Scrapie Free Goats at Capralogics

Strategic use of scrapie free donor animals in an international regulatory environment concerned with the control of transmissible spongioform encephalopathies (TSE)

By Stan White
Founder and President of Capralogics, Inc.

Abstract

With the discovery of Bovine Spongiform Encephalopathy (BSE), scientists and regulators were facing a new disease that rapidly infected many parts of the world due to the international transport of infected materials. Research has suggested that scrapie, a disease of sheep and goat, crossed the species barrier and created BSE. Implications for the In Vitro Diagnostic industry were significant. The international use of assays based on antibodies originating from sheep and goats are a mainstay in the industry. Fortunately, scrapie free animals have become available to the IVD industry, thus allowing for the continuation of these successful assays systems while addressing international regulatory concerns of prion based diseases.

Introduction

The link between scrapie, a disease found in goats and sheep, with Bovine Spongiform Encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has had a profound impact on both the agriculture and pharmaceutical industries. As information regarding vCJD has come to light, the impact on industry has grown in proportion. The disease is caused by mutated prions, and is unlike any other disease affecting either humans or domestic animals. In the effort to control the disease, the pharmaceutical industry is impacted in several ways. One effort involves preventing the international spread of this disease followed with the ultimate goal of eliminating the disease. Another effort involves continual risk assessment with regards to the product being imported. In addition, programs that advocate the use of TSE free animals are encouraged. Many diagnostic antibodies used in bio manufacturing worldwide originate from goats or sheep. With research suggesting the presence of scrapie in blood products out, serum and plasma from these animals are seeing increasing scrutiny from an animal health regulatory perspective as they enter the international diagnostic marketplace. Simple strategic solutions acceptable to international regulators and IVD/biopharmaceutical industry include the use of TSE free animals for diagnostics and pharmaceutical purposes.

History and Background of TSE

In 1976, the Nobel Prize for Medicine was awarded to Carleton Gajdusek for research on Kuru. Kuru is a brain wasting disease that was diagnosed in a New Guinea tribe involved with cannibalistic rituals. Later, Stanley Prusiner discovered links between Kuru and other encephalopathies such as Creutzfeldt-Jakob disease (CJD), scrapie and BSE. In 1997, Prusiner earned the Nobel Prize for Medicine for the discovery that a mutated prion that was responsible for these TSE diseases. Prions are unique in that these infectious protein particles can replicate without the presence of nucleic acids. Prions replicate by modifying the shape of adjoining proteins. Once protein reconfirmation is complete, the modified or mutated prion is infective. Though not identified as prion at the time, scrapie was first identified in 1700’s as a fatal disease in sheep and goats. Scrapie would have most likely remained on the backwater of sheep diseases until it was identified as a TSE, thus having very close ties with BSE and the human form, vCJD in humans. BSE was identified in November 1986 in the UK. Though not proven, the regulatory policies adopted are based on a suspected link between scrapie and BSE/vCJD. It is thought the mutated scrapie prion protein (PrP) crossed the species barrier to cattle, thus causing BSE. Once in cattle, the new PrP causing BSE is thought to have cross-species capabilities and be the cause of vCJD. There is also a concern that the BSE PrP might have the ability to cross back to sheep and goats.

Worldwide Impact of TSE

Over the past two centuries, scrapie migrated from the UK throughout the world due the importation of British sheep for agricultural purposes. During the 1980’s, BSE spread throughout the world via transport of infected animal by-products within animal feeds sold internationally. As a result, there was an almost instantaneous human and domestic livestock crisis regards to BSE and vCJD. Countries directly affected include most of Europe, Japan, Israel, Oman and Canada. BSE also had profound regulatory affects with regards to scrapie due to a strong suspicion that BSE’s origin was linked to scrapie.

History of Control of TSE

International health experts and regulators have a philosophical goal of eliminating both scrapie and BSE (thus vCJD) as a pathogen worldwide. The results of these policies had a profound and immediate effect in international commerce of livestock, food and animal products, human therapeutics, diagnostics, and research reagents. These policies are expected to continue and expand.

Initial regulations were concerned with eliminating the direct risk of TSE exposure to humans in the form of food products and therapeutics. This included:

• International bans and containment of animal products and by-products.
• Culling of suspected animals.
• Establishment of international (BSE and scrapie) eradication programs at the farm level.
• Adoption of definitions regarding “BSE free” and “scrapie free”
• Insistence of “TSE free” products for human therapeutics.

Impact on the Biopharmaceutical Industry

Research showed that blood products could be a carrier for TSEs. http://vir.sgmjournals.org/cgi/content/full/83/11/2897 International programs were enacted to reduce and eliminate scrapie and BSE and have impacted the In Vitro Diagnostics industry.

Polyclonal antibody products for the international clinical chemistry market are a multi-million dollar industry. Diagnostic assays developed and approved for international distribution using animal dervied reagents represent an even larger investment. Many diagnostic assays currently used worldwide have reagents of sheep or goat origin. Therefore, the theoretical spread of scrapie from products of sheep or goat origin is a significant problem. Regulatory and R&D costs of developing new diagnostics assays are significant. The industry needs to find an acceptable solution that allows the continued long term use of these diagnostic assays while complying with evolving international standards with regards to TSEs.

The increasing level of regulatory oversight can be chronicled with communications by CBER (Center for Biologics Evaluation and Research).

• May 3, 1991: In a letter to the “Biologic Product Manufacturer(s) from CBER, the following was stated: “We are therefore requesting, pursuant to 21 CFR 206. 31, that manufacturers of biologic products provide information regarding the source (s) and control of any bovine or ovine derived materials(s) used in preparing product to be administered to humans for prophylaxis, therapy, or diagnosis” http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/UCM162857.pdf
• An April 19, 2000 letter to the “Biologic Product Manufacturer (s) from CBER, it was stated that: “CBER strongly recommends that manufacturers take whatever steps are necessary to assure that materials derived from all species of ruminant animals born, raised or slaughtered in countries where BSE is known to exist, or countries where the USDA has been unable to assure FDA that BSE does not exist, are not used in the manufacture of FDA regulated products intended for administration to humans.” It went on to state: “It is the responsibility of the manufacturer to obtain up-to-date information regarding countries where BSE is known to exist, or countries where the USDA has been unable to assure FDA that BSE does not exist.” http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/UCM162938.pdf
• In August 2001, FDA issued guidance to blood collection establishments to reduce the theoretical risk of transmission of vCJD to those who receive blood products. Although there have been no reports of transmission of either the classical forms of CJD or vCJD through blood or blood products, FDA is making these recommendations until more is known about the risk. http://www.bcg-usa.com/regulatory/docs/2001/FDA200108G.pdf
• In February 2003, WHO published: “WHO Guidelines on Transmissible Spongiform Encephalopathies in Relation to Biological and Pharmaceutical Products” and states: “TSE infectivity has been detected in transfused blood of sheep with natural scrapie and with experimental BSE infections. Similar experiments have not been conducted in bovines nor has the effect of blood clot formation on TSE infectivity in serum been established. Studies using smaller amounts of blood components and spleen of cattle with BSE assayed in mice have failed to detect infectivity. A conservative regulatory approach would assume that bovine serum might potentially contain TSE infectivity-presumably in small amounts.” http://www.who..usdaint/bloodproducts/publications/en/WHO_TSE_2003.pdf
• July 14, 2004 [Federal Register Volume 69, Number 134; pages 42255 – 42274: FDA is currently developing a rule for medicinal products (human drugs, biologics, and medical devices, as well as veterinary drugs). It went on to state that they were considering: "Use of closed herds as a source of bovine materials, especially for higher risk materials, when such materials are needed.”

SPF Scrapie Free Animals for Production of IVD Polyclonals

With international consensus regarding the elimination of scrapie, companies are realizing that pre-qualifying animals against scrapie will obviate significant and growing regulatory hurdles, and allow for the continued use of clinical diagnostic assays based on these species.

There are two methods for the determination of a flock’s “scrapie Free” status: Genotype and extensive monitoring.

Genotype: Commercial testing with respect to the mutation of the prion gene, at codons 136 and 171, is available in the United States and other countries. This test is presently available for the commercial industry, but is not recognized by the USDA as the highest level of assurance against scrapie.

Monitoring:

• Country of Origin: The international community and the USDA recognize two countries as “scrapie free”. These are Australia and New Zealand. In both countries, the last reported case of scrapie was in the 1950’s.
• Approved Monitoring Program: The “Scrapie Free Certification Program” from the United States Department of Agriculture is the most comprehensive program for the continued monitoring of a flock’s scrapie status. The program monitors the animals, their environment and flock records for at least 5 years before certification is granted. Once certified, the USDA considers the animals as “scrapie free” with the assurance at the highest international level. http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/free-certi.shtml

In the USA, scrapie free sheep and goats are available. All of the animals are enrolled in the USDA Scrapie Free Certification Program. From the USDA perspective, these animals are interchangeable with animals originating from countries considered “free” of scrapie. Scrapie free animals offer IVD manufacturers a continued source of diagnostic antibodies that without the concerns of increased international regulatory actions or regulatory drift with regards to TSE.

Summary

The international control of scrapie and BSE is altering the definition of an acceptable animal for the pharmaceutical industry. This definition has worked its way from the therapeutic to the diagnostics and research reagents. There is a real concern of directly spreading the disease to people and animals with therapeutic products. The concern with the diagnostics was continued spread of disease due to the international distribution of potentially TSE contaminated products. The advent of more widely available scrapie free animals allows for the continuation of caprine and ovine antibody based diagnostic assays while rising to a new level of international assurance against TSE.