- 1 Active substance / Generic: Tetanus Toxoid
- 1.1 Equilis Te: Quality Assessment
- 1.2 Tetanus Toxoid: Safety Assessment
- 1.3 Tetanus toxoid: Efficacy Assessment
- 1.4 Equilis Te: Risk-Benefit
Active substance / Generic: Tetanus Toxoid
This medicine is approved for use in the European Union
|Invented name:||Equilis Te|
|Active substance/INN:||Tetanus toxoid|
|Therapeutic indication:||Active immunisation of horses from 6 months of age against tetanus to prevent mortality.|
|Withdrawal period:||Zero days|
|Pharmaceutical form:||Suspension for injection|
|Pharmaco-therapeutic group:||Tetanus vaccine|
|Marketing Authorisation Holder:||Intervet International B.V.
Wim de Korverstraat 35
NL-5831 AN Boxmeer
Equilis Te is presented in a 1 ml glass vial or a pre-filled glass syringe. The vaccine contains tetanus toxoid. The product is indicated for active immunisation of horses from 6 months of age against tetanus to prevent mortality. The route of administration is intramuscular.
Equilis Te: Quality Assessment
The vaccine contains tetanus toxoid 40 LF (flocculation equivalents)/ml. Standard excipients are used as stabilisers, buffer components and all comply with the Ph.Eur. Per dose the vaccine contains traces of formaldehyde as a remnant of the inactivation process. Depending on the tetanus toxoid supplier traces of thiomersal can be found as well.
Either glass vials or pre-filled glass syringes are used. The vials are closed with a halogenobutyl rubber stopper and encapsulated with a coded aluminium cap. The ending of the plunger and the tip cap closing of the syringe are of halogenobutyl rubber. Both containers are sterilised.
The tetanus component of Equilis Te is a standard tetanus toxoid. The sterile fractionated tetanus toxoid concentrate is supplied in bulk for incorporation into Equilis Te, which is then blended, filled, packed and released by Intervet. It contains a fixed amount of purified tetanus toxoid (40 Lf per dose of 1 ml) determined via flocculation testing. The final product is tested in the potency test as prescribed in the Ph.Eur. monograph 0697 by using a Toxoid Binding Inhibition (ToBI) assay.
The adjuvant is based on iscom-matrix technology. The iscom-matrix used here is an adjuvant formulation closely related to iscom but consisting of particles with a patented composition whose shape and appearance are as that of the iscom except for their lack of incorporated antigen. These iscom-matrix particles are formed by a HPLC-purified fraction of Quillaja saponins, cholesterol and phosphatidyl choline. The iscom-matrix is mixed with the antigen only. The iscom-matrix, possesses no or drastically reduced haemolytic activity. Induction of high levels of serum antibodies against tetanus which persisted for an unexpectedly long time was seen in studies and the matrix has an excellent safety profile in horses. The amount of purified saponin in the vaccine has been set at 375 ug/dose. The exact mechanism how the iscom-matrix adjuvant induces such a broad immune response remains yet unclear.
The analytical part of the dossier is well described. A satisfactory description of the production and quality control procedures was provided. The method of manufacture was well described and the main in-process controls detailed in full. Compliance of starting materials of animal origin used during production with the requirements of the Note for guidance on minimising risk of transmitting animal spongiform encephalopathy agents via human and veterinary products was shown. Following an extension of the marketing authorisation in 2008, the addition of another tetanus toxoid supplier was adequately justified.
Validation data for the ToBI test were provided and deemed satisfactory to differentiate between batches that pass or fail the batch potency test. The finished product and batch safety tests ensure a product of consistent quality is produced. Based on the stability data provided a shelf life of 24 months was justified for the finished product.
Tetanus Toxoid: Safety Assessment
Equilis Te is an inactivated adjuvanted vaccine containing tetanus toxoid as the active component. The minimum age for vaccination is 6 months. The basic vaccination scheme consists of two 1 ml intramuscular injections, each a single dose, with an interval of 4 weeks. Each dose (1 ml) contains as active substance Tetanus toxoid (40 Flocculation units). The safety studies were based on the relevant Ph.Eur. monographs and guidelines. All studies have been performed with Equilis Prequenza Te, which is an inactivated adjuvanted vaccine containing antigen of three different influenza strains and tetanus toxoid as the active components. Five laboratory studies and 6 field studies have been conducted. For the safety studies, vaccine batches produced and tested according to the production method and the standard release requirements described in Part II of the dossier were used.
Laboratory studies were conducted to assess the safety of a single, double and repeated single dose using batches of standard antigen content in horses of 2 to 4 months of age, older horses and pregnant thoroughbred mares. The vaccine may induce local reactions in the horse. These local reactions are characterised by soft or sometimes hard swellings mostly with a diameter smaller than 2 cm. In rare cases the size was up to 5 cm in diameter and the injection site was painful. The reactions were transient and they disappeared normally within 24 to 48 hours. Sometimes an increase in rectal temperature above the normal range could be observed for 24 hours, exceptionally for three days. Other systemic reactions were not induced by the vaccine. That means that the vaccine will be well tolerated by horses of different ages.
No negative influence on gestation, foaling and offspring of mares was observed after vaccination at different times during pregnancy. At the injection site, no remnants of the vaccine were found. The vaccine was administered at the same time, but at different sites with Tetanus serum. This administration was safe. An assessment of the ecotoxicity risks showed that the overall risk of the vaccine to the environment, humans and other animals is effectively zero.
Tetanus toxoid: Efficacy Assessment
Tetanus is an acute, often fatal disease caused by the neurotoxin of Clostridium tetani, a slender, gram-positive, anaerobic rod that may develop terminal spores, which are widely distributed in soil and intestines of animals and humans. The disease, which usually originates from contaminated wounds, is characterised by generalised rigidity and convulsive spasms of skeletal muscles. The muscle stiffness usually involves the jaw (lockjaw) and neck and then becomes generalised. Most susceptible species to tetanus are horses and humans. Effective prophylaxis against this disease is only obtained by means of vaccination.
Almost all efficacy experiments were performed with the full combination product Equilis Prequenza Te, which besides tetanus toxoid also contains inactivated antigen of three different equine influenza strains. The amounts of tetanus toxoid (40 Lf) and adjuvant (purified saponin: 375 ug) in one dose of 1 ml of Equilis Prequenza Te and the mono-component vaccine Equilis Te are identical.
Efficacy studies have been carried out in the target species, the horse, by the recommended route of administration (intramuscular). All efficacy experiments except one were performed with batches of Equilis Prequenza Te containing standard amounts of influenza antigens (A/equine-1/Prague/1/56 = 100 AU, A/equine-2/Newmarket/1/93 and A/equine-2/Newmarket/2/93 = 50 AU each), tetanus toxoid (40 Lf) and adjuvant (saponin: 375 µg) in one dose of 1 ml. In one field trial Equilis Te was used.
It was demonstrated that basic vaccination (consisting of two vaccinations 4 weeks apart) of seronegative foals at an age of five months onwards with Equilis Prequenza Te led to serum antitoxin levels against tetanus toxoid considered to indicate protection against tetanus 2 weeks after basic vaccination until at least 17 months after basic vaccination.
All foals used in the laboratory and field efficacy studies were seronegative to tetanus at the time of first vaccination. Thus, the influence of specific maternal antibodies on the efficacy of Equilis Prequenza Te against tetanus could not be assessed. As the presence of specific maternal antibodies to tetanus is known to have a significant inhibitory effect on the development of active immunity against tetanus in young foals after active immunisation, an appropriate minimum age of vaccination was fixed at 6 months.
Regarding the concurrent use of Equilis Prequenza Te and Tetanus-Serum Intervet, a passive protection against tetanus for at least 21 days after concurrent administration has been demonstrated. Nevertheless, the development of active immunity against tetanus is negatively influenced by concurrent use of Equilis Prequenza Te and Tetanus-Serum Intervet, as antitoxin titres obtained 2 weeks after the basic vaccination were significantly reduced compared to results obtained in the other laboratory efficacy studies 2 weeks after the second vaccination. As this might have a negative influence on the duration of immunity against tetanus, it is proposed to include a third vaccination at least 4 weeks later.
Duration of immunity of Equilis Prequenza Te against tetanus after first (and further) booster immunisation was demonstrated. Data provided show that protective serum antibody titres against tetanus persisted for 24 months after the first revaccination (V3) with Equilis Prequenza Te given at 5 months after the basic vaccination course.
The results of one field trial performed with Equilis Te demonstrate that vaccination of seronegative horses with Equilis Te under field conditions will induce a sero-response that is equal or higher when compared to the sero-response after vaccination with Equilis Prequenza Te. Therefore the claimed period for the duration of immunity for Equilis Te should be at least equal but may be even longer when compared to Equilis Prequenza Te.
Thus, the duration of immunity after the basic vaccination course (17 months) as well as the duration of immunity after the first booster vaccination (24 months) can be considered to be demonstrated after vaccination with Equilis Te under laboratory and field conditions.
Equilis Te: Risk-Benefit
Equilis Te is indicated for active immunisation of horses from 6 months of age against tetanus to prevent mortality. The vaccine contains tetanus toxoid prepared from toxin produced by Clostridium tetani. Clostridium tetani is a gram-positive, anaerobic, spore-forming bacillus, which produces a potent toxin that can cause spasticity and tetany of the skeletal muscle. Horses have a much higher susceptibility to the tetanus neurotoxin than other animals. In general tetanus prophylaxis should be incorporated into all equine health maintenance programmes.
The tetanus toxoid is formulated with iscom-matrix, a new innovative adjuvant. The iscom-matrix contains a purified saponin. The adjuvant has excellent immune-inducing properties and a good safety profile.
The analytical part is correctly documented, especially with regard to the production and control of the antigen and the control of the raw materials. The starting materials of animal origin used in the production of the final product comply with the current regulatory texts related to the TSE Note for Guidance (EMEA/410/01-Rev.2) and Commission Directive 1999/104/EEC.
The potential risks of the use of this inactivated adjuvanted vaccine against tetanus in horses may be that the vaccine causes abnormal local or systemic reactions in the target animal and the risk of self-injection administering the product. Both of these have been addressed and suitable warnings included in the SPC. No negative influence on gestation, foaling and offspring of mares was observed after vaccination at different times during pregnancy. The vaccine is safe in animals regarded as most sensitive. After administration of a double dose and the repeated administration of one dose no serious adverse systemic or local reactions were observed. Each vaccine batch is tested for safety in the target animal before batch release. Appropriate warnings are indicated in SPC sections 5.4, 5.9 and 5.12.
An assessment of the ecotoxicity risks showed that the overall risk of the vaccine to the environment, humans and other animals is minimal.
Vaccination with Equilis Te provides protection against tetanus starting at 2 weeks after basic vaccination. The basic vaccination course results in immunity to tetanus lasting at least 17 months. The first revaccination after the basic vaccination course results in immunity to tetanus lasting at least 24 months.
The interference of maternal antibodies on the efficacy of inactivated vaccines against tetanus is well known. Development of a humoral response of Equilis Te in the face of maternal antibodies against tetanus has not been demonstrated. Field data and laboratory data indicate that young animals at the age of 6 months that are without maternal antibody against tetanus respond adequately to vaccination. A complete vaccination response of seronegative foals at an age below six months could not be clearly demonstrated. Maternal antibodies to tetanus in the foal may persist up to 4-6 months of age depending on the amount of colostrum ingested shortly after birth and the immune status of the mare. In addition, it has also been recommended that foals born from mares vaccinated during the last two months of gestation should not be vaccinated before the age of 6 months.
Concurrent use of Equilis Te and Tetanus-Serum Intervet will lead to a passive protection against tetanus for at least 21 days. Development of active immunity against tetanus is negatively influenced by concurrent use of Equilis Prequenza Te and Tetanus-Serum Intervet. An appropriate statement has been proposed for point 5.8 of the SPC.
Based on the original and subsequent data presented, the Committee for Medicinal Products for Veterinary Use concluded by majority that the quality, safety and efficacy of Equilis Te was considered to be in accordance with the requirements of Council Directive 2001/82/EC.