Equilis Prequenza for Horses

By | 2012-01-29

Scientific discussion

This medicine is approved for use in the European Union

Invented name: Equilis Prequenza
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
Target species: Horses
Therapeutic indication: Active immunisation of horses from 6 months of age against equine influenza to reduce clinical signs and virus excretion after infection.
Wididrawal period: Zero days
Pharmaceutical form: Suspension for injection
ATCvet code: QI05AA01
Pharmaco-merapeutic group: Equine Influenza vaccine
Marketing Aumorisation Holder: Intervet International B.V.
Wim de Körverstraat 35
NL-5831 AN Boxmeer
The Netherlands

 

Equilis Prequenza is presented in a 1 ml glass vial or a pre-lilled glass syringe. The vaccine contains 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. The route of administration is intramuscular.

Equilis Prequenza: Quality Assessment

Composition

The vaccine contains 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.

Container

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.

Development Pharmaceutics

The choice of the 3 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 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 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.

Overall Conclusion

The analytical part of the dossier is well described. The production of the influenza antigens, purification and manufacture of the finished product was described in detail.

A detailed description of the manufacturing process for the adjuvant, the quantitative composition, the shelf life and the quality control was given. The risk of contamination with extraneous agents was assessed and deemed satisfactory. The method of manufacture was well described, validated and the main in-process controls detailed in full. Data showing that all three imfluenza master seed viruses are tested as free of avian extraneous agents was provided.

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.

Validation of the influenza virus batch potency test was addressed in detail and appropriate pass criteria defined. A satisfactory test for complete inactivation of influenza virus in the finished product was presented. Control tests on the finished product including the batch potency test provide confirmation that batches of consistent quality and potency are produced. Safety tests are carried out on each batch.

Based on the stability data provided a shelf life for the influenza bulk antigens and for the finished product of 24 months respectively was justified.

Equilis Prequenza: Safety Assessment

Equilis Prequenza 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. 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. All studies have been performed with Equilis Prequenza Te, an inactivated adjuvanted vaccine containing the same three influenza strains as Equilis Prequenza and tetanus toxoid (40 Flocculation units /ml) as the active components. 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 of the dossier were used.

Overall Conclusion

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. 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, any stress after vaccination, e.g. by training should be minimised.

Equine Influenza: 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.

Overall Conclusion

Efficacy studies have been carried out in the target species, the horse, by the recommended route of administration (intramuscular). All efficacy experiments 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. The full combination product Equilis Prequenza Te which also contains tetanus toxoid in addition to inactivated antigen of three different equine influenza strains, has been used in all efficacy and safety studies. According to the Note for Guidance “Requirements for combined Veterinary Vaccines” (CVMP/IWP/52/97-Final), this approach is acceptable. If the full combination product has been demonstrated to be safe, these results can also be regarded as indicative for the mono-component vaccines. Equivalence of the HI titres induced was demonstrated. The results confirm that for Equilis Prequenza Te and Equilis Prequenza the same level of protection can be expected.

The influenza vaccine strains of Equilis Prequenza 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 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 is two vaccinations 4 weeks apart followed by a third vaccination 5 months later with yearly booster vaccinations afterwards. 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 at 6 months. The presence of maternal antibodies against equine influenza will influence vaccine efficacy. In general, the majority of foals from 6 months of age will be free of maternal antibodies and therefore vaccination at an earlier stage is not recommended. The minimum age of vaccination is described in the SPC. Because of possible interference by maternally derived antibodies, foals should not be vaccinated before the age of 6 months, especially when born to mares that were revaccinated in the last two months of gestation. If vaccination is intended before 6 months of age, foals should be at least 4 months of age. Vaccination before 6 months of age should always be followed by a full basic vaccination course from 6 months of age onwards. No data are presented that support the sufficient basic immunisation starting at this young age therefore a full basic vaccination course from the age of 6 months has to follow this early vaccination.

In one field trial, several foals with a maternally derived antibody level did not respond to the vaccinations sufficiently. Therefore, it was agreed to fix the age for first immunisation to 6 months.

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.

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.

Equilis Prequenza: Risk-Benefit

Equilis Prequenza is indicated for active immunisation of horses from 6 months of age against equine influenza to reduce clinical signs and virus excretion after infection. Equilis Prequenza is an aqueous vaccine containing purified haemagglutinin subunits (A/equine-1/Prague/1/56 =100 AU, A/equine-2/Newmarket/1/93 = 50 AU, A/equine-2/Newmarket/2/93 = 50 AU) and 375 µg of purified saponin adjuvant per dose of 1 ml. The 3 influenza strains represent 2 subtypes of influenza A virus. The efficacy of vaccines against Equine influenza is monitored closely and surveillance programmes to detect new subtypes of Equine influenza have been implemented.

The hemagglutinin subunits 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, the production of the influenza antigens, purification and manufacture of the finished product was described in detail. Validation of the influenza virus batch potency test was addressed in detail and appropriate pass criteria defined. The starting materials of animal origin used in the production of the final product comply with the current TSE Note for Guidance (EMEA/410/01-Rev.2) and Commission Directive 1999/104/EEC.

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 was studied. The vaccine may induce local reactions. These local reactions are characterised by soft or sometimes hard swellings mostly with a diameter less 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 normally they disappeared 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 vaccine will be well tolerated by horses of different ages. 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.

The development of antibodies and the outcome of the challenges undertaken demonstrate a good efficacy of the vaccine. A complete protection against influenza at every time against field infections cannot be achieved by this vaccine. However, if any symptoms 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. 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 effective. The possibility of alternating revaccination with Equilis Prequenza Te and Equilis Prequenza is supported. According to the findings of the field trial undertaken in pregnant mares and their offspring the vaccine is fully efficacious in pregnant mares. 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 interference of maternal antibodies on the efficacy of inactivated vaccines against equine influenza well known. The majority of foals from 6 months of age will be free of maternal antibodies and therefore earlier vaccination is not recommended. Because of possible interference by maternally derived antibodies, foals should not be vaccinated before the age of 6 months, especially when born to mares that were revaccinated in the last two months of gestation. If vaccination is intended before 6 months of age, foals should be at least 4 months of age. Vaccination before 6 months of age should always be followed by a full basic vaccination course from 6 months of age onwards.

An assessment of the ecotoxicity risks showed that the overall risk of the vaccine to the environment, humans and other animals is minimal.

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 was considered to be in accordance with the requirements of Council Directive 2001/82/EC.