Herd Health Management for Transgenic Goats

A number of transgenic goat herds are now maintained for either research or commercial purposes around the world. These transgenic herds can be used for producing recombi­nant biopharmaceutical proteins in their milk, or for the production of other research/development or commercial products/therapies intended ultimately for use in humans.

The Importance of Establishing and Maintaining a Closed Herd and Specific Pathogen-Free Status

From the perspective of controlling diseases in goats, and particularly in transgenic goats, developing and main­taining a closed herd must be given significant consider - ation. There is no doubt that the number one threat to the spread of disease between goats comes from new introductions of animals into a herd. Additionally, the continued spread of disease within a herd most certainly comes from the infected or carrier animal(s) within a given herd.

Developing a closed herd is not a minor undertaking and must take into consideration a number of factors. First, one must consider the source of the nucleus herd to be derived. This either can be from the original existing herd at a given site/farm or the goats can be obtained from an outside source. This outside source can be a known entity with a defined specific pathogen-free (SPF) population of goats, or these animals can be obtained through the open market, either within one's own country or imported from a known disease-free country. Second, one must consider cost, because this significantly impacts the extent to which one will go to derive a closed SPF herd. Third, the specific dis­eases for which testing is required, the type of testing/ assays that will be performed, and the period of time involved in assembling and testing the animals need to be given appropriate consideration.

A significant amount of disease testing needs to be per­formed on the potential incoming or existing animals to ensure, as well as possible, their disease-free status when developing/starting a closed herd. However, not all diag­nostic tests have 100% sensitivity and specificity. It must be remembered that even the most intensive prescreening program is only a “snapshot” of the animal/herd's disease status and does not ensure that a given animal or herd is negative for certain diseases with long incubation times, such as Johne's disease or CAE. The list of diseases and/or disease agents to be considered in developing an SPF goat herd should include the following, at a minimum:

• Tuberculosis

• Brucellosis

• Caprine arthritis encephalitis

• Mycobacterium avium, subsp. paratuberculosis

(paratuberculosis or Johne's disease)

• Contagious ecthyma (orf)

• Caprine herspesvirus-1 (CapHV-1)

• Coxiella burnetti (Q fever)

• Neospora caninum

• Corynebacterium pseudotuberculosis (caseous lymphadenitis)

Once the closed herd is established, the testing regimen must continue for a specified period of time going forward in order to identify latent or chronic infections such as CAE and Johne's disease, which may have been undetected by initial screening tests, and can take years to become fully established and be serologically or clinically detected (Gavin et al.

Finally, once the closed herd is established, clinical mon­itoring and veterinary evaluations must be aimed at opti­mizing overall herd health, decreasing general morbidity/ mortality, and removing those disease entities that are associated with production environments. Monitoring, detecting, and removing sources or animals that are carri­ers or contributors to clinical entities such as contagious mastitis, foot rot, and certain bacterial or viral pneumonias are early priorities in a closed herd.

Specific Disease Implications for Transgenic

Herds and Product Quality and Safety

For transgenic herds of goats producing recombinant human therapeutic proteins, the list of diseases one may want or need to test for most certainly is more extensive than the minimum set defined above. The rationale for screening for these additional entities is to identify agents that pose zoonotic risks or those that may be produced or detected in the tissue or fluid being used as a source mate­rial for recombinant protein production. There are addi­tional viral- and prion-associated diseases, for example scrapie, that need to be addressed due to the nature of the value-added product these goats are generating in a num­ber of possible fluids or tissues. The following is a brief list of some of the additional viruses or families of viruses that should be considered, depending on the geographic region or emerging opportunistic nature of these entities around the world at any given time:

• Enzootic nasal tumor virus

• Ovine pulmonary adenocarcinoma virus (jaagsiekte)

• Pestivirus (border disease)

• West Nile virus

• Respiratory syncytial virus

• Powassan virus

• Bunyavirus (Cache Valley fever)

Although the full list of potential viral problems may seem never-ending, the best approach to managing these possible threats is to first consider all viral agents that are known to infect goats. Second, address those that are known to be in the geographic locale of the flock or herd.

Also, there are viruses, such as rotavirus and coronavi­rus, that may be manageable within a closed herd because they are typically found in young goats and are not prob­lematic in the adult population from which biologic mate­rials are collected or harvested. This type of decision, as to which viruses will or will not be acceptable within a given herd, must be made on a case-by-case basis according to the nature of the operation, the type of biologic product being produced, and the guidance of regulatory agencies involved, e.g., the United States Department of Agriculture (USDA) and the Food and Drug Administration (FDA).

The Use of Vaccines in Transgenic Goat Herds

While vaccines are an important component of any herd health program, their use in transgenic herds needs to be evaluated carefully. The use of modified live viral vaccines can pose potential regulatory agency challenges to product quality and safety when biopharmaceutical proteins are being produced in biologic fluids such as milk, blood, or serum. Because many vaccines are produced in some form of culture system (egg, mammalian, bacterial, etc.), the vaccine production environment itself poses potential routes of viral/bacterial contamination that must be con­sidered. The use of bovine serum, porcine trypsin, or any other animal-derived materials potentially allows for adventitious agents to inadvertently be introduced ulti­mately into the animals being administered the vaccine. Therefore, strategic use of vaccine(s) during times when the animal is not producing a biologic material for recombinant therapeutic protein production may need to be considered.

Alternatively, the use of killed vaccines (e.g., rabies) or toxins/toxoids (e.g. C. perfringens types C and D and tetanus) offers a slightly higher safety margin from a regulatory agency perspective. However, the use of these products may limit the protective nature of the vaccination so that the fre­quency of administration may need to be modified. Additionally, as with all pharmacologic agents administered to transgenic animals in production, one must consider all the subcomponents (adjuvant, animal-derived materials, etc.) of any vaccine being administered. Particular attention should be given always to final product quality and safety relative to ultimate use in human therapies. Finally, any vac­cines to be used within a closed transgenic herd must come from approved and reputable manufacturers and sources and should have appropriate documentation upon receipt.

The Use of Veterinary Medications in Transgenic Goat Herds

Any and all pharmacologic or medicinal agents used in the course of either preventive or clinical herd health manage­ment must be carefully considered and even scrutinized before use in transgenic goat populations. A thorough understanding of all the components within these products is critical to avoid administering something to a goat that could negatively impact any biologic material being pro- duced/collected from the animal. One must consider the potential for adventitious agents (viral or bacterial) inadvert­ently being administered. There have been a number of his­torical cases in which this has happened in goat herds or other animals, with significant detrimental effects to the ani­mals, or the loss of product from those animals due to