patho-
genesis of dental caries are susceptible to immune
intervention. Microorganisms can be cleared from
the oral cavity while still in the salivary phase by
antibody-mediated aggregation. Antibody could also
block the receptors necessary for colonization (e.g.,
adhesins) or accumulation (e.g., glucan-binding do-
mains of GBPs and GTF) within the dental biofilm.
Immune inactivation of GTF enzymes would pre-
vent formation of the glucan matrix. Modification
of metabolically important functions may also be
targeted. In addition, the antimicrobial activity of
salivary antibody may be enhanced or redirected by
synergism with innate components of immunity, such
as mucins or lactoferrin. As we will see, immuno-
logical intervention by many of these components
has achieved a measure of experimental success.
October 2003 Journal of Dental Education 1133
Ontogeny of Immunity in
Saliva
Immunological interception of the initial at-
tempts of mutans streptococci to colonize the tooth
surface would seem to be the preferred vaccine strat-
egy since these organisms are exceedingly difficult
to displace once they become part of the dental
biofilm. Given the natural history of mutans strepto-
coccal infection, this strategy would require year-
old children to be sufficiently mature immunologi-
cally to form protective levels of antibody in their
oral cavity at this time. Secretory IgA (SIgA) is the
principal immune component of major and minor
gland salivary secretions and thus would be consid-
ered to be the primary mediator of adaptive immu-
nity in the salivary milieu. The need to understand
the rate and characteristics of salivary immune de-
velopment triggered a series of studies that now sup-
port the rationale for caries vaccine applications in
early childhood (Figure 3).
These studies revealed that immunity in the oral
cavity undergoes rapid, early development (reviewed
in Smith and Taubman
16
). Although SIgA antibody
in saliva and other secretions is essentially absent at
birth, mature SIgAi.e., dimeric IgA with bound
secretory componentis the principal salivary im-
munoglobulin secreted by one month of age. Induced
by the environmental antigenic challenge, mucosal
IgA antibody to pioneer gut (e.g., Escherichia coli)
and oral (e.g., Streptococcus mitis and S. salivarius)
microbiota appears in secretions (including saliva)
within weeks of initial microbial exposure. By six to
nine months of age most children exhibit an adult-
like distribution of salivary IgA subclasses, which
include antibody to several antigens of the predomi-
nant pioneer oral flora.
Can children respond to natural exposure to
mutans streptococci? The answer is yes. Salivary
antibody to mutans streptococcal antigens is usually
first observed in the second and third years of life.
17
Salivary responses are often directed to those strep-
tococcal components that are important in coloniza-
tion and accumulation, such as antigen I/II, GTFs,
and GBPs. Longitudinal studies suggest that these
antibody specificities result from contact with mutans
streptococci, rather than with earlier colonizing oral
streptococci, since well-developed salivary IgA an-
tibody to pioneer oral streptococci is present prior to
the detection of antibody reactive with mutans strep-
tococci. Interestingly, in some children, antibody to
mutans streptococcal antigens can also be detected
independently of the ability to detect ongoing infec-
tion in the second year of life. As is the case with
many bacterial challenges throughout the body, the
threshold of immunological response can be lower
than that of persistent infection; therefore, it is not
surprising to observe antibody to S. mutans antigens
in the absence of its colonization. Thus colonization,
at least not extensive colonization, with mutans strep-
tococci is apparently not required for the develop-
ment of salivary antibody to associated mutans strep-
tococcal antigens.
Thus, the evidence from salivary IgA responses
to commensal oral microbiota indicates that the mu-
cosal immune system is relatively well developed
by the period during which children typically become
infected with mutans streptococci. Most children
apparently respond immunologically to transient in-
fection or ongoing colonization with mutans strep-
tococci in early childhood. Although the distribution
and specificity of childrens responses are not iden-
tical, antibody to a few major antigens predominates.
These data suggest the possibility that such responses
could be protective if induced prior to critical colo-
nization events.
Specific Vaccine Targets
What bacterial components make the most ef-
fective vaccines? Preclinical studies reveal that sev-
eral of the protein components involved in the mo-
lecular pathogenesis of mutans streptococci can
induce protective immunity. Furthermore, protective
immunity can be achieved by concentrating the im-
mune response on suspected functional elements of
these components either using synthetic peptides or
recombinant DNA approaches that permit the expres-
sion of complete functional domains (for recent re-
views see Russell,
18
Koga et al.,
19
and Smith
20
).
Adhesins. For example, the family of adhesins
from Streptococcus mutans and Streptococcus
sobrinus has been shown to be effective antigens,
both as intact proteins and as subunit vaccines. These
single polypeptide chains are approximately 1600
residues in length and, in S. mutans, contain salivary
binding domains associated with an alanine-rich tan-
dem repeating region in the N terminal third and a
proline-rich repeat region in the center of the mol-
ecule. Abundant in vitro and in vivo evidence, using
1134 Journal of Dental Education Volume 67, Number 10
a variety of active and passive immunization ap-
proaches, indicates that antibody with specificity for
mutans streptococcal adhesins can interfere with
bacterial adherence and subsequent dental caries
caused by S. mutans. Effective subunit vaccines have
been designed using synthetic peptides or recombi-
nant proteins to direct the immune response to do-
mains of salivary binding function. Immunization
with these constructs is also protective in experimen-
tal systems. Protection in these experiments could
conceivably occur by antibody blockade of initial
colonization events in the dental biofilm or by anti-
body-mediated aggregation and clearing of adhesin-
bearing streptococci from the bulk fluid salivary
phase.
Glucosyltransferases. Mutans streptococci
that have lost the ability to make glucan through natu-
ral or induced mutations in GTF genes do not pro-
duce significant disease in animal models. Growth
of mutans streptococci in the presence of antibody
to GTF significantly diminishes the amount of
biofilm on glass surfaces. Thus it was not surprising
that immunization studies using intact GTF vaccines
successfully protected animals infected with S.
mutans. Passive administration of antibody to GTF
in the diet was also protective. GTF is an interesting
protein in that it does several things. This enzyme
cleaves the bond between the glucose and fructose
moieties in sucrose. Activated glucose is then trans-
ferred to a growing glucan polymer. Glucans can also
bind to an area of repeating sequences in the C-
terminal third of the enzyme. These areas of func-
tion offered several possibilities for more targeted
immune responses. Synthetic peptide or recombinant
protein vaccines, designed to include one or more
suspected areas of function, protect animal models
from experimental dental caries. Since GTFs from
the two major cariogenic streptococcal species in
humans, S. mutans and S. sobrinus, have very simi-
lar sequences in these functional domains, immuni-
zation with GTF protein or subunit vaccines from
one species can induce a measure of protection for
the other species. Thus, the presence of antibody to
GTF in the oral cavity, prior to infection, can signifi-
cantly influence the disease outcome, presumably by
interference with one or more of the functional ac-
tivities of the enzyme.
Glucan-binding proteins. Since glucan-bind-
ing proteins on the surface of mutans streptococcal
cells may provide the receptors for glucan-mediated
aggregation, these proteins have also received atten-
tion as vaccines. Of the three S. mutans glucan-bind-
ing proteins identified to date, only GbpB has been
shown to induce protective immune responses to
experimental dental caries. Interestingly, salivas of
young children often contain IgA antibody to GbpB,
indicating that initial infection with S. mutans can
lead to natural induction of immunity to this protein.
Bioinformatic methods of identifying molecular re-
gions responsible for this immunogenicity have
yielded at least one GbpB subunit vaccine that was
effective in preclinical studies. Unlike GTF, how-
ever, protection induced by S. mutans GbpB does
not extend to S. sobrinus species.
Enhancing Strategies
Routes to Response
Since teeth and the attached biofilms are bathed
in antibody-containing saliva, many investigators
concentrated on inducing immunity by mucosal
routes. Mucosal (SIgA) immune responses can ap-
pear in saliva after induction at sites both near and
distant from the oral cavity.
21
An extreme example
of this is the recent demonstration in our laboratory
that rectal administration of GTF-induced salivary
immunity correlated with experimental dental car-
ies protection. Taking advantage of this characteris-
tic, several mucosal routes have been explored for
delivery of dental caries vaccines.
Early preclinical studies
22
and clinical trials
23
used oral delivery of S. mutans antigen to induce
immune response in the gut-associated lymphoid tis-
sue. These studies established the principle that pro-
tection could be achieved via the mucosal response
alone. The oral route is not ideal, however, in part
because of the detrimental effects of stomach acid
on antigen. Thus, inductive sites in closer anatomi-
cal relationship to the oral cavity were explored.
Many studies targeted the nasal route to take advan-
tage of the inductive characteristics of nasal-associ-
ated lymphoid tissue (reviewed in Russell
18
). Nasal
immunization with mutans streptococcal adhesins,
GTF, or GbpB each consistently induced relatively
high levels of salivary antibody with concomitant
reductions in experimental dental caries. Use of the
nasal route in humans is also strengthened by recent
successes with a nasally applied influenza vaccine.
Tonsillar tissue and minor salivary glands have
also been explored as routes to protective immune
responses. Although Japanese scientists have reported
October 2003 Journal of Dental Education 1135
preclinical protection in rabbits after tonsillar appli-
cation of mutans streptococci, Noel Childers group
24
showed that humans responded better to nasal ver-
sus tonsillar application of GTF when salivary anti-
body was the readout. A clinical trial in our own
laboratory suggested that topical application of GTF
to labial minor salivary glands could result in de-
layed reaccumulation of mutans streptococci in
young men.
25
Immunomodulators and Delivery
Systems
Mucosal application of soluble protein or pep-
tide antigens by themselves rarely results in sustained
IgA responses. Considerable effort, therefore, has
been expended to develop immunomodulators (ad-
juvants) and delivery systems that enhance mucosal
responses, including responses to dental caries vac-
cines. Enterotoxins such as cholera toxin are power-
ful mucosal adjuvants. Of course, inherent toxicity
precludes human use of the holotoxin. The toxicity
issue can be circumvented by using nontoxic parts
of the protein or by mutating various residues in the
A1 subunit associated with toxic properties. Various
degrees of adjuvant activity remain. In some cases,
antibody production and protective immunity
achieved by combining antigen with modified adju-
vants is nearly comparable to that achieved with the
holotoxin.
26,27
Efforts continue to engineer these en-
terotoxins for human applications.
Improvements have also been made in deliv-
ery of vaccine to inductive sites for mucosal immune
responses. Liposomes, which are phospholipid mem-
brane vesicles thought to home to mucosally associ-
ated lymphoid tissues, can be manufactured to con-
tain vaccine antigens. Preclinical and clinical studies
have shown superior salivary responses after mucosal
application of GTF-containing liposomes (reviewed
in Russell
18
and Childers et al.
24
). Microcapsules and
microparticles made of poly(lactide-co-glycolide)
(PLGA) have also been used to deliver dental caries
vaccines because of their ability to control the rate
of release, evade preexistent antibody clearance
mechanisms, and degrade slowly without eliciting
an inflammatory response to the polymer. Mucosal
application of antigens incorporated into PLGA en-
hance mucosal responses and can facilitate protec-
tive salivary immune responses to infectious chal-
lenge with mutans streptococci in preclinical
studies.
28
Starch microparticles can also increase mu-
cosal responses to soluble antigens.
29
The pathway to mucosal immune responses in
the gut begins by capture of antigens from the lumen
by specialized epithelial cells (so-called M cells)
that overlie mucosal lymphoid tissue. These cells then
pass their captured contents to underlying lymphoid
tissue, ultimately resulting in SIgA antibody in se-
cretions. Since Salmonella naturally colonize M cells,
these organisms have been engineered for use as rep-
licating antigen delivery systems for which mucosal
responses are desired. Attenuated expression vectors
can be designed to contain plasmids expressing re-
combinant peptides that contain mutans streptococ-
cal virulence epitopes alone or in combination with
sequences having adjuvant properties. These con-
structs can induce protective immunity for experi-
mental dental caries after oral, intragastric, or intra-
nasal administration (reviewed in Russell
18
and
Smith
20
).
Other Immune Sources of
Protective Antibody
Saliva need not be the only source of pro-
tective antibody in the oral cavity. Endogenous
sources of antibody can also be supplied via the gin-
gival crevicular fluid after systemic injection, chiefly
in the form of IgG antibody. Preclinical evidence for
the effectiveness of this route was provided in the
1970s by the British group led by Thomas Lehner
who showed that subcutaneous injection of primates
with mutans streptococcal cells led to significant re-
ductions in smooth surface and fissure caries.
30
Later,
this group showed that similar protection followed
injection of a purified mutans streptococcal adhesin.
31
Again, protective immunity was thought to be based
on exposure of infecting mutans streptococci to IgG
antibody emanating from gingival crevicular fluid.
The Lehner group then demonstrated that anti-
body need not be produced actively by the host, but
that protection could be achieved by passive admin-
istration of IgG antibody.
32
Early studies used mouse
monoclonal antibody to salivary binding determi-
nants of the adhesin as the passive antibody source
to demonstrate that exogenous antibody of the ap-
propriate specificity could also modify infection and
disease. Other groups have added antibody reagents
to drinking water, mouthwashes, or the diet and
achieved some protective effects in preclinical stud-
ies (reviewed in Koga et al.
19
). Julian Ma et al.
33
used
transgenic antibody fashioned in tobacco plants to
1136 Journal of Dental Education Volume 67, Number 10
provide a passive form of protection in small-scale
clinical trials. In these studies much of the dental
biofilm of young adult subjects was first removed
by vigorous treatment of the teeth with
chlorohexidine-based antibacterials. Repeated topi-
cal applications with mouse monoclonal reagents or
transgenic antibody were then administered for sev-
eral weeks. Recolonization with mutans streptococci
did not occur for at least two years after treatment of
subjects with mouse monoclonal antibody or at least
four months after treatment with the transgenic anti-
body. In contrast, the teeth of all control subjects were
recolonized with mutans streptococci within a few
months.
How does a short-term topical treatment with
antibody result in an apparent long-term interference
with S. mutans recolonization? The best explanation
may be an ecological one. Thus, antibody blockage
of an important adhesin epitope during the recon-
struction of the dental biofilm following
chlorohexidine treatment places indigenous mutans
streptococci at an insurmountable competitive dis-
advantage for recolonization. An interesting parallel
may be the observation that young children who do
not become naturally infected with mutans strepto-
cocci during the window of infectivity remain
undetectably infected for several years, potentially
because its habitat in the dental biofilm has been filled
by other indigenous flora.
Prospects for the Twenty-First
Century
Where do we stand today? Mutans streptococ-
cal GTFs, adhesions, and GbpB each induce caries-
protective immunity in experimental systems, thus
are likely candidates for initial pediatric clinical tri-
als. Mucosal application would be expected to be
safe since children are already naturally exposed to
these components during the first years of life. Re-
Figure 2. Molecular pathogenesis of mutans streptococci (MS)
October 2003 Journal of Dental Education 1137
finements to the vaccine approach, such as identifi-
cation of additional protective epitopes associated
with functional domains, continue to be made and
incorporated into single- or multi-component con-
structs to increase their protective value. Several
routes of administration can induce protective im-
mune responses, at least in model systems. Also, sig-
nificant progress is being made in the adjuvant field
to remove the toxic properties of powerful mucosal
adjuvants while maintaining their adjuvant proper-
ties. Animate (attenuated bacterial vectors) and in-
animate (liposomes, microparticles) delivery systems
can provide more efficient targeting of the vaccine.
Both passive and active immunization approaches
have demonstrated success in animal models and
human clinical trials in adults.
What about tomorrow? Traditional vaccine
therapy ideally induces protective immunity prior to
infection with the target pathogen. The window of
mutans streptococcal infection opens in the middle
of the second year of life under normal infectious
challenge. To meet this challenge, year-old children
would receive a caries vaccine in order to intercept
initial colonization events. Our understanding of the
ontogeny of the mucosal immune response indicates
that children at this age are competent to mount secre-
tory responses to the proteins that have been sug-
gested as vaccine components. A mucosally applied
pediatric dental caries vaccine would be truly novel
as the first nonreplicating vaccine applied by any
mucosal route. Furthermore, the character of the pe-
diatric response to a nasally applied caries vaccine
would tell us about the potential for immunization
by mucosal routes, not just for dental caries, but also
for the many pathogens that cause disease in the gut
or airways.
Provided that these trials demonstrate vaccine
efficacy, the refinements made to caries vaccine de-
sign, delivery, and immune enhancements may pro-
vide necessary flexibility in subsequent vaccine ap-
plications. For example, the ideal vaccine for a child
with asthma, the second most common chronic child-
hood ailment, may be at a mucosal site and with an
adjuvant (e.g., detoxified enterotoxin) that is quite
different from that sufficient to give a protective re-
sponse to a healthy child. Also, from economic and
Figure 3. Association of oral colonization with salivary IgA immune responses (Ab) to indigenous flora
1138 Journal of Dental Education Volume 67, Number 10
societal standpoints, a vaccine strategy for children
to whom the full advantages of pediatric care are
available may not be the ideal approach for children
with limited health care access. For the former group
of children, perhaps an intranasal application of a
GTF or AgI/II-based vaccine may be best. In con-
trast, for children in developing countries, the ideal
vaccine may be an attenuated Salmonella expression
system that contains vaccine epitopes for multiple
infectious diseases (e.g., mutans streptococcal, Sal-
monella, and rotovirus infections) in order to induce
protective responses to several childhood diseases
and to provide herd immunity by shedding the vac-
cine strain. Furthermore, passive immunization with
antibody that is mass produced in plants may have
particular application in older populations as well as
a supplement to active immunization strategies in
children.
Several challenges face the development of an
effective dental caries vaccine. However, the oral
health impact on children of the twenty-first century
would be enormous, especially for those whose eco-
nomic or cultural position puts them at increased
caries risk. The expected reduction in disease would
save tens of billions of dollars annually in expendi-
tures for dental treatment. Associated benefits may
accrue if new pathways to intercept some of the most
debilitating gastrointestinal diseases of early child-
hood are uncovered from knowledge gained through
clinical trials of mucosally applied dental caries vac-
cines.
REFERENCES
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Philadelphia: S.S. White Dental Mfg. Co., 1890.
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