Review Article

Insight into status of dental caries vaccination:

A review
Gayathri Cherukuri, Chandrasekhar Veeramachaneni1, G. V. Rao2, Venkat Baghirath Pacha, Sudheer B. Balla3
Departments of Oral and Maxillofacial Pathology and 3Forensic Odontology, Panineeya Mahavidyalaya Institute of Dental Sciences,
1
Department of Conservative and Endodontics, Malla Reddy Dental College for Women, Hyderabad, 2Department of Oral and
Maxillofacial Pathology, Mamata Dental College, Khammam, Telangana, India

Abstract
Despite advances in the 21st century, dental caries still remains to be one of the most common infectious diseases. Its prevalence
was confirmed by the World Health Organization and affirms dental caries as a major health problem in all over the world.
Even though the process of tooth decay is multifactorial, the oral bacteria, mutans streptococci, such as Streptococcus mutans
and Streptococcus sobrinus, are considered to be causative agents of dental caries in human. Numerous studies carried out
on animals and various categories of vaccines were developed such as whole cell vaccine, subunit vaccine, and synthetic
peptides. Irrespective of success from active and passive immunization based on animal trials, it is the phenomenon of
human heart reactivity that limited the applicability of these trials in humans. Continuous efforts are being made to overcome
these limitations and for further success in human trials. With the advent of various antibodies against antigens of mutans
streptococci, local passive immunization has become the safer approach in humans against the colonization of bacteria and
caries induction. This review provided insight into epidemiology, active and passive immunization in both animal and human
trials, as well as the prospects of caries vaccination.
Keywords: Active immunity; dental caries vaccine; passive immunity; Streptococcus mutans

INTRODUCTION
Oral health is considered to be a significant component
and is integral and essential to reflection of general health,
well‑being, and quality of life. Unfortunately, dental caries that
is an infectious microbial disease affecting the teeth remains
to be a prime concern affecting oral health and not limited
to developed countries but also becoming prevalent in poor
countries in world. Its prevalence was in turn confirmed by
the World Health Organization and affirms dental caries as
a major health problem in all over the world.[1] According
to Oral Health Atlas by the FDI World Dental Federation,
untreated decay of permanent teeth has a prevalence of
Address for correspondence:
Dr. Chandrasekhar Veeramachaneni,
Department of Conservative and Endodontics, Malla Reddy
Dental College for Women, Hyderabad, Telangana, India.
E‑mail: vcs_1818@yahoo.co.in
Date of submission : 13.08.2020
Review completed : 21.09.2020
Date of acceptance : 18.12.2020
Published : 11.02.2021
Access this article online
Quick Response Code:
Website:
www.jcd.org.in
40% for all ages combined, which is the most prevalent
condition among 291 diseases as per the Global Burden of
Disease Study with approximate 3.9 billion people affecting
worldwide.[2] On global scale, 60%–90% of schoolchildren and
nearly all the adults have tooth decay, which often leads to
pain and discomfort.[3] Therefore, clinicians must identify
patients who are at higher risk for caries or who have active
caries and must apply appropriate treatment or preventive
measures such as immunization, fluoride treatment, salivary
functioning, and antimicrobial agents.[4]
Global epidemiology of dental caries
As per the review of literature and the epidemiological
data of many countries, there is a marked decreased in the
prevalence of dental caries.[5] However, the situation was
reversed during the past decade indicating alarmed increase
in global prevalence of dental caries in both children and
adults, primary and permanent teeth, as well as coronal
and root surfaces. To obtain epidemiological data on the
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How to cite this article: Cherukuri G, Veeramachaneni C,

DOI: Rao GV, Pacha VB, Balla SB. Insight into status of dental caries
10.4103/JCD.JCD_402_20
vaccination: A review. J Conserv Dent 2020;23:544-9.

544 © 2021 Journal of Conservative Dentistry | Published by Wolters Kluwer - Medknow


prevalence and incidence of dental caries, a systematic
literature review was performed by Frencken et al.[6] In this
review, the authors divided the prevalence and severity of
cavitated dental carious lesions as per broader age groups,
based on mean decayed, missing, and filled teeth (dmft)
scores in five countries. Among 4–5 and 5–6‑year‑old age
groups, reduction in the rate of prevalence was observed in
the United Kingdom (UK) countries (46%) and Sweden (45%).
For 12‑year‑olds, median prevalence of lesions was 69.4%
in upper‑middle‑income groups compared to others, with
higher mean dmft score. In adolescents and adults, there
is big reduction in the prevalence as well as mean dmft
scores. In adults, the median mean dmft score among
35–44‑year‑olds was high in high‑income group and vice
versa in low‑income groups.
The prevalence of early childhood caries among
children aged 3–5 years varied on global scale. Mainly,
it is higher in most of the low‑income countries such
as Southeast Asia and Africa, suggesting more among
socioeconomically disadvantaged groups. The USA has
showed higher prevalence than European countries with
40% of children effecting around kindergarten age, while
12% of children had visible caries around 3 years of age in
the UK.[4] Accumulating evidence showed high prevalence
of 36%–85% in Asian countries, 38%–45% in Africa, and
22%–61% in the Middle East.[7] Studies also revealed that
preschool children with oral disease and decay have shown
poorer quality of life.[8]
Microbiota and dental caries
The process of tooth decay (dental caries) is multifactorial,
which is caused due to interaction between the surface
of the tooth, dental plaque, and the presence of sugars
obtained from food. An approximate of 700 different
species of bacteria has been found from human oral
microbiome. Among all, bacteria that plays vital role in
process of cariogenesis are oral streptococci, especially
the mutans group and lactic acid bacteria, i.e., Lactobacillus
species. In 1924, Clark found that Streptococcus mutans
grows best in a medium simulating saliva and is found in
the earliest stages of decay process.[9] In a study by Meiers
et al., the authors collected water spray during restorative
process of carious and noncarious lesions of naval recruits
and found multiple organisms among which S. mutans was
only bacterium found in significantly larger numbers in
carious lesions than in noncarious lesions.[10]
Microbial community is quite diverse, and often, the
dentinal lesions contain many facultatively and obligately
anaerobic microorganisms that belong to genera such as
Actinomyces, Eubacterium, Parvimonas, Bifidobacterium, and
Rothia. Dental decay can also be caused by other bacteria
which were mitis, anginosus, and salivarius groups of
Streptococcus, Propionibacterium, Enterococcus faecalis, and
Scardovia.[11‑13]
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Cherukuri, et al.: An insight into dental caries vaccination
Streptococcus mutans and dental caries
S. mutans is the leading causative microorganism of dental
caries worldwide and also considered as most cariogenic
among all oral streptococci.[14] S. mutans refers to a group
of seven closely related species which were collectively
referred to as mutans streptococci.[15] Multiple factors
such as adherence to tooth surfaces, acid production,
building glycogen reserves, and synthesis of extracellular
polysaccharides are involved in dental caries formation.
These bacteria change the environmental conditions of
the oral flora, which allows other fastidious organisms to
colonize and further enhances dental plaque formation.
Specially equipped receptors with S. mutans allow them
to attach to tooth surface, thereby creating a slimy
environment. Once they adhered to enamel salivary
pellicle, strong acid producers such as mutans streptococci
and Lactobacillus create acidic environment to promote the
process of cavity formation.[11]
The ability of S. mutans as potent initiator of caries is mainly
due to virulence factors that are mainly unique to itself,
thereby playing an important role in caries formation.
Further, it produces lactic acid as part of metabolism and
also its ability to adhere to tooth surfaces in the presence
of sucrose by formation of water‑insoluble glucans,
which are polysaccharides that help in binding bacteria
to tooth surface. These characteristics of production of
large amounts of lactic acid at rapid rate and tolerance
to extremes of sugar concentration, ionic strength, and
pH make mutans streptococci efficient at causing dental
caries.[16]
Molecular pathogenesis of dental caries
Initiation of dental decay mainly occurs due to the
dissolution of minerals of enamel and dentine of
teeth in the organic acids, such as lactic acid which
is produced by the microorganisms that were present
in the plaque. The molecular pathogenesis of mutans
streptococci‑associated dental caries was divided into
three possible phases by Taubman and Nash.[17] In the
initial phase, attachment of bacterium to the dental
pellicle takes place[18] which is mediated by adhesin
from mutans streptococci, known as antigen I/II.[19,20]
The second phase involves accumulation depending on
the presence of sucrose, glucosyl transferases (GTFs),
and glucan‑binding proteins (GBPs) from mutans
streptococci. After the breakdown of sucrose into
glucose and fructose, the GTFs of mutans streptococci
synthesize glucans which have various α‑1,3‑linkages
and α‑1,6‑linkages and different solubilities in water. In
the third and final phase, glucans that were produced
interact with GBPs and with glucan‑binding domain of
GTFs, on the surface of mutans streptococci.
Further, colonization and multiplication of these bacteria
result in the accumulation of biofilms, leading to formation
545
Cherukuri, et al.: An insight into dental caries vaccination
of dental plaques, with large masses of mutans streptococci.
When these accumulations of bacteria are of sufficient in
magnitude with adequate available sugars, it results in
production of large amounts of lactic acid, which further
leads to dissolution of enamel structure and leading to
dental decay.[14]
Historical background on caries vaccination
Clarke was the first to isolate streptococcus from carious
lesions and identified its association with disease and
further named his new species as S. mutans.[9] Later,
its role in caries etiology was further questioned and
led to disappearance of S. mutans from the literature.
Approximately 40 years later, again, the role of mutans
streptococci in caries pathogenesis was resurfaced,
establishing its infectious and transmissible nature.[21‑23]
Further, insight into the details of specific immune factors
was provided following the isolation of immunoglobulin
A (IgA) by Heremans et al.[24] and Tomasi et al.,[25] who
identified the secretory form of IgA (S IgA) in the saliva.
The principle of immunization against dental decay was
introduced by Bowen,[26] where the author showed that
monkeys that were immunized with S. mutans developed
less caries than those that were not immunized. Later,
many authors in the early 1970s conducted animal
studies, regarding immunization against dental decay
and demonstrated that caries is preventable by induction
of specific salivary IgA response to the salivary gland
region.[27,28] As tooth surfaces are continually flushed
by saliva and S IgA being its principle immunoglobulin,
induction of a salivary S IgA response against mutans
streptococci would provide first line of defense against
formation of bacterial colonies on tooth surfaces.[29]
Later, other studies used local immunization in rats to
induce salivary S IgA that further exhibited reduction
in mutans streptococci as well as the extent of dental
caries.[28] Russell et al. have explained the possible
mechanisms of action of salivary IgA antibodies through
interference of sucrose‑dependent and ‑independent
attachment of mutans streptococci to the surfaces of
the tooth.[30]
Many efforts have been made continuously so far for its
prevention and cure, both in developing and in developed
countries. Currently, many caries prevention strategies were
in practice such as topical fluoride applications, chemical
and mechanical control of plaque, and application of pit and
fissure sealants and through oral health education. Despite
all these strategies, this dental disease is still remained
to be an epidemic owing to economic, behavioral, and
cultural barriers on a global level.[31] Keeping in mind about
such barriers, it is vital for dental public health to develop
an effective caries vaccination, particularly for those who
fails to receive regular healthcare.
546 Journal of Conservative Dentistry | Volume 23 | Issue 6 | November-December 2020
ANTICARIES VACCINATION
Vaccines are immunobiological substances designed to
produce specific protection against any given disease.
They mainly act through stimulation for the production
of a protective antibody and other immune mechanisms.
They are mainly prepared from live‑modified organisms,
nonvital organisms, extracted cellular fractions, toxoids, or
a combination of these substances.[31,32] A caries vaccine is
mainly designed to play protective role against the process
of tooth decay. It is of a known fact that S. mutans plays a
major etiological role in the pathogenesis of tooth decay
as its cell mainly contains substances such as adhesins,
GTFs, GBPs, a 13 kDa protein antigen (antigen D), a 39 kDa
protein (AgIII), a 29 kDa protein antigen (antigen A), a 70 kDa
protein antigen (antigen C), and a 190 kDa protein (AgI/II).
As these substances were thought to play a vital role in
interactions between the organism and host, most of the
caries vaccine experimental designs were mainly directed
toward these compounds.
Similar to any other vaccine, caries vaccine should also
be administered before the introduction of the infectious
agent into the system.[33] When hosts were immunized
with antigens from mutans streptococci, antibodies then
formed within saliva will induce a process called cellular
aggregation. These large number of aggregates in turn
reduce the number of organisms adhering to the tooth
surfaces.[34] These antibodies also act by interfering the
epitopes of adhesins, the AgI/II (PAc), and the saliva‑binding
region of the antigen strongly inhibits sucrose‑independent
adherence of S. mutans cells to tooth surfaces.[35] It was
also found that the formation of aggregates, fine‑meshed
colonies, and long chains of bacteria promotes easy removal
of these bacteria and further reduces their pathogenic
potential. Antibodies to GTFs further inhibit the synthesis
of glucans by these enzymes, thereby the accumulation of
mutans streptococci on tooth surfaces.
Active immunization against dental caries
Animals
Many studies in the past have addressed active immunity
for dental caries in experimental animals such as rats and
monkeys. It was found to be that in human unstimulated
saliva, sIgA is in higher concentrations, with IgG the
most abundant immunoglobulin in the human serum and
gingival crevicular fluid. In animal models, the induction of
salivary IgA and serum IgG has been studied using various
immunization routes, such as subcutaneous, oral, intranasal,
and topical routes.[36] Lehner et al. in their study has reported
a 70% reduction in dental caries following the subcutaneous
immunization of Rhesus monkeys with AgI/II in Freund’s
incomplete adjuvant or “Alhydrogel”.[37] Subcutaneous
immunization of rats with peptide constructs and GTFs
near salivary glands induced high serum IgG and salivary

IgA responses.[38] Gut‑associated lymphoid tissue (GALT)
is considered to be one of the principal inductive sites
of mucosal immune responses, especially sIgA responses.
Stimulation of IgA precursor B‑cells in GALT induces sIgA
responses in remote secretions, including saliva, and to
enhance its response in saliva, various mucosal adjuvants
and delivery vehicles such as liposomes have been used.
When orally administered, these liposomes will be ingested
into GALT through M‑cells of Peyer’s patches which further
enhance the mucosal responses. The anti‑idiotype vaccine,
which is specific for antibodies against S. mutans when
incorporated into liposomes and administered orally in
rats, has significantly reduced caries and its colonization
in the oral cavity.[39]
In addition to GALT, nasal‑associated lymphoid tissue is
a major inductive site for mucosal immune responses.
Advantages of nasal delivery for vaccine include lower
doses of vaccine doses and relatively easier administration,
and it induces both systemic and mucosal immunities.
Further, few authors attempted topical immunization
routes using 3.8 kDa antigen applying on gingiva resulted
in significantly lower incidence of dental caries and
colonization of S. mutans.[40] Despite availability of different
routes and significant lowered incidence of dental caries in
animals, main drawback of streptococcal vaccine regarding
its applicability in humans is its cross‑reactivity with heart
tissue antigens, which might due to whole cell vaccines.
This further pointed out for the need of identification
and isolation of fractionated “protective antigens” for the
development of a safer vaccine for use in humans.[31]
Humans
Very few studies have analyzed the efficacy of active
immunity against mutans streptococci in humans. Most
of the authors verified the efficacy of oral administration.
Mestecky et al. demonstrated that ingestion of capsules
that contained Streptococcus sobrinus and this effectively
induced sIgA in the saliva.[41] Contradicting to these
findings, Gahnberg and Krasse when orally administered
heat‑killed S. sobrinus cells given to six subjects, resulting
in no salivary IgA response.[42] Oral immunization in seven
subjects with an enteric coated capsule containing 500
µg of GTF from S. mutans resulted in elevated salivary IgA
antibodies to the antigen preparation. When similar antigen
was administered intranasally or by topical application to
tonsils, it resulted in increase of salivary IgA antibodies.[43,44]
Passive immunity against dental caries
Recently, local passive immunization has received much
attention and is considered as a safe procedure for
controlling S. mutans and preventing dental caries. Evidence
has shown that repeated application of local passive
immunization using anti‑AgI/II monoclonal antibodies
to the deciduous teeth of Rhesus monkeys prevented
Journal of Conservative Dentistry | Volume 23 | Issue 6 | November-December 2020
Cherukuri, et al.: An insight into dental caries vaccination
significant colonization and subsequent development of
caries.[45] Ma et al. succeeded in cloning and expressing a
plant secretory antibody. Later, sexual crosses between
the transgenic plants and filial recombinants resulted
in the formation of high‑molecular weight secretory
immunoglobulin that retained for up to longer durations
in oral cavity and afforded specific protection in humans
against oral colonization by S. mutans for at least 4
months.[46,47] Monoclonal antibodies, in the secretory form,
are more effective as they have increased survival time in
oral cavity when compared to IgA.[43] Recently, local passive
immunization using murine monoclonal antibodies,
transgenic plant antibodies, egg‑yolk antibodies, and
bovine milk antibodies to antigens of mutans streptococci
has been used to control the colonization of the organisms
and the induction of dental caries in human.[36]
Human heart cross‑reactivity and caries
vaccination
Even though various types of vaccines have been developed,
tried, and proved to be successful in providing protection
against dental caries, literature evidence has reported for
the evidence of cross‑reactivity with human heart tissues
and skeletal muscle tissues by the antibodies generated.[31,48]
In 2013, Zhang tried to overcome the cross‑reactivity of
heart tissue using subunit vaccines; however, he reported
less immunogenicity.[49] Alam et al. believed that the
dextransucrase antibodies might have inhibitory effect
on the cariogenic potential of S. mutans, and they may
be helpful in combating the dental caries.[50] Recently, in
2020, Rather et al. indicated that dextransucrase antibodies
inhibited acid production and reduced hydrophobicity
of S. mutans, indicating the further enhancement of
anticariogenic potential of dextransucrase antibodies.[51]
Moreover, no cross‑reactivity with dextransucrase antibody
was seen indicating no harmful physiological effects in the
humans. This has given the hope that effective, safer, and
acceptable vaccines against human dental caries can be
achieved in the near future.
PROSPECTS OF CARIES VACCINATION
Conventionally available vaccines provide immunization to
the before to the development of disease. It is important
to make a note that the immunization following the
eruption of the primary teeth can prevent the colonization
of S. mutans, which may also provide extra benefit to the
permanent teeth through early immunization until their
eruption.. And also, as the dental caries is a slow undergoing
process throughout life, it would be considerably equal to
have an effective immunization mechanism that can exhibit
similarly long‑lasting immunity against caries. It is also of
equal importance that developed caries vaccination must
not cause phenomenon of any human heart cross‑reactivity
following its consumption. The National Institute of Dental
547
Cherukuri, et al.: An insight into dental caries vaccination
and Craniofacial Research in 2010 has continued their
support for basic research in mucosal immunology and also
made passive immunization approach as priority. It is often
a dilemma that whether if caries vaccine is a viable option
in dental caries and decay prevention? To answer this, the
caries vaccination trials must be conducted in stages such as
in infants (Phase 1, 2, 3 studies), preschool children (Phase
1, 2 studies), and preadolescent children (Phase 1, 2
studies), and these stages have to be strictly considered.
To make these immunization techniques more practical,
one has to make sure that these human experiments must
be transferred successfully humans as well. Despite any
number of advances regard caries immunization, it finally
comes to adequate oral health behaviors that continue to
be the key for good oral health and for decrease in caries
occurrence.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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