Key Points

• Rigorous immunogenicity and field safety studies were conducted to evaluate the efficacy and safety of FarrowSure^® GOLD B, the new 2-mL formulation of Pfizer Animal Health’s combination vaccine for use as an aid in protecting breeding swine against porcine parvovirus (PPV), leptospirosis, and erysipelas.^1-6
• FarrowSure GOLD B protected 85% of pigs challenged with virulent Erysipeolothrix rhusiopathiae at 18 weeks after vaccination.³
• The PPV, Leptospira bratislava, and L. hardjo fractions of FarrowSure GOLD B passed serological tests for non-inferiority to the licensed vaccine FarrowSure^® B.^1,2
• Field safety studies indicated that FarrowSure GOLD B in combination with the swine influenza virus vaccine FluSure^® was safe for use in pre-breeding gilts (2 doses) and in pregnant sows and gilts (dose given 2 to 4 weeks before farrowing).^4-6

FarrowSure GOLD B, introduced to the swine production industry in March 2008, is the 2-mL reformulation of Pfizer Animal Health’s vaccine for use in healthy breeding swine as an aid in preventing reproductive failure caused by PPV, erysipelas caused by Erysipelothrix rhusiopathiae, and leptospirosis caused by L. bratislava, L. canicola, L. grippotyphosa, L. hardjo, L. icterohaemorrhagiae, and L. pomona. The vaccine is a liquid preparation of PPV grown on an established porcine cell line; a serum-free, clarified E. rhusiopathiae culture; and whole-cell cultures, prepared using a proprietary manufacturing process, of the six Leptospira serovars listed above. All eight vaccine fractions are chemically inactivated and adjuvanted with two adjuvants, including Amphigen^®, to enhance the immune response.

Prior to introducing the 2-mL formulation, Pfizer Animal Health conducted a comprehensive series of immunogenicity and field safety studies to confirm vaccine efficacy and safety by demonstrating:

• Serological non-inferiority in swine of the PPV, L. bratislava, and L. hardjo fractions compared to the licensed product FarrowSure B
• Potency of the L. canicola, L. grippotyphosa, L. icterohaemorrhagiae, and L. pomona fractions by codified assays
• Duration of immunity (DOI) against E. rhusiopathiae in a challenge model
• Field safety in breeding-age swine when administered in combination with FluSure^®

Recapping Key Efficacy and Safety Studies

Non-inferiority of the PPV, L. bratislava, and L. hardjo fractions^1,2

The non-inferiority test model is widely accepted as a primary tool for comparing the immunogenicity of a new or reformulated vaccine to an already existing licensed product.^7,8

Non-inferiority studies were conducted with the PPV, L. bratislava, and L. hardjo fractions to compare the serological antibody responses of pigs vaccinated with 2-mL of FarrowSure GOLD B to the responses of pigs vaccinated with the 5-mL FarrowSure B product. In the PPV study, 28 or 32 pigs were assigned to each treatment group and 10 to the nonvaccinated control group; in the L. bratislava and L. hardjo study, 80 pigs to each group and 40 to the control group.

Treated pigs in all studies received two doses of their respective vaccine at a three-week interval. Blood samples were collected from each pig prior to each vaccination and again two weeks later (Day 35). Sera were analyzed by the hemagglutination inhibition (HI) test for antibodies to PPV and by the microscopic agglutination test (MAT) for antibodies to L. bratislava and L. hardjo. For serological equivalence, a non-inferiority value of 70% was considered passing.

RESULTS:

The non-inferiority values for the PPV, L. bratislava, and L. hardjo fractions of FarrowSure GOLD B on Day 35 were 79.4%, 384.9%, and 164.2%, respectively (Table 1). All three fractions of the 2-mL FarrowSure GOLD B product passed the test for non-inferiority to the 5-mL FarrowSure B vaccine.

Long-Term Efficacy of the Erysipelas Fraction³

An erysipelas challenge study was conducted at 18 weeks post-vaccination to establish duration of immunity with the E. rhusiopathiae fraction of FarrowSure GOLD B. Twenty vaccinates and 10 controls were enrolled in the study. Following challenge with a National Veterinary Services Laboratory (NVSL) strain of E. rhusiopathiae, vaccinates and controls were monitored once daily for seven days according to the following three categories:

RECTAL TEMPERATURE

• Control pigs were considered infected if they showed a fever of at least 105.6°F (40.9°C) for at least two consecutive days
• Vaccinates were judged unprotected if they showed a fever at the lower threshold of 104.6°F (40.3°C) on any two consecutive days

MORTALITY RELATED TO CHALLENGE

To confirm that death was caused by the challenge agent, E. rhusiopathiae had to be recovered from the spleen or liver.

SYSTEMIC CLINICAL SIGNS OF ERYSIPELAS

• Depression
• Hyperemia, primarily evident over the ears and underline
• Skin lesions characteristic of erysipelas
• Joint involvement characterized as lameness or stiffness

If controls showed clinical signs of erysipelas but failed to meet criteria in the other two categories during the seven-day post-challenge period, they still qualified as infected by having a positive culture on Day 7 following challenge.

Any vaccinate showing clinical signs was automatically considered unprotected against erysipelas.

A valid challenge study required that at least 8 of the 10 control pigs become infected as determined by at least one of the evaluation criteria.

RESULTS:

Table 2 presents results of the erysipelas duration of immunity challenge study:

• 80% of controls qualified as infected on the basis of temperature alone.
• 85% of vaccinates were protected following a virulent challenge at 18 weeks following vaccination. Three vaccinates had a qualifying fever and only one of these pigs exhibited hyperemia.

Safety Studies4-6

To test the safety of the new 2-mL formulation of FarrowSure GOLD BFluSure, field studies were conducted in commercial production units located in Indiana, Michigan, and North Carolina. Altogether, 205 pre-breeding gilts and 611 gestating sows and gilts were enrolled.

INDIANA STUDY PROTOCOL⁶

In the Indiana study, 205 pre-breeding gilts approximately 18 to 20 weeks of age were vaccinated intramuscularly on Day 0 with 2 mL of either one of two serials of FarrowSure GOLD B-FluSure followed by a second 2 mL dose three weeks later (Day 21). Gilts were observed for immediate post-vaccination reactions after each injection. Clinical observations were made and injection sites scored on Days 1 through 3, 10, 22 through 24, and 35. The scoring system (Table 3) ranged from 0 to 3; injection site reactions scored as a 3 were considered clinically relevant.All adverse reactions were observed until resolution. On Days 4 through 9 and 11 through 35, trained site staff made general health observations for injection-site reactions, changes in appetite, systemic reactions, lame animals, and any other abnormal observations. The Investigator reviewed all abnormal findings to determine whether they were attributable to vaccination.

MICHIGAN AND NORTH CAROLINA PROTOCOLS^4,5

At each of the sites in Michigan and North Carolina, approximately 300 gestating sows and/or gilts were vaccinated intramuscularly on Day 0 with a 2 mL dose of either one of two serials of FarrowSure GOLD B-FluSure (approximately 100 animals per serial) or a saline placebo (approximately 100 animals) at approximately two to four weeks prior to farrowing. Sows/gilts were blocked by parity class (0,1, or > 2) for allotment to treatment. All of the breeding females were observed for immediate post-vaccination reactions. Clinical observations were made and injection sites scored (Table 3) once daily on Days 1 through 3, 9, and 21. As in the Indiana study, only injection site reactions scored as 3 were considered as clinically relevant. General health observations (injectionsite reactions, changes in appetite, systemic reactions, reproductive abnormalities, lame animals, and others) were recorded daily by trained farm staff on Days 4-8 and 10-21, or until farrowing for sows and gilts that had not farrowed

by Day 21. In the North Carolina study, sows/gilts that farrowed before Day 21 were only observed until farrowing. Reproductive data were transcribed from farrowing cards or PigChamp™ records. Abortion data, litter information (alive/stillborn/mummies/dead), and percent of litters normal at farrowing were recorded but not analyzed.

RESULTS — PRE-BREEDING GILTS (INDIANA):

Table 4 presents results of the safety study conducted in pre-breeding gilts. Of the 205 vaccinated gilts, only one showed a clinically relevant injectionsite reaction during the period immediately after vaccination (Day 1). Characterized as raised and slightly pink in nature, the reaction resolved within one day. No other reaction was described as clinically relevant (score of 3) on Days 1 through 3 or 10. None of the general health observations performed by trained site staff on Days 4 through 9 and 11 through 35 were attributed to vaccination. Of the pre-breeding gilts revaccinated (n = 202) on Day 21, only one exhibited a clinically relevant injection-site reaction during the immediate post-vaccination period. By Day 25, this lone reaction was resolved (4 days post-vaccination). No other clinical observations were attributed to the vaccines on Days 22 through 24 or on Day 35. The data indicated that FarrowSure GOLD B-FluSure was safe for use in pre-breeding gilts when administered according to label directions.

RESULTS —GESTATING SOWS AND GILTS (MICHIGAN AND NORTH CAROLINA):

Results of injection-site scoring for gestating sows and gilts enrolled in the Michigan and North Carolina safety studies are recorded in Table 5 and Figure 1. At the Michigan site, 9 (8.8%) sows/gilts vaccinated with Serial 1 and 11 (11.0%) vaccinated with Serial 2 had scores of 3 on days 1, 2 or 3 post-vaccination. Described as a red and/or flat or raised area, the reactions were of short duration, with only a few (6 with Serial 1; 6 with Serial 2) present for more than a single day. No scores of 3 were observed on Day 9 or after. No abscesses were recorded during the study. At the North Carolina site, 11 (10.7%) sows/gilts receiving Serial 1 and 10 (9.9%) receiving Serial 2 had an injection site score of 3 on days 1, 2, or 3 post-vaccination. The reactions were described as a raised area with no discoloration. Only two sows/gilts had a score of 3 (one each with Serials 1 and 2) for more than one day, and no score 3 reactions were reported on Day 9. Farm staff described injection sites as a raised area with no discoloration in 24 sows/gilts on other days of the study. No sows/gilts had an injection site reaction remaining on Day 21 and no abscesses were recorded during the study.

Clinical observations other than injection- site reactions attributed to vaccination on Days 1 through 3 and Day 9 are reported in Table 6. At both sites, no clinical observations were evident on Day 21 after vaccination. Only four additional observations were recorded at the Michigan site. These sows/gilts were depressed or uncomfortable and left feed on a single post-vaccination evaluation time point. No sows/gilts had abnormal general health observations attributed to vaccination by the Investigator on any other study days. At the North Carolina site, six sows/gilts (placebo, n = 1; Serial 1, n =3; Serial 2, n = 2) were anorexic on a single day and 19 (placebo, n = 4; Serial 1, n = 10; Serial 2, n =5) had a decreased appetite at some point during the three days immediately following vaccination. One of Serial 1 sows/gilts was also depressed during the same observation period and one was off feed on Days 4 and 5. Swelling was observed in front of the injection site on Day 9 in six sows/ gilts. No other clinical signs or abnormal health observations were attributed to vaccination on any other study day.

No abortions occurred in vaccinated sows/gilts at either the Michigan or North Carolina sites; however, at the North Carolina site five abortions were observed in the control group sows/gilts. Although the data were not statistically analyzed, farrowing information was collected at each site. Tables 7 and 8 summarize the mean and percent born alive, mean number of pigs stillborn, mean number of mummies, mean low viability (North Carolina only), and percent of normal litters across all parities at each site. The five control group sows that aborted at the North Carolina site and their litters were not included in the reproductive variables documented in Tables 7 and 8. Data collected from pregnant sows/gilts at these two sites indicate that FarrowSure GOLD B-FluSure is safe for use in gestating swine.

Cumulatively, the field safety studies conducted with FarrowSure GOLD BFluSure involved substantial numbers of breeding swine and showed that two vaccine serials had a good safety record. Observed adverse events, injection-site reactions, and other clinical observations were transient and qualitatively inconsequential. The studies indicated that two doses of FarrowSure GOLD B can be safely administered to pre-breeding gilts and that booster doses can be safely given to pregnant sows as late as two to four weeks prior to farrowing (73 to 101 days of gestation).

Discussion

The 2-mL reformulation of FarrowSure GOLD B has been designed to maintain the superior efficacy associated with FarrowSure B against eight of the leading causes of reproduction failure in swine while at the same time providing a solid safety profile under field use conditions. Efficacy was established in a series of serological and challenge-ofimmunity studies that demonstrated:

• Non-inferiority of the PPV, L. bratislava, and L. hardjo fractions when compared with the same fractions of FarrowSure B
• Potency of the L. canicola, L. grippotyphosa, L. icterohaemorrhagiae, and L. pomona fractions by codified tests
• Duration of immunity with the erysipelas fraction that extended to 18 weeks after administration of the second vaccine dose

To assure safety, field studies involving substantial numbers of pre-breeding gilts and gestating sows and gilts were conducted at commercial sites. These studies established that:

• FarrowSure GOLD B-FluSure was safe for use in pre-breeding gilts when both doses of vaccine were administered according to label directions.
• FarrowSure GOLD B-FluSure administered to pregnant sows and gilts at 2 to 4 weeks prior to farrowing resulted in reactions that were minimal in number, of little consequence in severity, and transient in duration.
• Variations in reproductive measurements in pregnant sows and gilts vaccinated with FarrowSure GOLD B-FluSure were within the production norms of the commercial test sites.

Based on results of the efficacy studies, producers can expect comparable levels of protection against parvovirus, erysipelas, and leptospirosis by using the 2-mL FarrowSure GOLD B product as they would from using the 5-mL FarrowSure B product. Based on field safety studies, producers can also expect that the reformulated 2-mL vaccine is safe for use in breeding-age and gestating swine.

References

1. Data on file, Study Report No. 3125R- 60-04-324, Pfizer Inc.
2. Data on file, Study Report No. 3125R- 60-04-318, Pfizer Inc.
3. Data on file, Study Report No. 3121R- 60-05-339, Pfizer Inc.
4. Data on file, Study Report No. 3427R- 60-06-396, Pfizer Inc.
5. Data on file, Study Report No. 3427R- 60-06-397, Pfizer Inc.
6. Data on file, Study Report No. 3427R- 60-06-398, Pfizer Inc.
7. Jódar L, Butler J, Carlone G, et al. Serological criteria for evaluation and licensure of new pneumoccal conjugate vaccine formulations for use in infants. Vaccine 2003;21:3265-72.
8. Plikaytis BD, Carlone GM. Statistical considerations for vaccine immunogenicity trials. Part 2: noninferitority and other statistical approaches to vaccine evaluation. Vaccine 2005; 23:1606-1614.

Further Reading

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March 2008