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Avian infectious bronchitis vaccine (live) EUROPEAN PHARMACOPOEIA 5.0 better in group C than in group D and significantly better in group B than in group A. The test is not valid unless there is a drop in egg production in group A compared to the normal level noted before challenge of at least 35 per cent where challenge has been made with a Massachusetts-type strain ; where it is necessary to carry out a challenge with a strain of another serotype for which there is documented evidence that the strain will not cause a 35 per cent drop in egg production, the challenge must produce a drop in egg production commensurate with the documented evidence and in any case not less than 15 per cent. LABELLING The label states : — the category and age of the chickens for which the vaccine is intended, — the strains and serotypes of virus used in the production of the vaccine and the serotypes against which the vaccine is intended to protect, — whether the strain in the vaccine is embryo-adapted or cell-culture-adapted. 01/2005:0442 AVIAN INFECTIOUS BRONCHITIS VACCINE (LIVE) Vaccinum bronchitidis infectivae aviariae vivum 1. DEFINITION Avian infectious bronchitis vaccine (live) is a preparation of one or more suitable strains of different types of avian infectious bronchitis virus. This monograph applies to vaccines intended for administration to chickens for active immunisation against respiratory disease caused by avian infectious bronchitis virus. 2. PRODUCTION 2-1. PREPARATION OF THE VACCINE The vaccine virus is grown in embryonated hens’ eggs or in cell cultures. 2-2. SUBSTRATE FOR VIRUS PROPAGATION 2-2-1. Embryonated hens’ eggs. If the vaccine virus is grown in embryonated hens’ eggs, they are obtained from flocks free from specified pathogens (SPF) (5.2.2). 2-2-2. Cell cultures. If the vaccine virus is grown in cell cultures, they comply with the requirements for cell cultures for production of veterinary vaccines (5.2.4). 2-3. SEED LOTS 2-3-1. Extraneous agents. The master seed lot complies with the tests for extraneous agents in seed lots (2.6.24). In these tests on the master seed lot, the organisms used are not more that 5 passages from the master seed lot at the start of the test. 2-4. CHOICE OF VACCINE VIRUS The vaccine virus shall be shown to be satisfactory with respect to safety (5.2.6) and efficacy (5.2.7) for the chickens for which it is intended. The following tests for safety (section 2-4-1), increase in virulence (section 2-4-2) and immunogenicity (section 2-4-3) may be used during the demonstration of safety and immunogenicity. 720 2-4-1. Safety 2-4-1-1. Safety for the respiratory tract and kidneys. Carry out the test in chickens not older than the youngest age to be recommended for vaccination. Use vaccine virus at the least attenuated passage level that will be present between the master seed lot and a batch of the vaccine. Use not fewer than 15 chickens from an SPF flock (5.2.2) and from the same origin. Administer to each chicken by the oculonasal route a quantity of the vaccine virus equivalent to not less than 10 times the maximum virus titre likely to be contained in 1 dose of the vaccine. On each of days 5, 7 and 10 after administration of the virus, kill not fewer than 5 of the chickens, take samples of trachea and kidney. Fix kidney samples for histological examination. Remove the tracheas and cut 10 rings from each trachea (3 from the top, 4 from the mid-part and 3 from the bottom) ; examine each ring under low magnification and score for ciliostasis on a scale from 0 (100 per cent ciliary activity) to 4 (no activity, complete ciliostasis) ; calculate the mean ciliostasis score (the maximum for each trachea being 40) for the 5 chickens killed on each of days 5, 7 and 10. The test is not valid if more than 10 per cent of the chickens die from causes not attributable to the vaccine virus. The vaccine virus complies with the test if : — no chicken shows notable clinical signs of avian infectious bronchitis or dies from causes attributable to the vaccine virus, — the average ciliostasis score is not more than 25, — at most moderate inflammatory lesions are seen during kidney histological examination. 2-4-1-2. Safety for the reproductive tract. If the recommendations for use state or imply that the vaccine may be used in females of less than 3 weeks old that are subsequently kept to sexual maturity, it shall be demonstrated that there is no damage to development of the reproductive tract when the vaccine is given to chickens of the minimum age to be recommended for vaccination. The following test may be carried out : use not fewer than 40 female chickens not older than the minimum age recommended for vaccination and from an SPF flock (5.2.2) ; use the vaccine virus at the least attenuated passage level that will be present in a batch of vaccine ; administer to each chicken by a recommended route a quantity of virus equivalent to not less than the maximum titre likely to be present in 1 dose of vaccine ; at least 10 weeks after administration of the vaccine virus, kill the chickens and carry out macroscopic examination of the oviducts. The vaccine virus complies with the test if abnormalities are present in not more than 5 per cent of the oviducts. 2-4-2. Increase in virulence. The test for increase in virulence consists of the administration of the vaccine virus, at the least attenuated virus passage level that will be present between the master seed lot and a batch of the vaccine, to a group of five 2-week-old chickens from an SPF flock (5.2.2), sequential passages, 5 times where possible, to further similar groups and testing of the final recovered virus for increase in virulence. If the properties of the vaccine virus allow sequential passage to 5 groups via natural spreading, this method may be used, otherwise passage as described below is carried out and the maximally passaged virus that has been recovered is tested for increase in virulence. Care must be taken to avoid contamination by virus from previous passages. Administer by eye-drop a quantity of the vaccine virus that will allow recovery of virus for the passages described below. 2 to 4 days after administration of the vaccine virus, prepare a suspension from the mucosa of the trachea of each chicken and pool these samples. Administer 0.05 ml of the pooled samples by eye-drop to each of 5 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 5.0 Avian infectious bronchitis vaccine (live) other 2-week-old chickens from an SPF flock (5.2.2). Carry out this passage operation not fewer than 5 times ; verify the presence of the virus at each passage. If the virus is not found at a passage level, carry out a second series of passages. Carry out the test for safety for the respiratory tract and kidney (section 2-4-1-1) and, where applicable, the test for safety for the reproductive tract (section 2-4-1-2) using the unpassaged vaccine virus and the maximally passaged virus that has been recovered. Administer the virus by the route to be recommended for vaccination likely to be the least safe. The vaccine virus complies with the test if no indication of increase in virulence of the maximally passaged virus compared with the unpassaged virus is observed. If virus is not recovered at any passage level in the first and second series of passages, the vaccine virus also complies with the test. 2-4-3. Immunogenicity. Immunogenicity is demonstrated for each strain of virus to be included in the vaccine. A test is carried out for each route and method of administration to be recommended using in each case chickens from an SPF flock (5.2.2) not older than the youngest age to be recommended for vaccination. The quantity of the vaccine virus administered to each chicken is not greater than the minimum virus titre to be stated on the label and the virus is at the most attenuated passage level that will be present in a batch of the vaccine. 1 or both of the tests below may be used during the demonstration of immunogenicity. 2-4-3-1. Ciliary activity of tracheal explants. Use not fewer than 25 chickens of the same origin and from an SPF flock (5.2.2). Vaccinate by a recommended route not fewer than 20 chickens. Maintain not fewer than 5 chickens as controls. Challenge each chicken after 21 days by eye-drop with a sufficient quantity of virulent avian infectious bronchitis virus of the same type as the vaccine virus to be tested. Kill the chickens 4 to 7 days after challenge and prepare transverse sections from the upper part (3), the middle part (4) and the lower part (3) of the trachea of each chicken. Examine all explants as soon as possible and at the latest 2 h after sampling by low-magnification microscopy for ciliary activity. For a given tracheal section, ciliary activity is considered as normal when at least 50 per cent of the internal ring shows vigorous ciliary movement. A chicken is considered not affected if not fewer than 9 out of 10 rings show normal ciliary activity. The test is not valid if : — fewer than 80 per cent of the control chickens show cessation or extreme loss of vigour of ciliary activity, — and/or during the period between the vaccination and challenge more than 10 per cent of vaccinated or control chickens show abnormal clinical signs or die from causes not attributable to the vaccine. The vaccine virus complies with the test if not fewer than 80 per cent of the vaccinated chickens show normal ciliary activity. 2-4-3-2. Virus recovery from tracheal swabs.Use not fewer than 30 chickens of the same origin and from an SPF flock (5.2.2). Vaccinate by a recommended route not fewer than 20 chickens. Maintain not fewer than 10 chickens as controls. Challenge each chicken after 21 days by eye-drop with a sufficient quantity of virulent avian infectious bronchitis virus of the same type as the vaccine virus to be tested. Kill the chickens 4 to 7 days after challenge and prepare a suspension from swabs of the tracheal mucosa of each chicken. Inoculate 0.2 ml of the suspension into the allantoic cavity of each of 5 embryonated hens’ eggs, 9 to 11 days old, from an SPF flock (5.2.2). Incubate the eggs for 6-8 days after inoculation. Eggs that after 1 day of incubation do not contain a live embryo are eliminated and considered as non-specific deaths. Record the other eggs containing a dead embryo and after 6-8 days’ incubation examine each egg containing a live embryo for lesions characteristic of avian infectious bronchitis. Make successively 3 such passages. If 1 embryo of a series of eggs dies or shows characteristic lesions, the inoculum is considered to be a carrier of avian infectious bronchitis virus. The examination of a series of eggs is considered to be definitely negative if no inoculum concerned is a carrier. The test is not valid if : — the challenge virus is re-isolated from fewer than 80 per cent of the control chickens, — and/or during the period between vaccination and challenge more than 10 per cent of the vaccinated or control chickens show abnormal clinical signs or die from causes not attributable to the vaccine, — and/or more than 1 egg in any group is eliminated because of non-specific embryo death. The vaccine virus complies with the test if the challenge virus is re-isolated from not more than 20 per cent of the vaccinated chickens. 3. BATCH TESTS 3-1. Identification 3-1-1. Vaccines containing one type of virus. The vaccine, diluted if necessary and mixed with avian infectious bronchitis virus antiserum specific for the virus type, no longer infects embryonated hens’ eggs from an SPF flock (5.2.2) or susceptible cell cultures (5.2.4) into which it is inoculated. 3-1-2. Vaccines containing more than one type of virus. The vaccine, diluted if necessary and mixed with type-specific antisera against each strain present in the vaccine except that to be identified, infects embryonated hens’ eggs from an SPF flock (5.2.2) or susceptible cell cultures (5.2.4) into which it is inoculated whereas after further admixture with type-specific antiserum against the strain to be identified it no longer produces such infection. 3-2. Bacteria and fungi Vaccines intended for administration by injection comply with the test for sterility prescribed in the monograph Vaccines for veterinary use (0062). Vaccines not intended for administration by injection either comply with the test for sterility prescribed in the monograph Vaccines for veterinary use (0062) or with the following test : carry out a quantitative test for bacterial and fungal contamination ; carry out identification tests for microorganisms detected in the vaccine ; the vaccine does not contain pathogenic microorganisms and contains not more than 1 non-pathogenic microorganism per dose. Any liquid supplied with the vaccine complies with the test for sterility prescribed in the monograph Vaccines for veterinary use (0062). 3-3. Mycoplasmas. The vaccine complies with the test for mycoplasmas (2.6.7). 3-4. Extraneous agents. The vaccine complies with the tests for extraneous agents in batches of finished product (2.6.25). 3-5. Safety. Use not fewer than 10 chickens from an SPF flock (5.2.2) and of the youngest age recommended for vaccination. Administer by a recommended route to each chicken, 10 doses of the vaccine. Observe the chickens at least daily for 21 days. The test is not valid if more than 20 per cent of the chickens show abnormal clinical signs or die from causes not attributable to the vaccine. The vaccine complies with the test if no chicken shows notable clinical signs of disease or dies from causes attributable to the vaccine. General Notices (1) apply to all monographs and other texts 721 Avian infectious bursal disease vaccine (inactivated) EUROPEAN PHARMACOPOEIA 5.0 3-6. Virus titre. Titrate the vaccine virus by inoculation into embryonated hens’ eggs from an SPF flock (5.2.2) or into suitable cell cultures (5.2.4). If the vaccine contains more than 1 strain of virus, titrate each strain after having neutralised the others with type-specific avian infectious bronchitis antisera. The vaccine complies with the test if 1 dose contains for each vaccine virus not less than the minimum titre stated on the label. 3-7. Potency. The vaccine complies with the requirements of 1 of the tests prescribed under Immunogenicity (section 2-4-3) when administered according to the recommended schedule by a recommended route and method. It is not necessary to carry out the potency test for each batch of the vaccine if it has been carried out on a representative batch using a vaccinating dose containing not more than the minimum virus titre stated on the label. Eggs are collected for hatching 5 to 7 weeks after vaccination and the test described below is carried out with 3-week-old chickens from that egg collection. Eggs are collected again towards the end of the period of lay and the test is repeated with chickens from that egg collection which are at least 15 days old. Twenty-five chickens from vaccinated hens and ten control chickens of the same breed and age from unvaccinated hens are challenged with an eye-drop application of a quantity of a virulent strain of infectious avian bursal disease virus sufficient to produce severe signs of disease, including lesions of the bursa of Fabricius, in all unvaccinated chickens. 3 to 4 days after challenge, the bursa of Fabricius is removed from each chicken. The bursae are examined for evidence of infection by histological examination or by testing for the presence of infectious avian bursal disease antigen in an agar-gel precipitation test. The vaccine complies with the test if three or fewer of the chickens from 01/2005:0960 vaccinated hens show evidence of infectious avian bursal disease infection. The test is not valid unless all the chickens BURSAL DISEASE from unvaccinated hens are affected. AVIAN INFECTIOUS VACCINE (INACTIVATED) Vaccinum bursitidis infectivae aviariae inactivatum DEFINITION Inactivated infectious avian bursal disease vaccine consists of an emulsion or a suspension of a suitable strain of infectious avian bursal disease virus type 1 which has been inactivated in such a manner that immunogenic activity is retained. The vaccine is for use in breeding domestic fowl to protect their progeny from infectious avian bursal disease. PRODUCTION The virus is propagated in fertilised eggs from healthy flocks, in suitable cell cultures (5.2.4) or in chickens from a flock free from specified pathogens (5.2.2). An amplification test for residual live infectious avian bursal disease virus is carried out on each batch of antigen immediately after inactivation and on the final bulk vaccine or, if the vaccine contains an adjuvant, on the bulk antigen or the mixture of bulk antigens immediately before the addition of any adjuvant, to confirm inactivation ; the test is carried out in fertilised hen eggs or in suitable cell cultures or, where chickens have been used for production of the vaccine, in chickens from a flock free from specified pathogens (5.2.2) ; the quantity of inactivated virus used in the test is equivalent to not less than ten doses of the vaccine. No live virus is detected. The vaccine may contain one or more suitable adjuvants. CHOICE OF VACCINE COMPOSITION The vaccine is shown to be satisfactory with respect to safety (5.2.6) and immunogenicity (5.2.7). The following test may be used during demonstration of efficacy. Immunogenicity. Each of at least twenty chickens from a flock free from specified pathogens (5.2.2), and of the recommended age for vaccination (close to the point of lay), is injected with the minimum recommended dose of vaccine by one of the recommended routes. 4 to 6 weeks later serum samples are collected from each bird and the antibody response is measured in a serum-neutralisation (SN) test. A suitable standard, calibrated in Ph. Eur. Units against infectious avian bursal disease serum BRP, is included in the test. The vaccine complies with the test if the mean antibody level in the sera from the vaccinated birds is at least 10 000 Ph. Eur. Units per millilitre. 722 Where there is more than one recommended route of administration, the test described under Potency is carried out in parallel with the above immunogenicity test, using different groups of birds for each recommended route. The serological response of the birds inoculated by routes other than that used in the immunogenicity test is not significantly less than that of the group vaccinated by that route. IDENTIFICATION In chickens with no antibodies to infectious avian bursal disease virus type 1, the vaccine stimulates the production of specific antibodies. TESTS Safety. Inject twice the vaccinating dose by one of the recommended routes into each of ten chickens, 14 to 28 days old, from flocks free from specified pathogens (5.2.2). Observe the birds for 21 days. No abnormal local or systemic reaction occurs. Note : this test may be omitted if inactivation test C is carried out. Inactivation A. For vaccine prepared with embryo-adapted strains of virus, inject two-fifths of a dose into the allantoic cavity or onto the chorio-allantoic membrane of ten 9- to 11-day-old fertilised hen eggs from a flock free from specified pathogens (SPF eggs) (5.2.2). Incubate the eggs and observe for 6 days. Pool separately the allantoic liquid or membranes from eggs containing live embryos, and that from eggs containing dead embryos, excluding those that die from non-specific causes within 24 h of the injection. Inject into the allantoic cavity or onto the chorio-allantoic membrane of each of ten 9- to 11-day-old SPF eggs 0.2 ml of the pooled allantoic liquid or crushed chorio-allantoic membranes from the live embryos and, into each of ten similar eggs, 0.2 ml of the pooled liquid or membranes from the dead embryos and incubate for 6 days. Examine each embryo for lesions of infectious avian bursal disease. If more than 20 per cent of the embryos die at either stage repeat that stage. The vaccine complies with the test if there is no evidence of lesions of infectious avian bursal disease and if, in any repeat test, not more than 20 per cent of the embryos die from non-specific causes. Antibiotics may be used in the test to control extraneous bacterial infection. See the information section on general monographs (cover pages)