DURAMUNE Puppy DP + C
I.
SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
INTRODUCTION
Duramune Puppy DP + C is a vaccine containing live and inactivated components for the
protection of dogs from diseases caused by:

canine distemper virus (CDV) – which causes canine distemper, a serious, sometimes
fatal disease that mostly affects young dogs; it causes a wide range of clinical signs
including fever, diarrhoea, dullness, loss of appetite, discharge from the eyes and nose,
hardening of the paw pads and neurological signs such as twitching, unco-ordination
and fits;

canine parvovirus (CPV) - which can cause a serious and possibly fatal gastro-enteritis
in dogs, with vomiting, diarrhoea, a marked reduction in numbers of white blood cells
and sometimes fever;

canine coronavirus (CCV) - which may cause gastro-enteritis and predispose to other
infections, such as CPV.
There is no cure for any of these diseases and vaccination is therefore necessary. A vaccine
that is effective against several diseases is clearly advantageous as it reduces the number of
injections needed to provide adequate protection.
Duramune Puppy DP + C contains antigens from attenuated* forms of two viruses: CDV
(strain Onderstepoort), and CPV (strain SAH) and from inactivated* CCV (strain TN449).
It is supplied in single dose vials of freeze dried viral fraction, and single dose vials of diluent.
The vaccine is intended for subcutaneous injection in dogs from 6 weeks old onwards. It is
designed to produce active immunisation to prevent mortality and disease caused by CDV
and CPV, and to reduce infection at the intestinal level caused by CCV.
The initial vaccination programme consists of 2 doses of vaccine with an interval of 2 - 4
weeks. In puppies first vaccinated between 6 and 8 weeks, the second vaccination should
be given after the puppy has reached 10 weeks old. Booster vaccination is recommended at
annual intervals.
II.
QUALITY ASPECTS
Product Development and Composition
Duramune Puppy DP + C has been developed as one of a “family” of vaccines which contain
different numbers of antigens to protect dogs from a range of common diseases. Duramune
Puppy DP + C contains antigens from three different viruses, as indicated below. Other
members of the family may contain more or fewer antigens and this ensures that animals can
be given the most appropriate vaccine for the diseases they are likely to be exposed to.
*
An attenuated virus is one that has been treated so that it no longer causes disease (i.e. it is not
virulent), but it can still stimulate immunity and it can still replicate itself. An inactivated virus is one
that has been treated so that it can no longer replicate itself and cannot cause disease because of
this.
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DURAMUNE Puppy DP + C
SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
Duramune Puppy DP + C has two components:
1.
Freeze dried component:
Active ingredients:
 Canine Distemper virus, strain Onderstepoort
 Canine Parvovirus, strain SAH
Other ingredients:
 Phosphate buffer
 Bactopeptone
 Sucrose
 Gelatin
 Nutrient medium
2.
Liquid Diluent:
Active ingredients:
 Canine coronavirus, strain TN449
Other ingredients:
 Adjuvant (ethylene/maleic anhydride and neocryl XK-62)
 Medium
Active Ingredients
The production and, where appropriate, purification of the antigens has been described by
the applicant. The information provided included a detailed description of the manufacturing
process. Each of the three viruses is grown in separate cell monolayers using standard
techniques for the preparation of the cells and the production of the viruses. When the
viruses have grown to the required extent, as evidenced by changes in the cells, they are
collected and stored frozen ready for later use.
Quality control of these antigens has been described, with testing in accordance with the
relevant guidelines. Data provided show freedom from relevant extraneous agents (i.e.
unwanted viruses, bacteria, etc).
Other Ingredients
Certificates of Analysis were provided where appropriate, and reference made to the
appropriate pharmacopoeia.
Packaging Materials
The freeze-dried component is presented in 3 ml glass vials. The diluent is presented in 3 ml
high-density polypropylene vials. The containers and stoppers are sterile, made of standard
materials and comply with the European Pharmacopoeia where necessary.
Manufacture of the Product
All production steps are performed according to GMP*.
equipment and materials are sterile.
*
Where applicable, conditions,
GMP = Good Manufacturing Practice
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
The required amounts of the antigens are prepared for production, appropriate quantities
determined, and the blending diluent quantity calculated. The final product is then prepared
under sterile conditions. The product may be produced in different batch sizes depending on
the amount needed at the time.
Final production steps are the filling of 3 ml vials with a target volume of 1.2 ml, freezedrying, and capping, followed by quality control.
Validation data were provided for multiple batches of viruses, as was information to show
that production variables did not adversely affect these viruses. Data were also provided on
the stability of the viral antigen stock. The live virus assay was validated, and showed that a
satisfactory batch could be distinguished from a minimum or sub-potent batch, as well as a
concentrated vaccine, thus satisfying consistency requirements. The assays were
repeatable, accurate, precise and showed a log-linear relationship between the quantity of
virus present and potency. The assays described were therefore considered satisfactory for
potency determination of batches. Validation data were also provided for sterilisation
processes. The validation data were considered satisfactory, and demonstrated efficiency
and consistency of manufacture.
In-process control tests were described in detail, and included tests for sterility, mycoplasma
and viral content and identity, and absence of contaminating viruses.
The components of the product were demonstrated to comply with relevant guidance on
minimising the risk of transmitting animal spongiform encephalopathy agents via veterinary
medicines.
Finished Product Control
Standard tests (visual tests, pH, sterility, extraneous agents, etc) are applied to the finished
product. Each viral component is identified by fluorescent antibody, and quantified, under
virus-specific conditions, to confirm the amount of virus is within the range required.
Batch safety tests are carried out in the target species. The specifications for all tests are
appropriate to control the quality of the product.
Results of the analysis of consecutive production runs of finished vaccine were presented,
and show consistency of production.
Stability
Stability of bulk antigen
Satisfactory stability data for the bulk antigen storage were provided.
Stability of finished product
Stability data for several batches of the finished product were provided.
information a shelf life of 12 months was accepted.
Based on this
Stability of the reconstituted product
The reconstituted product is intended to be used immediately on reconstitution, so
information on the stability of the reconstituted product is not relevant.
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
CONCLUSIONS ON QUALITY
The analytical part of the dossier included satisfactory descriptions of the production and
quality control procedures, including appropriate diagrams. The method of manufacture was
well described, and the in-process controls detailed in full. Starting materials of animal origin
were shown to be compliant with legislative requirements.
The finished product tests, including the potency test and batch safety test, ensure an
efficacious, safe and consistent product. The stability data provided shows that shelf lives of
24 months for the freeze-dried fraction and 12 months for the diluent are justified when
stored at 2 – 8°C, protected from light.
III.
SAFETY ASPECTS
Introduction
The vaccine is intended for dogs from the age of six weeks, and a primary course consists of
two vaccinations, 2 - 4 weeks apart, the second of which must occur after the pup is 10
weeks old.
An annual booster is recommended. The vaccine is administered
subcutaneously in a volume of 1 ml.
Details of the batches of Duramune Puppy DP + C used in the laboratory safety trials were
provided. The freeze dried antigen component used in the studies contained two additional
viruses. The diluent used in the studies contained two additional inactivated antigens, rather
than just CCV, adjuvant and medium. This is considered acceptable, as any safety issues
would be worse in the presence of additional antigens. Maximum potency batches of
product were used in the studies so that safety of the product could be demonstrated at high
potency.
Details of the batches used in the field safety trials were also provided. Again the more
complex freeze-dried portion and diluent was used. Batches of mid - low potency were used,
as is usual for such trials.
No studies were performed to investigate safety of the product for pregnant or lactating
animals and the product is therefore not recommended for use in such animals.
Laboratory Tests
Laboratory safety studies were carried out in accordance with GLP*, as is required.
The applicant carried out a combined study into the potential side effects of a single dose, a
single overdose (10 times the normal dose) and a repeated dose of the vaccine (3 doses at
two-week intervals). The animals had no antibodies to the antigens of interest at the
beginning of the study.
Safety was assessed clinically, over an appropriate time course, through observation,
physical examination, and body temperature determinations.
*
Good Laboratory Practice
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
The adverse effects seen following administration of an overdose and repeated single doses
in healthy animals of the minimum age for which the vaccine is recommended were minor,
transient and resolved within an acceptable time frame.
Details are given in the SPC:
Following the first vaccination, up to 80% of puppies develop a small visible swelling (<2 cm)
lasting for generally only two days. Following the second vaccination, occasionally a small
visible swelling (up to 5 cm) may be seen at the injection site, which may last for up to five
days. The swelling may be painful for 1 to 2 days. In most cases these small and transient
injection site reactions resolve with no need for treatment.
Overdose: Some puppies may exhibit a transient lethargy by 4 hours post vaccination but
recover by two days post vaccination. Occasionally a small visible swelling (<2 cm) may be
seen at the injection site, which may last for up to 17 days.
Special Requirements for Live Vaccines
Further compulsory tests were carried out on the two live viruses in the vaccine (CDV and
CPV), to determine the potential for spread and dissemination of the vaccine constituents,
and any tendency to revert to virulence*. The studies were designed to demonstrate
compliance with the relevant European Pharmacopoeia monographs.
To investigate the properties of CDV, young dogs which had no antibodies to CDV were
inoculated with a suitable amount of the CDV strain used in Duramune Puppy DP + C. No
CDV could be found in nasal swabs or in samples of various tissues collected from these
dogs although, as expected, the dogs did show an antibody response to the virus.
Untreated dogs that were in contact with the treated ones did not have an antibody response
to CDV and this showed that the virus had not spread to these animals. None of the animals
showed any signs of disease.
In the case of CPV, a similar experiment was done, in that young dogs which had no
antibodies to CPV were given an injection of an appropriate amount of the CPV used in
Duramune Puppy DP + C. In this case, however, CPV was found in samples of faeces
collected from these animals. The virus found in the faeces was extracted and administered
to other young dogs. This process was repeated five times and at each stage, animals were
checked for signs of CPV-related disease, such as a reduction in the number of white blood
cells. No such signs were observed. In the same study, dogs were examined for evidence
of CPV in various organs.
Neither of the viruses showed any reversion to virulence. Specific adverse biological effects
of the viruses present in Duramune Puppy DP + C, for example adverse effects on the
nervous system (CDV) and enteritis or thymic atrophy** (CPV), were not observed in any of
the studies. The studies also demonstrated that dissemination within the vaccinated animal
was negligible and that CDV does not spread to animals which are in contact with the
vaccinated animals. Although CPV did spread to in-contact animals, animals are not at risk
of disease from this spread because the viruses do not revert to virulence. The SPC reflects
this situation:
The live vaccine strains may spread to unvaccinated animals, but do not cause disease.
*
If a virus reverts to virulence, it regains the ability to cause disease.
Thymic atrophy means that the size of thymus gland (which is an important part of the immune
system) is reduced.
**
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
Field studies
Two field studies were conducted using parent vaccine that had been manufactured and
tested in accordance with the dossier. These studies were appropriately controlled and fully
documented. They investigated both the safety and the efficacy of the vaccine.
Dogs of a variety of breeds, aged 6 - 8 weeks old, were examined before entry into the trial.
They were then randomly assigned to one of two groups. One group received the vaccine
while the other group received either a vaccine that was already approved or a placebo
(sterile saline), depending on the trial. The first dose of vaccine was given at 7 - 8 weeks of
age and a second 4 weeks later.
The safety of the vaccine in these young dogs was determined through observation and the
measurement of body temperatures. No animal showed any fever. Reactions at the
injection site were observed, with a maximum dimension of 5 cm. Pain (lasting less than 24
hours) was detected in a third of the vaccinated animals after the first injection, and in half
after the second injection. These results were similar to the results of the laboratory studies.
Environmental Safety
The applicant provided an environmental risk assessment in compliance with the relevant
guideline. Ecotoxicity was adequately addressed, and the risk to the environment is
considered negligible. Therefore no further assessment is required.
Warnings and precautions are listed in the SPC, and are adequate to ensure safety to the
environment when the product is used as directed.
Dispose of waste by boiling, incineration or immersion in an appropriate
disinfectant approved for use by the competent authorities.
CONCLUSIONS ON THE SAFETY ASPECTS
The safety part of the dossier fulfils the legislative requirements, and provides adequate
information to assess the safety of the product.
The vaccine often produces local reactions in dogs when used, and these are explained in
the SPC. The safety of the product, including biological properties, excretion, spread and
reversion to virulence has been demonstrated by the laboratory studies carried out. The
vaccine was shown to be safe when used in a variety of dog breeds in a normal “field”
situation.
The vaccine contains no ingredients that represent a significant hazard to people
administering the product.
Since the product is for use in dogs only, there are no concerns regarding consumer safety. *
*
Consumer safety relates to consumers of food derived from treated animals, and is thus only
applicable to food-producing animals such as cattle, sheep, fish and poultry.
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
In summary, this product has been shown to be safe when used according to the directions
for use, and the SPC adequately reflects the likelihood and severity of any reaction that may
be seen.
IV.
EFFICACY ASPECTS
Introduction
The vaccine is intended for dogs from the age of 6 weeks. A primary course consists of two
vaccinations, 2 - 4 weeks apart, with the second being given when the animal is at least 10
weeks old.
A booster is recommended annually.
The vaccine is administered
subcutaneously in a volume of 1 ml.
Information on the composition of batches used in the laboratory efficacy trials was provided.
In cases where the composition differed from that of the authorised product, data were
provided to show that the studies were relevant to Duramune Puppy DP + C.
Information on the composition of batches used in the field efficacy trials was also provided.
The batches were essentially identical to the final licensed product. Batches were generally
produced in order to be at minimum or low potency in order to investigate if the product is
efficacious even at low potency levels.
Laboratory trials
Laboratory trials were carried out to show short-term efficacy of two doses, duration of
immunity, efficacy of a single booster, and effect of maternal antibody on efficacy for each of
the viral components. Also, as supporting data, the applicant provided information on the
efficacy of a single dose of CDV.
Canine Distemper Virus
Young dogs which had no antibodies to CDV were inoculated with complete vaccine on two
occasions, with an interval of 3 weeks. Three weeks after the second vaccination, the
animals were exposed to virulent CDV. Blood samples from the vaccinated animals showed
a strong antibody response to the first vaccination, and antibodies reached protective levels
two weeks after the second vaccination. Vaccinated animals were generally protected
against fever, and showed virtually no clinical signs following exposure to virulent CDV. The
CDV component of the vaccine was shown to be in compliance with the European
Pharmacopoeia monograph.
In two further studies, animals vaccinated twice at 3-week intervals were exposed to virulent
CDV after one or three years. It was shown that antibody levels remained elevated for at
least a year after the course of vaccination and when the animals were exposed to virulent
CDV, there was a strong “memory response”, with protective levels of antibodies being
attained quickly. Animals exposed to virulent CDV one year after vaccination showed no
signs of disease and animals exposed three years after vaccination showed either minimal or
no signs of disease. These data therefore demonstrated a 3-year duration of immunity.
The company also provided data demonstrating protection from virulent CDV three weeks
after the administration of a single injection of the complex vaccine. These data, combined
with the results of a study in which antibody levels were measured following a single booster
dose given one year after the initial two-dose course of vaccination, indicate that a single
booster dose will be sufficient to provide protection.
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
Studies were conducted to investigate whether the vaccine was efficacious in dogs with
maternal antibodies to CDV. When two doses of vaccine were given, 2 - 4 weeks apart, to
animals with low or moderate levels of maternal antibodies to CDV, the vaccine did provide
protection against CDV, although the protection was not as effective as when the vaccine
was given to animals with no maternal antibodies. It was therefore concluded that the
presence of maternal antibody could affect the performance of the vaccine. The SPC
contains a warning of the potential for interference from maternal antibody and a statement
on the efficacy of the product in the face of low to moderate levels of maternal antibody.
Canine Parvovirus
Young dogs which had no antibodies to CPV were inoculated with complete vaccine on two
occasions, with an interval of 3 weeks. Three weeks after the second vaccination, the
animals were exposed to virulent strains of CPV. Blood samples from vaccinated animals
showed a strong antibody response to the CPV components of the vaccine from two weeks
after the second vaccination. Vaccinated animals were protected against fever and
leucopenia*, showed virtually no signs of disease and only one excreted virus following
exposure to the virulent virus. The vaccine was shown to protect against virulent CPV.
In another study, animals vaccinated twice at 3-week intervals, were exposed to virulent CPV
after one year. This study demonstrated that immunity continued for at least one year after
the initial vaccination programme. A similar study in which vaccinated animals were exposed
to virulent CPV three years later showed that antibody levels remained high throughout the
study and vaccinated animals had few signs of disease when exposed to virulent CPV.
Further data were submitted that showed that, when given on one occasion, the vaccine
protected animals from oral and intranasal exposure to virulent CPV at 3 weeks after
vaccination. Blood samples from vaccinated animals showed a strong antibody response to
CPV, and antibody levels remained high until the animals were exposed to virulent CPV.
Vaccinated animals were relatively protected against CPV infection. This indicates that the
CPV component of the vaccine is efficacious and indicates that a single booster dose will be
sufficient. Full compliance of CPV with the European Pharmacopoeia monograph was
shown in this study. The company also provided data from a study in which antibody levels
were measured following a single booster one year after the initial course of vaccination, and
these data supported the conclusion that a single booster dose is appropriate.
When two doses of vaccine were given, 2 - 4 weeks apart, to animals with low or moderate
levels of maternal antibodies to CPV, the vaccine could provide protection against CPV. The
protection was not as effective as when the vaccine was given to animals without maternal
antibodies. It was therefore concluded that the presence of maternal antibody could affect
the performance of the vaccine. The SPC contains a warning of the potential for interference
from maternal antibody and a statement on the efficacy of the product in the face of low to
moderate levels of maternal antibody.
Canine Coronavirus
Young dogs which had no antibodies to CCV were inoculated with parent vaccine on two
occasions, with an interval of 3 weeks. Three weeks after the second vaccination, the
animals were exposed to virulent strains of CCV. Blood samples from vaccinated animals
showed an antibody response to the CCV component of the vaccine. There was no clinical
*
Leucopenia is a reduction in the number of white blood cells.
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SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
difference between vaccinated and control animals, although the vaccine was shown to
reduce CCV infection at the intestinal level.
In another study, animals vaccinated twice at 3-week intervals were exposed to CPV after
one year. Again, virus shedding appeared to be lower for vaccinated than unvaccinated
animals.
The applicant showed that levels of maternal antibody to CCV are always low in dogs of 6 - 8
weeks old, and therefore no further data were required.
Field Trials
The antibody responses observed in the laboratory studies were confirmed in two field
studies which were controlled and fully documented, one in Germany, and one in the UK,
using young dogs of various breeds. These studies investigated both the safety and efficacy
of the product, and the safety aspects have already been discussed in Part III of this report.
CONCLUSIONS ON CLINICAL ASPECTS
The data provided on efficacy fulfils the legislative requirements, and allows adequate
assessment of the product.
Each of the viral antigens in the product stimulate an immune response in the susceptible
target animal, and this has been shown to provide protection in each case. The protection
afforded by the CDV, CPV and CCV components has been shown to last one year. An
annual booster has been shown to provide protection. In the presence of high levels of
maternal antibody, a beneficial effect is still obtained, although the vaccine is not as
efficacious as when used in animals without maternal antibodies. This situation is
adequately reflected by the warning in the SPC.
V.
OVERALL CONCLUSION ON THE PRODUCT
The data submitted in the dossier demonstrate that when the product is used in accordance
with the Summary of Product Characteristics, the risk benefit profile for the target species is
favourable and the quality and safety of the product for man and the environment is
acceptable.
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DURAMUNE Puppy DP + C
SCIENTIFIC DISCUSSION
Fort Dodge Animal Health Limited
POST-AUTHORISATION ASSESSMENTS
The SPC and package leaflet may be updated to include new information on the quality,
safety and efficacy of the veterinary medicinal product. The current SPC is available on the
Product Information Database of the Veterinary Medicines Directorate website.
(www.gov.uk/check-animal-medicine-licensed)
The post-authorisation assessment (PAA) contains information on significant changes which
have been made after the original procedure which are important for the quality, safety or
efficacy of the product.
The PAA for this product is available on the Product Information Database of the Veterinary
Medicines Directorate website.
(www.gov.uk/check-animal-medicine-licensed)
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