This medicine is approved for use in the European Union
|Invented name:||Equilis Prequenza Te|
|Active substance/INN:||A/equine-1/Praque/1/56 ― 100 AU/ml
A/equine-2/Newmarket/1/93 ― 50 AU/ml
A/equine-2/Newmarket/2/93 ― 50 AU/ml
Tetanus Toxoid ― 40 LF/ml (flocculation equivalents)
|Therapeutic indication:||Active immunisation of horses from 6 months of age against equine influenza to reduce clinical signs and virus excretion after infection, and active immunisation against tetanus to prevent mortality.|
|Wididrawal period:||Zero days|
|Pharmaceutical form:||Suspension for injection|
|Pharmaco-merapeutic group:||Equine Influenza and tetanus vaccine|
|Marketing Aumorisation Holder:||Intervet International B.V.
Wim de Körverstraat 35
NL-5831 AN Boxmeer
Equilis Prequenza Te is presented in a 1 ml glass vial or a pre-filled glass syringe. The vaccine contains tetanus toxoid and purified haemagglutin subunits (HA) from three different equine influenza virus strains. The product is indicated for active immunisation of horses from 6 months of age against equine influenza to reduce clinical signs and virus excretion after infection, and active immunisation against tetanus to prevent mortality. The route of administration is intramuscular.
Equilis Prequenza Te: Quality Assessment
The vaccine contains tetanus toxoid 40 LF (flocculation equivalents)/ml and purified haemagglutin subunits (HA) from three different equine influenza virus strains; A/equine-1/Prague/1/56 100 AU (antigenic units)/ml; A/equine-2/Newmarket/1/93 50 AU/ml; A/equine-2/Newmarket/2/93 50 AU/ml. Standard excipients used as stabilisers or buffer components all comply with the Ph.Eur. Per dose the vaccine contains traces of thiomersal as a remnant of starting materials, as well as traces of formaldehyde.
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 choice of the three strains of equine influenza virus included in the vaccine was justified based on current outbreaks of influenza. The development of a subunit vaccine was justified. The subunit vaccine also reduces potential adverse effects by means of the production process.
The vaccine contains purified haemagglutinin and neuraminidase glycoproteins; however the neuraminidase content of the vaccine is not measured.
The influenza potency is determined in-vivo (guinea pigs Ph.Eur. 0249). The initially proposed release limits for the three influenza components (Prague/56, Newmarket-1 and Newmarket-2 respectively) were revised and higher limits with revised pass criteria agreed.
The tetanus component of Equilis Prequenza Te is a standard tetanus toxoid. 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 for this vaccine 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. Thus, the iscom-matrix possesses no or drastically reduced haemolytic activity. Induction of high levels of serum antibodies against equine influenza and tetanus, which persisted for an unexpectedly long time were seen in studies and the matrix has an excellent safety profile in the target species. The amount of purified saponin in the vaccine has been set at 375 µg/ dose.
The analytical part of the dossier is well described. Documentation and specifications reflecting the actual manufacturing and testing process for the tetanus component were provided. The production of the influenza virus antigen was described in detail. 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. Validation of the influenza virus batch potency test was addressed and appropriate pass criteria defined. 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.
Equilis Prequenza Te: Safety Assessment
Equilis Prequenza Te is an inactivated adjuvanted vaccine indicated for the active immunisation of horses against the effects of an infection with wild type equine influenza virus of the subtypes A/equine-1 or A/equine-2, and infection with Clostridium tetani. The basic vaccination scheme consists of two 1 ml intramuscular injections, each a single dose, with an interval of 4 weeks. The minimum age for vaccination is 6 months. The safety studies were based on the relevant Ph.Eur. monographs and guidelines.
Five laboratory studies and 6 field studies have been conducted. Equilis Prequenza Te contains standard antigen content for all components. 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 3 days. Other systemic reactions were not induced by the vaccine. That means that 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.
As the adverse reactions following vaccination with a single dose, an overdose and a repeated single dose to foals and older horses as well as to pregnant mares were minor and transient in all studies the vaccine may be used safely in competition horses. Vaccination of horses just before or just after competition should be not performed. Additionally, the stress after vaccination, e.g. by training should be minimised.
Equilis Prequenza Te: Efficacy Assessment
Equine influenza is an infectious respiratory disease caused by a virus belonging to the orthomyxovirus group. It is one of the most severe equine respiratory diseases and rapid spreading of the infection is typical. In an unprotected population morbidity rates of more than 80 % may occur. The disease is characterised by high fever and persistent severe cough. Infections caused by influenza virus often predispose to bacterial superinfection of the respiratory tract. This leads to a much more severe course of the disease than influenza infection itself. Strains belonging to the influenza subtypes A/Equi-1 and A/Equi-2 are responsible for the disease in horses. During recent years no A/Equi-1 field strains appeared. Strains belonging to subtype A/Equi-2 continue to circulate and cause large epidemics throughout horses world-wide (except for Australia and New Zealand). Vaccination is one of the accepted methods to prevent the disease. The protective antigenic proteins of the influenza virus correspond to the haemagglutinin and neuramidase contained in the membrane part of the viral envelope.
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 wound, 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.
Efficacy studies have been carried out in the target species, the horse, by the recommended route of administration (intramuscular). All efficacy studies 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 (375 µg) in one dose of 1 ml.
Equine Influenza components
The influenza vaccine strains of Equilis Prequenza Te are in accordance with the actual recommendation of the OIE. The presented studies are undertaken in accordance with the Ph.Eur. monograph 0249. The test batches of the vaccine used in the efficacy trials were produced as for batches for the market. So the amount of antigen and adjuvant was not adjusted to minimum level. The use of batches with standard amounts of antigen and adjuvant is acceptable for the efficacy trials.
The development of antibodies and the outcome of the challenges undertaken demonstrate good efficacy of the vaccine. If any signs of equine influenza occur after infection, they are very mild and only a small amount of virus shedding is expected. Complete recovery of the horse will only take a few days. This is in accordance with the SPC. The chosen immunisation scheme for the vaccine with two vaccinations 4 weeks apart followed by a third vaccination 5 months later with yearly booster vaccinations afterwards is sufficient. The possibility of alternating revaccination with Equilis Prequenza Te and Equilis Prequenza is supported as indicated in the SPC section 5.8. According to the findings of the field trial undertaken in pregnant mares and their offspring the vaccine is fully efficacious in pregnant mares.
Should the vaccine product be changed, no renewed basic immunisation is necessary.
Foals born to mares with high influenza antibody titres after an immunisation in the late stage of pregnancy developed a high level of maternally derived antibodies. This provides an excellent protection for the first months of life. However, antibody levels can persist up to an age of 5 months, therefore the age of the first vaccination was fixed to 6 months. Foals born to unvaccinated mares or foals with known low levels of maternally derived antibodies are recommended to start the immunisation at 3 months of age.
The safety data have shown that Equilis Prequenza Te can be administered to foals aged 2-4 months old. The laboratory efficacy trials and the field trials have shown that foals when free or having low levels of antibodies against equine influenza, from the age of 3 months can develop the same humoral immune response as e.g. adult horses.
A strain exchange related to the A-Equi-2 American lineage was discussed and at the current time (April 2005), a strain update of the vaccine is not considered necessary.
Tetanus toxoid component
It was demonstrated that basic vaccination (consisting of two vaccinations 4 weeks apart) of seronegative foals at an age of 5 months onwards with Equilis Prequenza Te led to serum antitoxin levels against tetanus toxoid considered to indicate protection against tetanus two 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. Results from a study to assess the duration of immunity against tetanus induced by Equilis Prequenza Te after the basic vaccination course and the first revaccination 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 duration of immunity (17 months) after the basic vaccination course as well as the duration of immunity (24 months) after the first booster vaccination is considered to be demonstrated after vaccination with Equilis Prequenza Te under laboratory and field conditions.
Equilis Prequenza Te: Risk-Benefit
Equilis Prequenza Te is an aqueous subunit vaccine intended for horses from 6 months of age, in order to protect them against equine influenza and tetanus. The vaccine contains purified haemagglutinin (HA) of three different strains of equine influenza virus, and tetanus toxoid prepared from toxin produced by Clostridium tetani. The 3 influenza strains represent 2 subtypes of influenza A virus. Subtype A/equine 1 (H7N7) virus strains have not caused major outbreaks of equine influenza since the 1970s. Both H3N8 subtype vaccine strains are antigenetically distinguishable and it has been recommended by OIE to include them in current influenza vaccines for horses in Europe and US.
The haemagglutinin subunits and the tetanus toxoid are 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 antigens 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 adjuvated subunit vaccine against equine influenza and 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 sections 5.4, 5.9 and 5.12 of the SPC.
An assessment of the ecotoxicity risks showed that the overall risk of the vaccine to the environment, humans and other animals is minimal.
Equine influenza is highly contagious and spreads rapidly between horses causing disease of high morbidity but low mortality. The clinical signs are typical for an acute respiratory disease and can consist of serous and/ or mucopurulent nasal discharges, a harsh dry cough and pyrexia. Normally the clinical signs end within 2-3 weeks post infection. Depending on the region, vaccine coverage of horses with regard to equine influenza is estimated between 50-70%. The efficacy of vaccines against Equine influenza is monitored closely and surveillance programmes to detect new subtypes of equine influenza have been implemented.
The causative agent for tetanus is Clostridium tetani, a gram-positive, anaerobic, spore-forming bacillus, which produces a potent toxin that can cause spasticity and tetany of the skeletal muscle. This potent neurotoxin is produced during the anaerobic growth of the bacterium in dead tissues, e.g. in dirty wounds. The bacterium is a common inhabitant of the intestinal tract of humans and animals and is abundant in soil. Horses have a much higher susceptibility to the tetanus neurotoxin than other animals. Immunity to tetanus toxin is induced only by immunisation; recovery from clinical tetanus does not result in protection against further attacks. Therefore, in general tetanus prophylaxis should be incorporated into all equine health maintenance programmes.
Equilis Prequenza Te is indicated for active immunisation of horses from 6 months of age against equine influenza to reduce clinical signs and virus excretion after infection, and active immunisation against tetanus to prevent mortality.
Vaccination with Equilis Prequenza Te provides protection against challenge at 2 weeks after basic vaccination, 5 months after basic vaccination, and at 12 months after revaccination for influenza as well as at 2 weeks until at least 17 months after the basic vaccination course, and until at least 24 months after revaccination for tetanus.
The interference of maternal antibodies on the efficacy of inactivated vaccines against equine influenza and tetanus is well known. The data from the field trials presented in the dossier indicate that also the humoral response of Equilis Prequenza Te may be impaired by interference with maternal antibodies against influenza. Development of a humoral response of Equilis Prequenza 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 influenza or tetanus respond adequately to vaccination. Maternal antibodies to equine influenza and 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 2 months of gestation should not be vaccinated before the age of 6 months.
Concurrent use of Equilis Prequenza Te and Tetanus-Serum Intervet will lead to a passive protection against tetanus for at least 21 days after concurrent administration. Development of active immunity against tetanus is negatively influenced by concurrent use of Equilis Prequenza Te and Tetanus-Serum Intervet. No negative influence on the development of HI antibody titres could be seen after concurrent administration 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 Prequenza Te was considered to be in accordance with the requirements of Council Directive 2001/82/EC.