Panel on Caries Vaccine
Final Report
January 28, 2003
Sponsored by: The National Institute of Dental and Craniofacial
Research
National Institutes of Health
I. Background:
The National Institute of Dental and Craniofacial Research (NIDCR) is the
primary sponsor of research and research training in oral, dental and craniofacial
diseases. It fulfills its mission through both intramural research programs
and the support of extramural investigators and mentors in academic institutions
and other research organizations. Its research support portfolio includes a
strong component in dental caries and oral infectious conditions. Part of this
program involves support of research on the development of a caries vaccine.
As there are a number of scientific, economic and ethical issues in this activity,
the Institute Director asked that an Expert Panel be convened to help the Institute
explore these issues and make recommendations on how to address them and delineate
the manner in which NIDCR can move research in this area forward.
The Panel was convened on January 28, 2003 and this represents a summary report
of its deliberations. The agenda included presentations by groups currently
doing research in caries vaccine development and an extended discussion by
the Panel of the various issues outlined above.
The Institute Director opened the meeting by thanking the participants for
their contributions to the Panel. He indicated that NIDCR has supported research
related to the development of a caries vaccine for several years and that it
is at a point where decisions have to be made about the support of clinical
trials in this area. The Institute will continue to support fundamental research
in immunobiology but has also reinvigorated its efforts in the support of clinical
research, particularly clinical trials. Caries vaccine trials would be an obvious
candidate within this effort but this comes with a series of questions from
the scientific, ethical and economic angles. That is why the Panel includes
a number of content experts with experience in vaccines from all those different
angles. The recommendations from the Panel will be presented to the Institute’s
National Advisory Council in June.
SCIENTIFIC PRESENTATIONS
There were five presentations from various research groups throughout the
country. Dr. Martin Taubman from the Forsyth Institute indicated that dental
caries is a major health problem in the U.S. Eighty percent of Americans have
dental disease by 18 years or age and two-thirds of disadvantaged children
have untreated decay, so there is a lot of unmet needs. The problem is worldwide
and numbers on prevalence are high in countries like China, Japan and Brazil.
The disease is caused by a group of organisms called Streptococcus mutans
(S. mutans) and occurs in 3 phases: an initial interaction with the tooth
surface mediated by adhesins; the accumulation of the bacteria in a biofilm
and the production of glucose and glucans by the bacterial enzyme glucosyl
transferase; and the formation of lactic acid.
The target for vaccine development in his research group has been the glucosyl
transferases (GTF) and the glucan binding proteins (GbP). The basic hypothesis
is that mucosal induction of salivary IG antibody to GTF interferes with the
accumulation of S. mutans in hard surfaces like glass and teeth. The
enzyme is inhibited by this antibody both in vitro and in vivo. Their research
has extended to sub unit vaccines, delivery systems, mucosal adjuvants and
various routes of application. They have synthesized a variety of peptides
from the catalytic domain and from the glucan-binding domain and prepared mono
and diepitopic constructs. A peptide from GbpB has been shown to protect against
caries.
The group has utilized several delivery methods, including subcutaneous injection,
intra gastric intubation, oral capsules and topical application. More recently.
they have used intranasal administration in aluminum phosphate or PLGA micro
particles. They have also utilized attenuated salmonella typhus expressing
the glucapeptide.
The primary vaccine is the GTF from Streptococcus sobrinus, but
other materials have also been tested. Two clinical trials were conducted in
adolescents 10 years ago, and they now propose a pediatric vaccine in a target
population of children approximately one year of age. In the phase I trial
they measured safety, antibody activity and the reaccummulation of indigenous mutans species.
The data indicated significant reductions in S. mutans and antibody
increases after 42 days in individuals in the GTF group.
At birth, there are no bacteria in the oral cavity, but there is subsequent
colonization with certain “pioneer” oral bacteria that come essentially
from the mother, including S. midus and S. salivarius. Teeth
emerge at about 6 months and certain teeth-associated flora begins to be found,
such as S. sanguis. S. mutans is not present (in a certain
portion of individuals) until between 18 and 36 months of age. IG levels also
rise and by 12 months children have adult levels of IG and of antibody to certain
antigens. At 5 weeks of age one can find antibody salivary IgA to S. midus antigen
in saliva. When infected, children can respond to a variety of antigens associated
with microorganisms.
The group is convinced of the safety of the GTF, as exposure to multiple
doses of orally and topically applied GTF did not cause any health problems.
GTF is the only streptococcal component in vaccine materials. The plan is to
use GTF as the antigen, administered with PLGA micro particles by the intranasal
route, 2-3 doses between 12 and 24 months of age. This would be a phase I trial.
The cost of the trial would be between 2 and 3 million dollars.
In response to questions, Dr. Taubman indicated that there is no precise correlation
data, but that a general correlation exists between IgA levels and the reduction
in bacterial titers. The dose of GTF used in the previous trials was approximately
10 times the amount being normally swallowed and there were no theoretical
basis to anticipate untoward effects. There is no accurate data on the proportion
of children under the poverty level who become colonized with S. mutans but
in studies done in Alabama and Brazil, the evidence suggests that the dose
increases the risk of colonization and that there is a direct correspondence
between the level of infection and the caries. There are other acidogenic bacteria
that can cause caries, but S. mutans is the most heavily implicated
and solving the mutans problem would solve 90 percent of the caries
problem. The end point would be safety, plus some type of surrogate outcome,
such as colonization and antibody efficacy.
Dr. Noel Childers from the University of Alabama indicated that the pathogenesis
of dental caries is complex, but that the idea is that, if you can prevent
the initial colonization, this will have an effect on the disease process.
Their studies have focused on the two antigens already mentioned. The first
is that involved in the initial attachment (antigen I-II) and the second, the
one associated with the more tenacious attachment mediated by GTF. Preclinical
studies in rodents have shown that oral or nasal immunization with bacterial
lysates, purified antigen I-II, GTF, combinations of antigen and GTF, and recombinant
GLU can confer protection. Antigen alone was poorly immunogenic and modifications
of antigen preparations with adjuvant or using other delivery systems have
been necessary to improve immunogenicity. One such system involves the use
of biologically safe liposomes of 100 nm diameter. This preparation has been
used in phase I trials with small numbers of subjects to determine safety and
immunogenicity. Seven studies have been conducted, three involving oral immunization
and four intranasal applications. Volunteers ingested enteric-coated capsules
containing 500 µg of antigen or placebo and the same protocol was repeated
after 28 days. Follow up was for 8 weeks to monitor changes in antibody activity.
There was a 50 percent increase in IgA response in the experimental group,
occurring between day 28 and day 35. In the intranasal immunization, individuals
received 250 µg of the same antigen either as free antigen or in liposomes;
twice, seven days apart. The response in the nasal wash secretions occurred
in both groups and began about day 14 and peaked around day 21-28. It also
appeared to persist longer. The salivary IgA response was no different in the
2 groups, where a 75 percent increase occurred on day 21.
Oral, nasal and tonsilar administration of the liposomal antigen was found
to be safe. The nasal spray vaccine induced the best specific mucosal IgA responses
and these appeared to be dose-specific. The IgA response may be associated
with a delay in recolonization. Their next step is to carry out a phase I trial
in pre-adolescents and the ultimate goal is to conduct phase I, II and III
studies in an infant population. The idea is to immunize them prior to the
eruption of the teeth, as there may be multiple windows of infectivity as specific
teeth erupt.
The prospect of industrial support is unclear because of patentability issues
and because these would be long-term studies that extend past a patent time
frame.
In response to questions from the Panel, Dr. Childers indicated that different
immunization protocols may be used in the phase II trial in infants. Issues
of the safety and efficacy of the nasal spray system were discussed and a study
will be performed in mice to clarify these issues. The vaccine would be administered
between 12 and 16 months of age in the infant trial being planned. There is
conflicting information on the benefits of breast-feeding in preventing dental
caries.
Dr. Michael Russell, SUNY at Buffalo, indicated his work has focused on the
antigen I-II. The antigen has been cloned and sequenced and occurs only in S.
mutans and not in other cariogenic bacteria, except S. sobrinus.
It is a large protein on the surface of the mutans and has a characteristic
gram-positive wall anchor and involves the cleavage and insertion of the c-terminal
tail into the cell wall. His research has focused on the saliva-binding region
where certain residues appear to be important in attachment to the salivary
pellicle tooth surface. Antibodies against this part of the molecule can exert
an anti adherence function. Antibodies against antigen I-II, are effective
anti adherence antibodies. There is no evidence that antigen I-II has heart
cross reactivity.
Interest is now focused on developing mucosal vaccines exploiting the immunogenicity
of cholera toxin and its B subunit. Potent immune responses have been found
in monkeys and rats by coupling the antigen to cholera toxin. The same is true
in the rat model when the saliva-binding region is genetically coupled to the
non-toxic components of antigen I-II. Mice immunized intragastrically with
antigen coupled to the B subunit of cholera toxin maintain memory of the event.
Antigen has been chemically conjugated to cholera toxin B and so-called chimeric
antigen A1-B5 immunogens have been subsequently developed. A similar approach
using segments of GTF has proven more difficult because of the way that E.
coli processes these segments. Trials need to be performed to demonstrate
that chimeric immunogens are effective in humans. They can be incorporated
into liposomes or other micro particles. These chimeric antigens skirt the
toxicity issue associated with enterotoxins as adjunvants or delivery vehicles.
The issue of a correlation between antibodies to antigen I-II and a decrease
in S. mutans colonization was again brought up. No longitudinal study
from infancy onward has been done that would clearly answer this question.
Saliva is contaminated with other bacteria that have cross-reactive antigens
and it is very difficult to show that kind of correlation. A small-scale human
trial to demonstrate that immunogens coupled to CTB induce a potent response
needs to be done as a prelude to more extensive trials.
Dr. Debra Trantolo from Cambridge Scientific, Boston, spoke about her work
in developing a delivery system for GTF through a phase I-phase II SBIR grant.
The issues being faced are similar to those in the development of any vaccine.
The delivery system uses the biopolymer polyactide (PLGA), which is a bioabsorable
substance used in sutures and in drug delivery. It is used as an adjuvant and
as something that provides some release characteristics. A lot of preclinical
work has been done with this delivery system. Because they are looking at mucosal
delivery, the other piece of the system is the incorporation of a bioadhesive.
The three components of the delivery system are compatible for the FDA clearance
process and the Company has a patent on the system.
The system is called a matrix system and is a non-encapsulation system where
the biological or drug is dispersed throughout the polymer. There are no organic
solvents used in the manufacturing process. An aqueous solution of the biological
is sucked under vacuum into the polymer foam, which is then lyophilized and
compressed to yield a spaghetti-like rod that can be ground into a particulate
for suspension. There are several issues in terms of how much of biological
and of the bioadhesive to use and also manufacturing considerations like pressure,
temperature, etc. SOPs have to be prepared for the combination of the polymer
with GTF as part of a technology transfer document for INDs.
In terms of funding, the SOPs and putting the material together would add
another million dollars to the estimate given by Forsyth. Another piece is
corporate partners to help in the manufacturing of the product.
In response to questions, Dr. Trantolo indicated that there is no major additional
cost in scaling the technology up and that there is no definitive information
about the long-term stability of the product. There has been no interaction
with the pharmaceutical industry so far in terms of a large scaling-up of the
process. There have been some clinical trials using polyactide micro particles
in a matrix material with disappointing results. This may be related to adhesive
issues. A better uptake is seen in the oral and nasal applications in the presence
of an adhesive. Another issue may be particle size.
Dr. James Larrick from Planet Biotechnology, California, explained their work
in developing secretory IgA antibodies in a product called Cario Rx. The Company
has focused on manufacturing monoclonals in plants that can make large amounts
of IgA. The antibodies block adherence of microbes and neutralize toxins and
viruses. IgA has more stability on the tooth surface and in the GI tract and
is used to produce large amounts of antibody in tobacco plants. The extraction
process has been worked out and yields products of high purity in a relatively
short period of time.
Cario Rx is a nominal therapy to reduce the adherence of S. mutans to
teeth and it’s devoid of any adverse effect. The hypothesis is that in
an altered biofilm, the antibody blocks the repopulation dynamics of S.
mutans. There were animal studies that supported the clinical development
of these SA I-II antibodies. There was a reduction in the recolonization of Strep
mutans and protection against caries. Elimination of caries will likely
be required as the end point by the FDA in this type of passive immuno-therapy.
There have been about 100 patients in phase 1-phase 2 trials and the data indicate
that passive immunotherapy can eliminate or significantly reduce S. mutans.
The first trial was with antibodies that blocked SA I-II biding. One day after
a regimen of carsodyl or gel and mouthwash, the reagent was applied directly
to the teeth. The antibody prevented recolonization for up to a year. Other
trials have shown that some antibodies are not effective and that multivalency
was required to prevent recolonization. Another study has shown that combinations
of antibodies can be effective against S. mutans but not against actinomyces
(species specificity). A confirmatory trial used a different protocol for the
initial antisepsis and the outcome was not uniform, as 35-40 percent of subjects
did not clear the S. mutans. Still, there was a large portion of subjects
that did not recolonize. The antisepsis will be standardized and optimized
in the future to completely eliminate the biofilm.
In response to questions, Dr. Larrick indicated that the purity of the final
antibody is 98-99 percent and that the antibody cannot be detected after 2
months. The approach does not work if the strep already there is not
eliminated. Theoretically, the antibody can be put into something like a formula.
The plan is to start with adolescents and then move down to infants.
GENERAL DISCUSSION
The general discussion following these presentations focused on the following
topics:
- The issue of safety and how to evaluate it. Do small children have different
safety issues or different side effects than older children and adults because
of the extent of the development of their immune system? There is not a lot
of data, but it is known that a detectable mucosal immune response can be
seen within 2 weeks of oral colonization. Mucosal antibody to S. mutans develops
within 2 months. Immune response in children is less active than in adults
and intense untoward reactions would be less likely.
There is public concern about the number of vaccines that infants/children
currently receive. The assurance of safety is paramount. Any vaccine that
is targeted for use in children will need to take into account this factor,
as well as the impact that such a vaccine will have on other routinely administered
vaccines.
- The lack of colonization in a subset of the infant population. Is the observation
that children who do not become colonized with S. mutans the result
of the biofilm they develop preventing the colonization or are there other
factors (i.e., genetic factors)?
There is no answer to this question. Children, who are heavily colonized,
have more than one genotype, so the lack of colonization could be related
to many factors. There are clearly different immune responses among siblings
and some respond more favorably to GTF. Adopted children do not get the adoptive
parents’ S. mutans. Then there is a second window of infectivity
when the permanent teeth erupt and everybody is colonized.
- The burden of tooth decay and its effect on the quality of life.
There is some idea on the cost of treatment, but there is really no accurate
information on the real burden (i.e., lost school or work days) or the cost
in terms of pain and suffering. A large portion of the economic burden comes
from the latter. Only 25 percent of children eligible for Medicaid are able
to get care in any given year and probably even less in the pre-school population.
The burden will not be fixed by the care delivery system. Medicaid mandates
that all children have preventive and corrective dental services, but the
reality is that they do not get the necessary care.
- The lack of longitudinal studies that identify risk factors for colonization
and outcomes.
One risk factor (sucrose in the diet) is well known and it is also true there
is probably no correlation between antibody levels and infectivity.
- The issue of economic costs.
The last IOM report on prioritizing vaccine development on the basis of economics
does not highlight caries. It will require lots of money to reach licensed
products. Children below the poverty line are the big problem and they also
have lower access to vaccines. A vaccine or vaccines would need to be compared
in economic terms to other approaches, such as giving vouchers to the children
to visit dentists. One of the barriers is that reimbursement is not sufficient.
The other issue is the parental sense of the importance of visiting the dentist.
There is no evidence that a system of annual visits will be very helpful
in this regard.
- The question of the role of fluoride. Is fluoride a solution or just an
ancillary approach?
The issue is actually access to fluoride. We don’t know what the true
behavior is (as opposed to that described in answers to surveys and questionnaires)
in terms of use of fluoride. There is a subset of children who experience
high rates of tooth decay even though they live in fluoridated communities.
Fluoride cannot be, therefore, the sole solution.
RECOMMENDATIONS
The Director of NIDCR reviewed briefly the major characteristics of dental
caries and its links to behavior and to access issues. The clinical research
portfolio of NIDCR is mainly in caries and periodontal diseases, but phase
III trials have never been done in caries. The treatment of caries has not
changed significantly over the years, although new chemotherapeutic agents
and efforts to disturb signaling in the plaque are now of mounting interest.
There is a lack of longitudinal studies and the need to clearly identify those
who are most at risk.
Panel members then brought up several general issues in vaccine development:
- Elements in successful vaccine development. A good reference is the CDC’s
retrospective study on what was involved in creating a successful vaccine.
- The economic/risk benefit issue. Where is the product going to be utilized?
The rationale is that introduction of a vaccine in a community will be cost-saving.
If the regimen requires too many contacts with the health care provider,
this may make the vaccine unfeasible.
- Industry partnerships. From the point of view of industry, the market will
drive development and ACIP recommendation for routine use in everybody is
a plus. An industrial partner is needed beyond phase II, but here may be
limited partner potential in terms of pilot lots, clinical trial development
and manufacturing. An approach is to develop a solid science foundation,
a system for the economic surveillance of the epidemiological data and a
complete infrastructure (including animals models and assay development and
standardization) and then bring in the industrial partner. Another approach
is to target small industry, particularly small biotech companies and to
provide support through an SBIR award to do some initial production and carry
the research through phase I and II trials.
- The way a caries vaccine may fit into the existing model of dental care
(self pay mode) and the need to come up with a relatively inexpensive, but
efficient delivery model for a vaccine.
After extensive additional discussion, the Panel made the following broad
recommendations:
- There is intrinsic value in learning more about the science in terms of
the mucosal immune system and NIDCR should continue to support basic research
in immunobiology.
- Real world barriers have to be considered and overcome if starting from
the premise that a product will be delivered. Perhaps, NIDCR should frame
the goal differently and provide guidance to the community. The approach
can be to only reach to proof of principle in phase III trials.
- There might be some intrinsic advantage to a passive immunity approach,
both in terms of cost and of acceptance.
- There is definitely a need for more longitudinal epidemiology correlates.
This can be achieved through a “center’ where expert consultants
can work with the core staff in addressing the various problems.
- Advantage should be taken of natural experiments, especially children who
are not colonized despite significant exposure. More research is needed on
possible differences in innate (i.e., saliva) factors and on longitudinal
follow-ups of how the oral environment changes.
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