Saturday, December 3, 2011

Candidate Cell Substrates, Vaccine Production, and Transmissible Spongiform Encephalopathies

Volume 17, Number 12—December 2011

Research

Candidate Cell Substrates, Vaccine Production, and Transmissible Spongiform Encephalopathies



Pedro Piccardo , Larisa Cervenakova, Irina Vasilyeva, Oksana Yakovleva, Igor Bacik, Juraj Cervenak, Carroll McKenzie, Lubica Kurillova, Luisa Gregori, Kitty Pomeroy, and David M. Asher


Author affiliations: University of Edinburgh, Easter Bush, UK, (P. Piccardo); Food and Drug Administration, Kensington, Maryland, USA (P. Piccardo, I. Bacik, J. Cervenak, L. Kurillova, L. Gregori, K. Pomeroy, D.M. Asher); Holland Laboratory American Red Cross, Rockville, Maryland, USA (L. Cervenakova, I. Vasilyeva, O. Yakovleva, C. McKenzie)



Abstract

Transmissible spongiform encephalopathy (TSE) agents have contaminated human tissue–derived medical products, human blood components, and animal vaccines. The objective of this study was to determine the potential susceptibility to infection of 5 cell lines used or proposed for manufacture of biological products, as well as other lines. Cell lines were exposed to the infectious agents of sporadic and variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy (BSE). Exposed cultures were tested for TSE-associated prion protein (PrPTSE) and TSE infectivity by assay in rodents and nonhuman primates. No PrPTSE or infectivity has been detected in any exposed cell line under study so far. Animals inoculated with BSE brain homogenate developed typical spongiform encephalopathy. In contrast, animals inoculated with cells exposed to the BSE agent remained asymptomatic. All cell lines we studied resisted infection with 3 TSE agents, including the BSE agent.





Transmissible spongiform encephalopathies (TSEs or prion diseases) are a heterogeneous group of fatal neurodegenerative diseases that affect animals and humans. TSEs can be sporadic, transmitted iatrogenically, or expressed as familial disorders. TSEs include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in cervid ruminants, and mink encephalopathy. In humans the most common TSEs are sporadic, familial, and variant Creutzfeldt-Jakob disease (sCJD, fCJD, and vCJD, respectively). TSEs are characterized by the accumulation in the central nervous system and, less often, in lymphoid tissues of TSE-associated prion protein (PrPTSE), a conformational variant of a normal host cellular prion protein (PrPC). PrPC is a nonessential protein but, at least in mice and cows, must be expressed by animals susceptible to TSE infection. There is compelling evidence that the BSE agent has infected humans, causing vCJD. Most cases of vCJD are attributed to exposure to contaminated beef products (1–3). In addition, vCJD infections have been transmitted by transfusions of nonleukoreduced erythrocyte concentrates and by a human-derived coagulation factor (factor VIII) (4–6).

The conclusion that PrPTSE is central to the pathogenesis of TSE is based o



n the temporal and anatomic correlations between accumulation of PrPTSE and the development of pathologic changes in tissues of the central nervous system (1). However, TSEs can develop in the absence of detectable PrPTSE and, conversely, PrPTSE might accumulate without causing either clinical illness or the neuropathologic alterations typical of TSEs (i.e., a progressive fatal illness with spongiform degeneration of the brain) (7,8). In short, the molecular basis of TSE infection and the role of PrPTSE (unquestionably important in pathogenesis of TSEs) are not yet entirely clear, and both remain key issues in TSE research (9,10). The standard assay for detecting a TSE agent remains bioassay in susceptible animals.





Many investigators once believed that TSE agents infected mainly, if not exclusively, cells of neuronal and lymphoid lineages. It has become clear, however, that the susceptibility of cells to infection with TSE agents cannot be reliably predicted either from their tissue of origin or level of expression of PrPC (11,12). Studies showing that murine fibroblast cell lines are susceptible to infection with mouse-adapted scrapie agent (11,12) increased concern that nonneuronal cell substrates used to propagate viruses for vaccine production might become infected with a TSE agent contaminating some component of culture medium, especially bovine serum (13). The theoretical risk of contaminating vaccines or other biologic products prepared in culture cells with TSE agents from animal-derived materials in media has been considered low. However, 1) as noted above, the blood of asymptomatic humans has transmitted vCJD, and 2) in a variety of experimentally TSE-infected animals, TSE agent has been detected in blood, mainly in nucleated cells and plasma (4–6,14–17). Fortunately, no human vaccine has ever been implicated as a source of iatrogenic TSE. However, 2 animal tissue–derived vaccines have caused outbreaks of scrapie in sheep, and 2 medical products of human origin—dura mater allograft and human cadaveric pituitary hormones (no longer marketed in the United States)—have transmitted hundreds of cases of CJD; corneal grafts have transmitted a few cases as well (2,18). Since 1993, the US Food and Drug Administration has recommended against the use in the manufacture of biological products of bovine-derived materials from countries identified by the US Department of Agriculture (USDA) as having BSE or being at increased risk for BSE in native cattle (19).





The recognition of >20 BSE cases in North America since 2003 (most in Canada) has increased the need to determine whether cell substrates that might be accidentally exposed to the BSE agent are capable of acquiring and propagating the infectious agent and potentially transmitting infections to vaccine recipients (20). To address these issues, we investigated the susceptibility of cell lines used or proposed for manufacture of biologics and controls to propagate TSE agents, especially the BSE agent, under simulated worst-case conditions.





snip...





Results


TSE in TgBo Mice and Primates Inoculated with BSE agent


Neuropathologic characterization of TgBo mice inoculated with BSE agent showed spongiform degeneration in the cerebrum with variable amounts of fine-punctate, coarse, and, in some cases, plaque-like deposits in the cerebrum, cerebellum, and brain stem. Mice inoculated with the bacteria-free filtrate of 1% BSE-infected brain suspension used to expose cells also developed signs of TSE, and PrPTSE was detected in brains, demonstrating that the inoculum used to expose cell cultures contained a TSE agent transmissible to mice (Figure 1).



Figure 2


Histopathologic analysis of squirrel monkey inoculated with bovine spongiform encephalopathy agent (A, B). Spongiform degeneration in the cerebral cortex (A), adjacent section showing abundant prion protein (PrP) immunopositivity (B). Squirrel monkey...





Squirrel monkeys were inoculated with serial dilutions of the same material used to inoculate TgBo mice. At the time this report was written, 6 monkeys have already developed neurologic signs typical of TSE. Three animals inoculated with 10–1 (10%) unfiltered low-speed clarified BSE reference material became ill and were euthanized ≈3.2 years after inoculation; 2 primates inoculated with 10–2 unfiltered, low speed–clarified BSE suspension were euthanized 3.7 years after inoculation; and 1 primate inoculated with the 0.45-μm filtered bacteria-free 10–2 (1%) BSE-infected brain suspension used to expose cells also developed signs of TSE and was euthanized 3.3 years after inoculation. Brain extracts from each of these monkeys contained PrPTSE demonstrated by WB. Preliminary neuropathologic studies of formalin-fixed paraffin-embedded brain sections of each of the 6 animals showed severe spongiform degeneration of the cerebrum, cerebellum, and brainstem. Immunohistochemical studies showed widespread accumulations of PrP-immunopositive deposits throughout the brain of each monkey (Figure 2). Control brains from 4 other squirrel monkeys dying of nonneurologic diseases, including 1 housed with monkeys used to titrate BSE agent, showed no evidence of TSE (Figure 2). A detailed neuropathologic report of all monkeys is in press (22).





Attempts to Infect Actual or Candidate Cell Substrates


Analysis of Cell Cultures and Bioassay in Rodents


Figure 3



Western blot of recombinant prion protein (PrP) 5 ng (lane 1), CHO cells (lanes 2–5) and Vero cell (lanes 6–9). Cells exposed to normal bovine brain and passaged 30 times (lanes...





No PrPTSE was detected in cells exposed to normal brain extracts (controls) or after passage 5 in any of the cell substrates or control TSE-resistant cells exposed to brain extracts containing TSE agents. PrPTSE was detected in some samples of cells collected 96 h after inoculation (passage 0), suggesting the probable presence of residual inoculum. The consistent failure to detect PrPTSE in any cell line exposed to TSE agents after >5 passages suggests that proteinase K–resistant PrP was not generated de novo under these experimental conditions. WB analyses of cells collected after 30 serial passages showed no detectable PrPTSE in any cell line (Figure 3). Samples of each cell line exposed to human TSE agents (sCJD, vCJD) and BSE agent were expanded after 30 passages for bioassay in TgHu and TgBo mice. At the time of this report, no mice inoculated with cells exposed to TSE agent have evidence of TSE illness during their expected lifespan (Table 2, Table 3). WB with extracts of brain tissue from all culled animals showed no PrPTSE. Neuropathologic analyses of selected mouse brains found no spongiform encephalopathy or accumulations of PrP (data not shown). The results confirm that no cell substrate propagated infectivity detectable by mouse bioassay, even when mice were observed for their expected lifespan.





Nonhuman Primate Bioassay


Lysates of Vero, CHO, WI-38, and R9ab cells exposed to BSE agent and passaged 30 times were inoculated into squirrel monkeys in May 2006. Lysates of MDCK and HEK-293 cells exposed to BSE agent and passaged 30 times were inoculated into squirrel monkeys in August 2007. No monkey inoculated with those cells had neurologic signs. One monkey inoculated with Vero cells exposed to the BSE agent was attacked by a cage mate; the wound became infected, suppuration increased despite treatment with antimicrobial drugs, and the injured monkey was euthanized several days later without ever showing any sign of neurologic disease. The brain showed no neuropathologic changes of TSE or PrPTSE by WB (data not shown). In contrast, as noted above, primates inoculated with Swiss Reference BSE brain extracts at 10–1 and 10–2 dilutions developed typical TSE confirmed by neuropathologic results (Figure 2) and by WB (not shown). These results indicate that 1) squirrel monkeys are susceptible to infection with the BSE agent, and 2) BSE infectivity was present in the bacteria-free filtrate used to expose cell substrates.





Murine Fibroblast Cell lines Generate PrPTSE after Exposure to Mouse-adapted Scrapie Agent


Figure 4



Western blot of brain extract from C57/Bl mouse inoculated with 22L mouse-adapted scrapie agent (lanes 1, 2); NIH-3T3 cells exposed to normal mouse brain and passaged 30 times (lane 3); NIH-3T3...


Several murine tissue cultures have been successfully infected with TSE agents, providing a promising alternative to assays of TSE agents by time-consuming and expensive bioassays in animals (9,11,12,23–28). Previous studies reported that several commonly used mouse fibroblast cell lines can be efficiently infected with the scrapie agent and support formation of PrPTSE (11). We studied 2 such cell lines as a positive control to confirm that our protocol would have detected an infected cell line and that our failures to find PrPTSE or infectivity by bioassay in cell substrates exposed to the BSE agent were more likely to have resulted from an intrinsic resistance of the cells to infection rather than to some technical problem. We exposed monolayers of NIH-3T3 and L929 murine fibroblast cells to the mouse-adapted 22L strain of scrapie agent and observed the formation of readily detectable PrPTSE that persisted through 30 passages (Figure 4). We are performing bioassays of the PrPTSE-positive cells in C57/BL6 mice to determine amounts of infectivity. Several mice inoculated with samples of NIH-3T3 and L929 fibroblasts collected 30 passages after exposure to 22L mouse-adapted scrapie agent have already developed spongiform encephalopathy, confirming that the agent was successfully propagated in vitro (unpub. data).





Discussion


Candidate cell substrates used to produce biologics were not infected by a simulated worst-case exposure to BSE agent. Similar more limited studies exposing the same cultures to vCJD and sCJD agents also gave negative results.

The finding of PrPTSE in several cell culture samples collected at passages 0–4 probably resulted from small amounts of residual inoculum. This conclusion is reinforced by our consistent failure to detect PrPTSE in any cell sample at or after passage 5. However, we cannot rule out the possibility of a transient de novo generation of PrPTSE in the earliest passages of the cultures. Other investigators (23) have shown some immediate (acute) formation of new PrPTSE in infection-resistant cell cultures exposed to scrapie agent; the new PrP formed did not depend upon the strain of TSE agent used or cell type involved and was not associated with infectivity (23). Whether the failure of infectivity to persist after transient formation of PrPTSE resulted from death of the infected cells or the dilution of a small amount of TSE agent is unknown. We recognized no overt cytotoxicity in any cell line inoculated with a TSE-infected brain suspension. Thus, our data so far suggest that several cell substrates actually or potentially used to produce biologics were not susceptible to the propagation of TSE agents under the experimental conditions we used. In agreement with these results, others showed that MDCK cells were refractory to infection with human and mouse TSE agents (24). MRC5 human diploid cells also failed to support the replication of a TSE agent (25).





Because bioassays are time-consuming and expensive, a few lines of cells susceptible to infection with certain strains of TSE agent have been derived (9,11,12,26–30). However, for unknown reasons, most cell lines have resisted TSE infections. In addition, most cell lines infectable with TSE agents have been highly heterogeneous and not stable, requiring repeated subcloning of susceptible cells, and they have been successfully infected with only a few strains of TSE agent (27). Thus, it was vital to verify that the protocol we chose as a simulated worst-case model would successfully infect previously characterized cell lines with a TSE agent to which they were known to be susceptible. We demonstrated that the protocol we used was valid by persistently infecting 2 murine fibroblast cell lines with a mouse-adapted scrapie agent. However, we must caution that even cell lines susceptible to infection have shown widely different responses when exposed to various TSE agent strains (27). Furthermore, the emergence of atypical forms of BSE raises a new concern, i.e., that cell substrates resistant to infection with the original classic BSE agent (31) might not resist infection with newer strains of BSE agent (if new strains are implicated in atypical BSE).





Although BSE has been transmitted to many animal species, the efficiency of transmission between species has been difficult to predict. Low transmission rates and long incubation periods are often observed when TSEs are transmitted to a new species—commonly known as a species barrier (32)—but experience with squirrel monkeys (sensitive to almost all TSE agents affecting humans and to several animal TSEs as well) suggests that they are an especially useful model species (33). To that end we initiated titration experiments of the BSE agent and found at the time of writing this report that squirrel monkeys develop TSE when inoculated with BSE brain suspensions at high concentration 10–1 and 10–2 dilutions (work in progress). Given the long incubation time (years) needed to elicit disease in this primate model, we will continue the observation of monkeys inoculated with cell cultures exposed to the BSE agent in an attempt to determine whether low infectivity could potentially be detected in this model.





Because few cell lines used as substrates for biologics are of bovine origin, it is tempting to speculate that the potential for contaminating biologics with the BSE agent is low. However, an observation that cells derived from a pheochromocytoma of the rat adrenal medulla (PC12 cells) could be infected with a mouse-adapted scrapie agent and murine hypothalamic cells with a human TSE agent demonstrates that cross-species transmissions of TSE agents in cells in culture are possible (29). Recent studies showed that passage of TSE agents through different animal species altered key characteristics of the agent, sometimes producing variants with increased virulence or broader host range, as happened when BSE agent was passaged through sheep (34). Thus, further experiments are needed to evaluate the potential susceptibility of various cultured cell lines to infection with new emerging TSE strains.





Dr Piccardo is Senior Investigator in the Laboratory of Bacterial and TSE Agents, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, and professor in the Neuropathogenesis Division, The Roslin Institute, University of Edinburgh, UK. His research interest is in the pathogenesis of TSE and other neurodegenerative diseases.



snip...



see full text ;





http://wwwnc.cdc.gov/eid/article/17/12/11-0607_article.htm





PPo3-9: Potential of Cell Substrates used for Production of Biologics to Propagate Transmissible Spongiform Encephalopathy (TSE) Agents: 5-year Update



P. Piccardo,1,* L. Cervenakova,2 I. Vasilyeva,2 O. Yakovleva,2 I. Bacik,1 J. Cervenak,1 L. Gregori,1 K. Pomeroy,1 L. Kurillova,1 C. McKenzie2 and D.M. Asher1



1Laboratory of Bacterial and TSE Agents; CBER; FDA; USA; 2J. Holland Laboratory; American Red Cross; USA



*Presenting Author



Key words: cell culture, animal models, biologics, prion, TSE-agent



Background. TSE agents have contaminated human-tissue-derived therapeutics and animal vaccines. Many biologics are prepared in cell cultures. Although most cultures studied resisted infection with TSE agents, a few were susceptible.



Objectives. We are investigating susceptibility of several cell lines to infection with TSE agents.



Results. We studied Vero, CHO, MDCK, HEK-393 and WI-38 cells. We also studied SH-SY5Y cells overexpressing wild-type PrP and mutant PrPs. Cells exposed to TSE agents were serially propagated for 30 passages and samples tested for TSE-associated PrP (PrPTSE) and infectivity by intracerebral inoculation into transgenic mice and squirrel monkeys (BSE-exposed cells only). No exposed cell substrate has transmitted TSE to mice or monkeys to date. No PrPTSE was found in any exposed cells after 30 passages. Known susceptible murine cells exposed to mouse-adapted scrapie agent as positive controls accumulated PrPTSE. Three monkeys inoculated with BSE reference material have developed TSE to date.



Discussion. To date, no candidate cell substrate exposed to 3 TSE agents accumulated PrPTSE or propagated a TSE agent. Squirrel monkeys provide a new model to study BSE pathogenesis.



Methods. We inoculated brain suspensions containing agents of bovine spongiform encephalopathy (BSE), variant Creutzfeldt-Jakob disease (vCJD) or sporadic CJD into several cell lines important in manufacture of biologics. Serial dilutions of the BSE reference material used as inoculum were also inoculated into mice and squirrel monkeys.



The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Administration determination or policy.



Acknowledgements



Support. NIAID-NIH AI-4893-02/FDA 224-05-1307





International Prion Congress: From agent to disease



September 8–11, 2010



Salzburg, Austria



PRION



Volume4 Issue3July/August/September 2010



www.landesbioscience.com/journals/prion




http://www.prion2010.org/online/page.php?P=34





Tuesday, February 8, 2011




U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001





Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001





Date: Tue, 9 Jan 2001 16:49:00 -0800





From: "Terry S. Singeltary Sr."





Reply-To: Bovine Spongiform Encephalopathy





To: BSE-L@uni-karlsruhe.de







######### Bovine Spongiform Encephalopathy #########







Greetings List Members,





I was lucky enough to sit in on this BSE conference call today and even managed to ask a question. that is when the trouble started.





I submitted a version of my notes to Sandra Blakeslee of the New York Times, whom seemed very upset, and rightly so.





"They tell me it is a closed meeting and they will release whatever information they deem fit. Rather infuriating."





and i would have been doing just fine, until i asked my question. i was surprised my time to ask a question so quick.





(understand, these are taken from my notes for now. the spelling of names and such could be off.)





[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.





[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?





[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]





[host Richard] could you repeat the question?





[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?





[not sure whom ask this] what group are you with?





[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.





[not sure who is speaking] could you please disconnect Mr. Singeltary





[TSS] you are not going to answer my question?





[not sure whom speaking] NO





from this point, i was still connected, got to listen and tape the whole conference. at one point someone came on, a woman, and ask again;





[unknown woman] what group are you with?





[TSS] CJD Watch and my Mom died from hvCJD we are trying to tract down CJD and other human TSE's world wide. i was invited to sit in on this from someone inside the USDA/APHIS and that is why i am here. do you intend on banning me from this conference now?





at this point the conference was turned back up, and i got to finish listening. They never answered or even addressed my one question, or even addressed the issue. BUT, i will try and give you a run-down for now, of the conference.





IF i were another Country, I would take heed to my notes, BUT PLEASE do not depend on them. ask for transcript from;





RBARNS@ORA.FDA.GOV 301-827-6906





he would be glad to give you one ;-)





Rockville Maryland, Richard Barns Host





BSE issues in the U.S., How they were labelling ruminant feed? Revising issues.





The conference opened up with the explaining of the U.K. BSE epidemic winding down with about 30 cases a week.





although new cases in other countries were now appearing.





Look at Germany whom said NO BSE and now have BSE.





BSE increasing across Europe.





Because of Temporary Ban on certain rendered product, heightened interest in U.S.





A recent statement in Washington Post, said the New Administration (old GW) has a list of issues. BSE is one of the issues.





BSE Risk is still low, minimal in U.S. with a greater interest in MBM not to enter U.S.





HOWEVER, if BSE were to enter the U.S. it would be economically disastrous to the render, feed, cattle, industries, and for human health.





(human health-they just threw that in cause i was listening. I will now jot down some figures in which they told you, 'no need to write them down'. just hope i have them correct. hmmm, maybe i hope i don't ???)





80% inspection of rendering





*Problem-Complete coverage of rendering HAS NOT occurred.





sizeable number of 1st time FAILED INITIAL INSPECTION, have not been reinspected (70% to 80%).





Compliance critical, Compliance poor in U.K. and other European Firms.





Gloria Dunason Major Assignment 1998 goal TOTAL compliance. This _did not_ occur. Mixed level of compliance, depending on firm.





Rendering FDA license and NON FDA license





system in place for home rendering & feed 76% in compliance 79% cross contamination 21% DID NOT have system 92% record keeping less than 60% total compliance





279 inspectors 185 handling prohibited materials





Renderer at top of pyramid, significant part of compliance. 84% compliance





failed to have caution statement render 72% compliance & cross contamination caution statement on feed, 'DO NOT FEED TO CATTLE'





56 FIRMS NEVER INSPECTED





1240 FDA license feed mills 846 inspected





"close to 400 feed mills have not been inspected"





80% compliance for feed.





10% don't have system.





NON-FDA licensed mills There is NO inventory on non licensed mills. approximately 6000 to 8000 Firms ??? 4,344 ever inspected. "FDA does not have a lot of experience with"





40% do NOT have caution statement 'DO NOT FEED'.





74% Commingling compliance





"This industry needs a lot of work and only half gotten to"





"700 Firms that were falitive, and need to be re-inspected, in addition to the 8,000 Firms."





Quote to do BSE inspection in 19 states by end of January or 30 days, and other states 60 days. to change feed status??? Contract check and ask questions and pass info.





At this time, we will take questions.





[I was about the third or fourth to ask question. then all B.S.eee broke loose, and i lost my train of thought for a few minutes. picked back up here]





someone asking about nutritional supplements and sourcing, did not get name. something about inspectors not knowing of BSE risk??? the conference person assuring that Steve Follum? and the TSE advisory Committee were handling that.





Some other Dr. Vet, whom were asking questions that did not know what to do???





[Dennis Wilson] California Food Agr. Imports, are they looking at imports?





[Conference person] they are looking at imports, FDA issued imports Bulletin.





[Linda Singeltary ??? this was a another phone in question, not related i don't think] Why do we have non-licensed facilities?





(conference person) other feed mills do not handle as potent drugs???





Dennis Blank, Ken Jackson licensed 400 non FDA 4400 inspected of a total of 6000 to 8000, (they really don't know how many non licensed Firms in U.S. they guess 6000 to 8000??? TSS)





Linda Detwiler asking everyone (me) not to use emergency BSE number, unless last resort. (i thought of calling them today, and reporting the whole damn U.S. cattle herd ;-) 'not'





Warren-Maryland Dept. Agr. Prudent to re-inspect after 3 years. concerned of Firms that have changed owners.





THE END





TSS





############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############





snip...see full text and more here on tissue donor herds and the TSE Prion disease ;




http://tseac.blogspot.com/2011/02/usa-50-state-bse-mad-cow-conference.html





Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America

14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America

update October 2009

T. Singeltary

Bacliff, TX, USA

Background:

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

Methods:

12 years independent research of available data

Results:

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

Conclusion:

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

page 114 ;




http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf






International Society for Infectious Diseases Web: http://www.isid.org/




please see full text ;



http://transmissiblespongiformencephalopathy.blogspot.com/






To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.



http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2




Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed. ***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat

snip...



http://www.neuroprion.org/en/np-neuroprion.html






Saturday, June 25, 2011

Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque


"BSE-L in North America may have existed for decades"


http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/transmissibility-of-bse-l-and-cattle.html





Sunday, June 26, 2011

Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/risk-analysis-of-low-dose-prion.html





Thursday, June 23, 2011

Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/experimental-h-type-bovine-spongiform.html




Wednesday, July 06, 2011

Swine Are Susceptible to Chronic Wasting Disease by Intracerebral Inoculation



(see tonnage of mad cow feed in commerce USA...tss)


http://chronic-wasting-disease.blogspot.com/2011/07/swine-are-susceptible-to-chronic.html




Monday, June 27, 2011


Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates


http://chronic-wasting-disease.blogspot.com/2011/06/zoonotic-potential-of-cwd-experimental.html





Saturday, December 3, 2011



Isolation of Prion with BSE Properties from Farmed Goat


Volume 17, Number 12—December 2011



http://transmissiblespongiformencephalopathy.blogspot.com/2011/12/isolation-of-prion-with-bse-properties.html






Thursday, August 4, 2011

Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis, Date aired: 27 Jun 2011

(SEE VIDEO)


http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/terry-singeltary-sr-on-creutzfeldt.html





Sunday, August 21, 2011

The British disease, or a disease gone global, The TSE Prion Disease


(SEE VIDEO)



http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/british-disease-or-disease-gone-global.html




Saturday, March 5, 2011

MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA



http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/mad-cow-atypical-cjd-prion-tse-cases.html





http://transmissiblespongiformencephalopathy.blogspot.com/




Sunday, May 18, 2008

MAD COW DISEASE BSE CJD CHILDREN VACCINES

Sunday, May 18, 2008


MAD COW DISEASE BSE CJD CHILDREN VACCINES


TIP740203/l 0424 CONFIDENTIAL


http://www.mad-cow.org/00/may00_news.html#aaa





TWA LITTLE minute

2. We have identified one problem over where we are unable to act and this is the use of gonadotrophins in embryo transfer work. Some veterinary surgeons are quite legally using this exemption from the Medicines Act contained in Section 9(2) to prepare gonadotrophins from pituitary glands from various species, including cattle. These hormones are used to stimulate superovulation in donor cows.



http://collections.europarchive.org/tna/20080102164806/http://www.bseinquiry.gov.uk/files/yb/1988/06/10001001.pdf





http://collections.europarchive.org/tna/20080102164811/http://www.bseinquiry.gov.uk/files/yb/1988/06/13010001.pdf





http://collections.europarchive.org/tna/20080103031215/http://www.bseinquiry.gov.uk/files/yb/1988/06/14006001.pdf






COMMERCIAL IN CONFIDENCE

3.2 Minute 5.3 - 5.4 Bovine Spongiform Encephalopathy

It was reported that some replies had been received from Companies using pituitary glands in their products. Copies of the BSE document had also been sent to DHSS and NIBSC.

and then another 3 + pages of blank space. ...TSS



http://collections.europarchive.org/tna/20080102164813/http://www.bseinquiry.gov.uk/files/yb/1988/09/06005001.pdf





COMMERCIAL IN CONFIDENCE


BSE - CURRENT POSITION WITH VETERINARY LICENCED PRODUCTS (MA.1968)

There are three areas of particular concern, vaccines (including emergency vaccines), pharmaceuticals which are covered by MA licences and unlicenses hormonal products produced under exemptions claimed under (Section 9(2) Medicines Act).

1) Vaccines


http://collections.europarchive.org/tna/20080103033809/http://www.bseinquiry.gov.uk/files/yb/1988/10/06005001.pdf




NOT FOR PUBLICATION

another 6 pages of blank space. ...TSS



http://collections.europarchive.org/tna/20080103032658/http://www.bseinquiry.gov.uk/files/yb/1988/11/01012001.pdf



http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf



http://collections.europarchive.org/tna/20080103033926/http://www.bseinquiry.gov.uk/files/yb/1988/04/00007001.pdf




COMMERCIAL IN CONFIDENCE



http://collections.europarchive.org/tna/20080103034137/http://www.bseinquiry.gov.uk/files/yb/1988/07/00007001.pdf





COMMERCIAL IN CONFIDENCE

Medicines Act - Veterinary Products Committee


http://collections.europarchive.org/tna/20080103034140/http://www.bseinquiry.gov.uk/files/yb/1988/09/00004001.pdf





COMMERCIAL IN CONFIDENCE



http://collections.europarchive.org/tna/20080102164744/http://www.bseinquiry.gov.uk/files/yb/1988/10/00003001.pdf





MANAGEMENT IN CONFIDENCE

CERTIFIED BSE-FREE HERDS FOR SOURCE OF MATERIAL FOR BIOLOGICAL PRODUCTS



http://collections.europarchive.org/tna/20080102184729/http://www.bseinquiry.gov.uk/files/yb/1989/01/04001001.pdf






COMMERCIAL IN CONFIDENCE


NOT FOR PUBLICATION


http://collections.europarchive.org/tna/20080102185137/http://www.bseinquiry.gov.uk/files/yb/1989/01/26007001.pdf





http://web.archive.org/web/20030515185220/http://www.bseinquiry.gov.uk/files/yb/1989/01/30001001.pdf




COMMERCIAL IN CONFIDENCE

NOT FOR PUBLICATION


http://web.archive.org/web/20030704202503/http://www.bseinquiry.gov.uk/files/yb/1989/09/06011001.pdf




NON-LICENSED HUMAN TISSUE DEVICES WERE NOT COMMERCIALLY AVAILABLE

snip...

I was quite prepared to believe in unofficial pituitary hormones, also in the 1970's, whether as described by Dr. Little, or in other circumstances, for animal use.

snip...

The fact that there were jars of pituitaries (or extract) around on shelves is attested by the still potent 1943 pituitaries, described in Stockell Hartree et al. (J/RF/17/291) which had come from the lab. at Mill Hill. Having taken the trouble to collect them, they were not lightly thrown out...



http://collections.europarchive.org/tna/20090114045856/http://www.bseinquiry.gov.uk/files/ws/s467bx.pdf




more on the 1968 medicine act, they forgot to follow i.e. no Scrapie-like disease. ...TSS



http://web.archive.org/web/20030526124448/http://www.bseinquiry.gov.uk/files/yb/1989/01/30008001.pdf




Draft cover letter to product licence holders (considered by Human and Vet Medicines including deer)

CONCERN ABOUT BSE IN HUMAN MEDICINE


http://collections.europarchive.org/tna/20080103002832/http://www.bseinquiry.gov.uk/files/yb/1989/02/22008001.pdf




http://collections.europarchive.org/tna/20081105201818/http://www.bseinquiry.gov.uk/files/yb/1989/02/22011001.pdf




(It was noted with concern that hormone extracts could be manufactured by a veterinary surgeon for administration to animals under his care without any Medicines Act Control.)


http://collections.europarchive.org/tna/20080102164725/http://www.bseinquiry.gov.uk/files/yb/1988/06/08011001.pdf






http://collections.europarchive.org/tna/20090505223756/http://www.bseinquiry.gov.uk/files/yb/1988/06/08011001.pdf





COMMERCIAL IN CONFIDENCE



http://collections.europarchive.org/tna/20080102164736/http://www.bseinquiry.gov.uk/files/yb/1988/06/07010001.pdf





TWA LITTLE STATEMENT 331


http://collections.europarchive.org/tna/20080102163939/http://www.bseinquiry.gov.uk/files/ws/s331.pdf




snip...


http://www.fda.gov/ohrms/dockets/dailys/03/Mar03/031403/96N-0417-EC-2.htm


http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf




8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).



CONFIDENTIAL


http://collections.europarchive.org/tna/20080102164642/http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf





From: TSS

Subject: How many NHS patients as having received blood from a donor who later developed vCJD were people with haemophilia

Date: December 21, 2006 at 9:13 am PST

Health: vCJD Lord Morris of Manchester asked Her Majesty's Government:

How many NHS patients identified by the National Blood Service as having received blood from a donor who later developed vCJD were people with haemophilia. [HL750]

19 Dec 2006 : Column WA291

The Minister of State, Department of Health (Lord Warner): No patient with haemophilia or other bleeding disorders have been identified as having received blood from a blood donor who subsequently developed vCJD, nor have there been any reported cases of vCJD associated with receipt of plasma products.

However, all haemophilia patients who received plasma products between 1980 and 2001 sourced from UK donor plasma have been designated as "at risk of vCJD for public purposes". All plasma products are now sourced from non-UK plasma. The United Kingdom Haemophilia Centre Doctors' Organisation is collecting data that will provide an estimate of the number of haemophilia patients who have been exposed to plasma products which may be implicated with vCJD.

Lord Morris of Manchester asked Her Majesty's Government:

What is their response to the findings of Professor John Collinge in the December 2006 edition of the Lancet on the transmission by infected blood of variant CJD; and what action they are planning to take. [HL751]

Lord Warner: The Lancet article refers to the third known case of vCJD transmission via blood transfusion from a vCJD-infected donor. This case was originally notified to the department in January 2006 and announced by the Health Protection Agency in a press release on 9 February 2006, a copy of which has been placed in the Library.

There are 24 living patients in a group of people who had received blood components from donors subsequently known to have developed vCJD. They were all notified in 2005 or earlier, through their GPs, of their risk status and have been provided with information and support. The Health Protection Agency contacted the GPs earlier in the year to notify them of this third case and the agency has ensured that the GPs are fully informed and briefed about the subsequent Lancet publication.

The department has implemented a series of measures to reduce the risk of vCJD being transmitted through the blood supply. Shortly after vCJD was first identified in 1996, the possibility of human-to-human transmission through blood was considered, and the department implemented precautionary measures to reduce what was, at that time, a theoretical risk. These measures have been strengthened since evidence of transmission via blood began to emerge from animal studies, and following the first case of transfusion-associated transmission in humans, reported in December 2003. An important additional step, introduced in March 2004, was to exclude from blood donation those people who had themselves received a blood transfusion since January 1980. Other precautionary measures include:

from December 1997, blood components, plasma products or tissues obtained from any individual who later develops vCJD, were withdrawn/recalled;

19 Dec 2006 : Column WA292

in July 1998, it was announced that plasma for the manufacture of blood products, such as clotting factors, would be obtained from non-UK sources;from November 1999, white blood cells, which may carry a significant risk of transmitting vCJD, were removed from all blood used for transfusion;in August 2002, it was announced that fresh frozen plasma for treating babies and young children born on or after 1 January 1996 would be obtained from the USA; in July 2004, the exclusion criteria for blood donation were extended to include previously transfused platelet donors, and donors who were unsure if they had previously had a blood transfusion;in September 2004, the department announced further precautionary measures for patients who had received certain batches of plasma products;in July 2005, the use of USA-sourced fresh frozen plasma was extended to all children up to the age of 16;in July 2005, the department announced further precautionary measures for those patients who donated blood to three people who later developed vCJD. The department continues to keep all the evidence in relation to transmission of vCJD by blood under close review.


http://www.publications.parliament.uk/pa/ld200607/ldhansrd/text/61219w0004.htm#06121940000034




http://www.whale.to/v/singeltary7.html






Subject: Re: VACCINES/CHILDREN/TSE'S -- 'CONFIDENTIAL'

Date: Wed, 6 Sep 2000 18:20:09 -0800

From: tom

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de References: 1

######### Bovine Spongiform Encephalopathy #########

Just when I was thinking the Internet had reached a terminal condition of shallow pages and broken links, some young people come along and invent a really effective Internet search engine: http://www.google.com/ This works quite well to search the entire http://www.mad-cow.org site (or find 393 web sites such as GenBank that link to it, or 936 sites that cite it in text) back to 1996 as well as the BSE Inquiry http://www.bse.org.uk/

Thus for louping ill (unnecessary cites suppressed):

http://www.bse.org.uk/witness/htm/stat537.htm


Witness Statements 537 - Coulthard

29.Pituitary FSH from pigs has been used in the USA prior to its use in the UK and much more extensively there and Canada.... 30.Thousands of embryos were exported from this country to the USA prior to the ban being imposed... 42. No cow pituitaries were used in the preparation of FSH [follicular stimulating hormone] products compared with the case of louping ill vaccine for scrapie.

http://www.mad-cow.org/~tom/fda_late.html#ill



In the 1930's: 18,000 UK sheep were inoculated against louping ill, a brain inflammatory illness spread by ticks. Despite formalin-treatment of the inoculated agent, the procedure gave rise to 1,500 cases of scrapie. Louping is a Scottish word for fleeing or leaping, related to loping. In humans, louping ill is called Russian spring-summer encephalitis, a meningo-encephalitis with muscular tremors and spasms followed by varying degrees of paralysis.... [John Lanchester 2 Dec 96 New Yorker]

http://www.foodsafety.org/consumer/ht/ht294.htm



In what the story calls a grand historical irony, this landmark series of experiments was being confirmed at the same time in England as a result of an outbreak of scrapie in several hundred sheep that had been immunized against louping ill with a vaccine prepared from tissue from the brain, spinal cord, and spleen of sheep that were belatedly discovered to have been exposed to natural scrapie infection.[6.Gordon WS. Advances in veterinary research. Vet Rec 1946; 58: 516-520] The transmissible nature of the scrapie agent was thus established beyond any doubt. [P Brown, 1755 and All That: A Historical Primer of TSE.

We need to look at the full text of the article and its cites to see how they actually made the vaccine, whether they exported vaccine-infected sheep to Canada and the US, and what became of the vaccinated flocks. Perhaps there is still sample available, Moredun Institute is still around.

Gordon WS. Advances in veterinary research. Vet Rec 1946; 58: 516-520 (not covered by Medline) Gordon, Bronlee and Wilson 1939 [full cite is available only in a letter we don't have)

Terry was reading Draft Factual Account 17



http://www.bse.org.uk/dfa/dfa17.htm





http://bseinquiry.blogspot.com/2008/05/bse-inquiry-draft-factual-account-dfa.html






236. Mrs Alderman replied on 3 June 1988, listing products containing bovine insulin and noting there were two rabies vaccines listed but the species used in manufacture was not shown.[282] 237. On 6 June 1988 Mr Lawrence wrote to Sir Richard Southwood and enclosed some brief answers to the questions that had been tabled at the meeting on 19 May.[283] In relation to Q6, which asked OWhat is meat and other material from scrapie infected sheep used for - does it include pet food and material for biological products?¹ Part of the answer stated: ...

There has been one instance of inadvertant [sic] transmission of the scrapie agent to sheep through louping ill vaccine (Gordon, Bronlee and Wilson 1939). One of the three batches of vaccine made in 1935 at the Moredun Institute contained the scrapie agent resulting in 7% of the recipients of the 18, 000 doses in the batch developing scrapie. This vaccine was made from formalin-inactivated sheep brain, and brought to the attention of research workers that formalin, at a concentration of 0.35% for at least 3 months, which inactivated conventional viruses, did not totally inactivate the scrapie agent.


----------------------------


4. Questions we might want to have answered are: the highest risk would be from parenterals prepared from brain (eg rabies vaccine). Any species in which transmissible spongiform encephalopathies have been described would be suspect ("natural" infections in sheep, goats, cattle, deer, mink, but can be transmitted to hamster, mouse, guinea-pig etc). Are sterilisation processes adequate for the most resistant strain of scrapie agent or for CJD agent? Should companies be asked to include investigation for inclusion of scrapie agent (eg mouse innoculation [sic]) in at least some batches? If BSE behaves like scrapie, then we might expect other nervous tissue, spleen, lymph nodes and placenta to be contaminated. Infection has been described in other tissues too, eg gut wall, and we can not [sic] be sure blood is free. Do we know what bovine materials are used in which products, both as the active ingredient and in production? Bovine active ingredients in human products include insulin, vasopressin, bone, immune globulins, fibrin, dermal collagen, albumin. Bovine serum albumin and fetal calf serum must be used in preparation of very many products. For each of these products would any "BSE agent" be destroyed or eliminated in processing? If not, and the product is administered parenterally or topically into an open wound, might there be a risk? [For oral products, there would only be a trivially increased load on top of that taken in food in omnivores/carnivores including man. But for some herbivores, this might allow the agent to be introduced into yet another species].


--------------------------


Medicines and medical devises;

Subject: 2 known incidents of iatrogenic scrapie

Date: Thu, 7 Sep 2000 09:51:14 -0800

From: tom

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de References: 1

######### Bovine Spongiform Encephalopathy #########

One really has to wonder what went on in veterinary products produced during the peak BSE years. At this point, there are only 2 known incidents, both involving sheep brain vaccines.

I found a better source for needed references for iatrogenic scrapie in a nice review by Ray Bradley at http://www.iica.org.ar/Bse/6-%20Bradley.html. Disclosure has been meagre on the 1998 vaccine incident in Italy. Note 3 of the 5 references are totally off Medline and the other 2 fail to have abstracts or links, due to journal ineptness, burial in conference proceedings, and age of article.

If anyone has the first 3, I would appreciate a fax 542-484-0669 US.

tom

GORDON , W.S., 1959. Scrapie panel. In: Proceedings of 63rd Annual Meeting of the US Livestock Sanitary Association, 63, 286-294. [no medline record]

GORDON, W.S., 1946. Advances in Veterinary Research: Louping ill, tick-borne fever and scrapie. Veterinary Record, 58, 516-525. [no medline record]

GORDON , W.S., BROWNLEE, A.& WILSON, D.R., 1939. Studies in louping-ill, tick-borne fever and scrapie. 3rd International Congress for microbiology, 362-363. [no medline record]

-=-=--=

CAPUCCHIO, M.T., GUARDA,F., ISAIA,M.C., CARACAPPÀ, S. & DiMARCO,V., 1998. Natural occurrence of scrapie in goats in Italy. Veterinary Record, 143, 452-453. [title only]

AGRIMI, U., GLUSOPPE, R.U., CARDONE, F., POCCHIARI, M. & CARAMELLI, M., 1999. Epidemic transmissible spongiform encephalopathy in sheep and goats in Italy. Lancet, 353, 560-561. [title only]

IATROGENIC DISEASE IN ANIMALS



http://www.iica.org.ar/Bse/6-%20Bradley.html



Ray Bradley Private BSE Consultant Veterinary Laboratories Agency, United Kingdom

There have been two reported incidents of iatrogenic disease in animals, both involving scrapie. One was in Great Britain (Gordon, Brownlee and Wilson, 1939, Gordon 1946, 1959) the other in Italy (Capucchio et al, 1998, Agrimi et al, 1999). Both resulted from infection being introduced into vaccines, louping ill vaccine in Great Britain, Mycoplasma agalactiae vaccine in Italy. Each of these vaccines was prepared from tissues that included sheep brain. In both episodes it seems most likely that natural scrapie infection was present unknowingly in some brains used for the purpose. Once prepared and having passed all the conventional vaccine tests large numbers of sheep in Great Britain, and goats and some sheep in Italy were inoculated. After the necessary incubation period large numbers (> 1,000 in each case) of inoculated animals came down with scrapie. In the meantime some inoculated clinically healthy goats and sheep may have entered food and feed chains or have been used for other purposes. In the British outbreak there appears to have been no consequence for humans who may have consumed infected sheep. It is too early to say what may be the consequences in Italy but measures have been taken to reduce any risk there may have been. .........end



Louping-ill vaccine documents from November 23rd, 1946 FULL TEXT

THE VETERINARY RECORD 516 No 47. Vol. 58 November 23rd, 1946

NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND

ANNUAL CONGRESS, 1946

The annual Congress, 1946, was held at the Royal Veterinary College, Royal College Street, London, N.W.I. from September 22nd to September 27th.

Opening Meeting

[skip to scrapie vaccine issue...tss]

Papers Presented to Congress

SNIP...FULL TEXT ;




http://www.whale.to/v/singeltary7.html

 

 

although 176 products do _not_ conform to the CSM/VPC guidelines.



COMMERCIAL IN CONFIDENCE

NOT FOR PUBLICATION


http://web.archive.org/web/20030704202503/http://www.bseinquiry.gov.uk/files/yb/1989/09/06011001.pdf






8. The Secretary of State has a number of licences. We understand that the inactivated polio vaccine is no longer being used. There is a stock of smallpox vaccine. We have not been able to determine the source material. (Made in sheep very unlikely to contain bovine ingredients).



CONFIDENTIAL


http://collections.europarchive.org/tna/20080102164642/http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf





CONFIDENTIAL



http://collections.europarchive.org/tna/20080103002544/http://www.bseinquiry.gov.uk/files/yb/1989/02/14011001.pdf





more on the 1968 medicine act, they forgot to follow



http://web.archive.org/web/20030526124448/http://www.bseinquiry.gov.uk/files/yb/1989/01/30008001.pdf




Draft cover letter to product licence holders (considered by Human and Vet Medicines including deer)



http://collections.europarchive.org/tna/20080103002832/http://www.bseinquiry.gov.uk/files/yb/1989/02/22008001.pdf





http://collections.europarchive.org/tna/20080102155758/http://www.bseinquiry.gov.uk/files/yb/1989/02/22011001.pdf






2.3.Iatrogenic exposure

Iatrogenic exposure of scrapie has probably occurred twice. The first report determined that the vehicle was a louping ill vaccine prepared from sheep tissues and this infected a large number of sheep sheep (Gordon, 1946, Greig, 1950). The second was more recent and in this case a vaccine against Mycoplasma agalactiae prepared from sheep tissues was incriminated (Agrimi et al 1999, Capucchio, 1998) but not all outbreaks could be linked to the use of the vaccine. In this episode goats were predominantly affected10.


http://ec.europa.eu/food/fs/sc/ssc/out170_en.pdf



http://ec.europa.eu/food/fs/sc/ssc/out247_en.pdf





5.3.3 The greatest risk, in theory, would be from parenteral injection of material derived from bovine brain or lymphoid tissue. Medicinal products for injection or surgical implantation which are prepared from bovine tissues, or which utilise bovine serum albumin or similar agents in their manufacture, might also be capable of transmitting infectious agents. All medicinal products are licensed under the Medicines Act by the Licensing Authority following guidance, for example from the Committee on Safety of Medicines (CSM), the Committee on Dental and Surgical Materials (CDSM) and their subcommittees. The Licensing Authority have been alerted to potential concern about BSE in medicinal products and will ensure that scrutiny of source materials and manufacturing processes now takes account of BSE agent.




http://collections.europarchive.org/tna/20080102132706/http://www.bseinquiry.gov.uk/files/ib/ibd1/tab02.pdf





BEFORE the BSE Inquiry went online, i was requesting the daily hearings and submissions, and they were sending them to me via air mail. then, when the BSE Inquiry finally went online, i was then able to go back and match up some of what i had with the YB numbers (above), with the official documents. ...TSS

BSE offals used in cosmetics, toiletry and perfume industry Sun, 3 Sep 2000. Unpublished Inquiry documents obtained by CJD activist Terry S. Singeltary Sr. of Bacliff, Texas Miss Marion Kelly Cosmetic, Toiletry and Perfumery Association 35 Dover Street London W1X3RA

Department of Trade and Industry 10-18 Victoria Street London SW1H ONN Enquiries 01-215 5000 Telex 8811074 DTHQ G 01 215 3324 1 February 1990


http://www.mad-cow.org/00/sep00_news.html#bbb




40,000 human heart valves a year from BSE herds Sun, 3 Sep 2000. Unpublished Inquiry documents obtained by CJD activist Terry S. Singeltary Sr. of Bacliff, Texas

Opinion (webmaster): Below are some shocking documents. Here is a British company preparing 40,000 heart valves a year from bovine pericardium, primarily for export, and they are not required to source this material from BSE-free herds even in peak epidemic years. It is amazing to watch health "authorities" grovelling on their bellies to wring petty concessions from middle management at obscure little companies. The main worry is not the practise of using 800 potentially infected cows a week for human heart transplant material but that the press or recipients will get wind of it, hurting business.

BSE wasn't the problem, it was awkward queries from importing countries like the US. The cows are stunned using brain penetration -- can't do anything about the chunks of bovine brain blasted into the circulatory system, it's the norm. Can't use younger lower-risk animals either, patch would not be big enough. It is fascinating to see the British government worrying about, but doing nothing, with pigs with BSE 10 years ago.

While scrapie was long used as an excuse for continuing with human use of BSE-tainted material, little sheep material was used medically. Bovine transplants, vaccines, insulin doeses, etc. are far more dangerous than dietary material as injections, and are done on a very wide scale. So scrapie was never a valid analogy to BSE, as MAFF knew full well.

The British government deferred to the manufacturer's rep for an opinion on how contaminated pericardium might be, just as this appeared showing that this tissue is extremely dangerous:

http://www.mad-cow.org/00/sep00_news.html#hhh



England worried briefly about infecting other countries 27 Aug 00 confidential correspondence obtained by Terry S. Singeltary Sr.

BSE11/2 020;

SC1337p

DEPARTMENT OF HEALTH AND SOCIAL SECURITY Richmond House, 79 Whitehall, London SWIA 2NS Telephone 01-210 3000 From the Chief Medical Officer Sir Donald Achson KBE DM DSc FRCP FFCM FFOM

Mr K C Meldrum Chief Veterinary Officer Ministry of Agriculture, Fisheries and Food Government Buildings Hook Rise South Tolworth Surbiton Surrey KT6 7NG 3 January 1990

Dear Mr Meldrum

BOVINE SPONGIFORM ENCEPHALOPATHY

You will recall that we have previously discussed the potential risks of BSE occurring in other countries as a result of the continuing export from the UK of meat and bone that may be contaminated by scrapie or possibly BSE.

I remain concerned that we are not being consistent in our attempts to contain the risks of BSE. Having banned the feeding of meat and bone meal to ruminamts in 1988, we should take steps to prevent these UK products being fed to ruminants in other countries. This could be achieved either through a ban on the export of meat and bone meal, or at least by the proper labelling of these products to make it absolutely clear they should not be fed to ruminants [or zoo animals, including rare and endangered primates -- webmaster]. Unless some such action is taken the difficult problems we have faced with BSE may well occur in other countries who import UK meat and bone meal. Surely it is short sighted for us to risk being seen in future as having been responsible for the introduction of BSE to the food chain in other countries.


http://www.mad-cow.org/00/aug00_last_news.html#fff




The documents below were provided by Terry S. Singeltary Sr on 8 May 2000. They are optically character read (scanned into computer) and so may contain typos and unreadable parts.

TIP740203/l 0424 CONFIDENTIAL

Mr Cunningham CMP3 From: D O Hagger MBI Dr Salisbury MED/IMCD3 Mr Burton PD/STB/PG1B B/17/2 Date: 15.02.1989 Mr Dudley PD/AD4

BOVINE SPONGIFORM ENCEPHALOPATHY


http://www.mad-cow.org/00/may00_news.html#aaa




Other US BSE risks: the imported products picture 24 Jul 00 Trade Statistics: UK to US Compiled by Terry S. Singeltary Sr of Bacliff, Texas

[Opinion (webmaster): The US has focused for years on tracing, containing, and eradicating live animal imports from the UK or other countries with acknowledged BSE like Belgium, including some 499 cattle and the Vermont sheep. This strategy does not acknowledge imports of rendered bovine products from England during the BSE period nor secondary products such as surgical catgut, which is to say surgical cowgut, or dairy cattle embryos, vaccines for veterinarian and human medicines. What has become of these?

Mr. Singeltary, who lost his mother to CJD of unexplained origin a few years back and went on to became a well-known TSE activist, has tracked down voluminous pertinent import data through correspondence with UK officials and searches of government web sites. Imports of such products are frequently cited by Europeans in rating BSE risks in the US and in shutting out US exports.

Many people's eyes glaze over when reviewing reams of sometimes older trade statistics. There is no proof that any of the imported products was contaminated with BSE nor if so, any evidence that any BSE product lead to infection in US livestock, surgical patients, or what not. Nonetheless, the data obtained by Mr. Singeltary establish that an appalling variety and tonnage of products that were imported by the US from the UK and othr BSE-affected countries during the peak of the BSE epidemic years.]

10 January 1990 COMMERCIAL IN CONFIDENCE

NOT FOR PUBLICATION

COMMITTEE ON SAFETY OF MEDICINES WORKING PARTY ON BOVINE SPONGIFORM ENCEPHALOPATHY

SURGICAL CATGUT SUTURES 2.1 At the first meeting of the Working Party on Bovine Spongiform Encephalopathy on 6 September 1989, detailed consideration was given to XXXXX Surgical Catgut. This arose from the Company's response to the Letter to Licence Holders, indicating that the bovine small intestine source material was derived from UK cattle, unlike 8 other licenced catgut sutures. In contrast XXXXX Surgical Catgut was stated to hold over 90% share of the market for catgut sutures, and to constitute approximately 83% of all sutures used in U.K. IMPORTS OF SUTURES FROM THE KNOWN BSE COUNTRY;


http://www.mad-cow.org/00/jul00_dont_eat_sheep.html#hhh




The documents below were provided by Terry S. Singeltary Sr on 8 May 2000. They are optically character read (scanned into computer) and so may contain typos and unreadable parts.


TIP740203/l 0424 CONFIDENTIAL

Mr Cunningham CMP3 From: D O Hagger MBI Dr Salisbury MED/IMCD3 Mr Burton PD/STB/PG1B B/17/2 Date: 15.02.1989 Mr Dudley PD/AD4

BOVINE SPONGIFORM ENCEPHALOPATHY

1. The purpose of this minute is to alert you to recent developments on BSE as they affect medicines and to invite representatives to a meeting in Market Towers on 22 February 1989.

2. The report of the Working Party on Bovine Spongiform Encephalopathy (BSE) was submitted by the CMO to the Secretary of State for Health and Minister for Agriculturer on 9 February.

3. The summary at the end of the report records, inter alia: 'we have drawn the attention of the Licensing Authority to the potential of transfer of BSE agent in human and veterinary medicinal products. In paragraph 7 of his submission (Annex A), the CMO notes:

"I am also putting work urgently in hand to satisfy myself that everything possible has been done to ensure .... that transfer of the BBE agent in human and veterinary medicinal products does not occur."

4. The Veterinary products Committee meets on 16 February and The committee on Safety of Medicines on 23 February when each will be considering a draft of some joint guidelines for manufacturers of medicinal products which use bovine material as an ingredient or an intermediate in the manufacturing process (Annex B).....

6. Although a wide range of medicines may be implicated - and the present proposal is to write to companies for more information - an "instant" telephone survey of manufacturer of vaccines used for children has already been undertaken in response to a request from Dr Harris. The results are in Dr Adams' minute of 14 February (Annex C) - the proviso in his second paragraph, last sentence should be noted. 89/02.15/11.1

89/02.15/11.2 MF580439/1 0584 SOUTHWOOD REPORT: BSE AND MEDICINAL PRODUCTS

1. I attach a list of questions on BSE and medicines compiled with the aim of providing question and answer briefing to DH and MAFF Ministers upon publication of the Southwood Report. I have suggested names of those who may be able to provide answers. All recipients are invited to consider which if any important areas have been missed. Also attached is copy QA briefing being proposed by MAFF. I understand MAFF have produced General QA briefing on the reports as a whole. ..

MF580439/1 0585 Question

1. Which medicines are affected? (person to provide reply) Dr. Jefferys

2. Are the risks greater with some medicines than others? Dr. Jefferys

3. Why are medicines affected? Dr. Jefferys

4. Are some affected products available over the counter from pharmacies or shops? Dr. Purves

5. Are only UK products at risk? Dr. Jefferys

6. Are existing stocks safe? Dr. Jefferys

7. Are pre 1980 stocks available? Mr. Burton

8. Are these alternatives to the use of bovine material? Dr. Purves

9. Why can't we throw away suspect stock and import or manufacture safe medicines? Dr. Jefferys

10. Which patients are at risk? Dr. Jefferys

11. Are some patients particularly vulnerable? Dr Jefferys

12. What risks exist to those who have already used these medicines? Dr. Jefferys

13. HOW might patients be affected? Dr. Jefferys

14. Can BSE be transmitted to patients by medicines? Dr. Jefferys

15. How long will it be before risks are quantified? Dr. Jefferys

100 89/02.17/10.2 MF580439/1 0586

16. What research is going on to find out if medicines can transmit this disease and if any patients have been affected? Dr Jefferys

17. Could recent cases of Creuuzfeld Jacob Disease have been caused by transmission of BSE through medicines? Dr. Jefferys

18. What action is the Licensing Authority taking to ensure proper scrutinising of source materials and manufacturing processes? Dr. Jefferys/Dr. Purves

19. Are the guidelines practical? Dr. Jefferys/Dr. Purves

20. Will the guidelines remove the risk? Dr. Jefferys

21. How will the guidelines be enforced? Dr. Jefferys/Dr. Purves

22. How soon will they come into force? Dr. Jefferys

23. Will the guidelines be published? Mr. Hagger

24. What is being done to reassure patients, parents etc? Mr. Hagger/Dr. Salisbury

25. What advice is being given to doctors, pharmacists etc? Mr. Hagger

26. What advice is the Government giving about its vaccination programme? Dr. Salisbury

27. Is the vaccination programme put at risk because of BSE? Dr. Salisbury

89/02.17/10.3

Q. Will government act on this?

A. Yes - thymus is not used in preparation of baby foods but it is contacting all manufacturers to seek their urgent views on use of kidneys and liver from ruminants. Will consider any necessary measures in the light of their response.

VETERINARY MEDICINES

Q. Can medicines spread BSE to other cattle/animals?

A. The report describes any risks as remote.

Q. How can risks be avoided?

A. In liaison with the DOH the Veterinary Products Committee is examining guidelines for the veterinary pharmaceutical industry which will be issued shortly.

Q. What will Guidelines say?

A. In essence they call for non-bovine sources to be used if possible, including synthetic material of biotechnological origin. Where this is not possible the industry should look for sources which are free of BSE and which are collected in a manner which avoids risk of contamination by the BSE agent.

89/02.17/10.4 MF580439/1 0588

A. Bovine source material is used in [garbled, cannot read...TSS] and some other medicines.

Q. How many medicines are involved?

A. Computer records show that about 300 of the 3,050 veterinary medicines licensed in the U.K. are manufactured directly from bovine source material. However, other medicines may be produced from bovine sources and a letter is going to all license holders so that a comprehensive list can be drawn up.

89/06.19/8.1 BSE3/1 0191 Hr J Maslin (MAFF) Ref: Maslin3g

From: Dr H Pickles Med SEB/B Date: 3 July 1989

CATTLE BY-PRODUCTS AND BSE

I was interested to see the list of by-products sent to the HSE. Those of particular concern included:

* small intestines: sutures (I thought the source was ovine but you are checking this)

* spinal cord: pharmaceuticals

* thymus: pharmaceuticals

Are you able to give me more information on which UK manufacturers use these materials? Our proposed ban on bovine offal for human consumption would not affect these uses, I assume.

Id No. 1934/RD/1 89/08.10/6.1 117A

BOVINE SPONGIFORM ENCEPHALAPATHY MEETING HELD ON 21 AUGUST 1989 AT 2;15 IN ROOM 720 Miss M Duncan (Chairman) Mr W Burton Dr E Hoxey Mrs J Dhell Ms K Turner Dr S Whittle Mr N Weatherhead ... 5. The MCA had sent 2700 questionnaires out, 1,124 had made valid returns; of these 122 use animal material of some kind and there are 582 products involved. ... 6. The MCA/BSE working group will meet on 6th September. Their aim is to review responses from professional officers in MCA who have suggested seven categories of importance (with 1 being the most important} for medical products:

ID 2267/NRE/1 89/08.21/10.1

1. Products with Bovine brain/lymph tissue administered by injection.

2. Products with bovine tissue other than brain/lymph administered by inection.

3. Tissue implants/open wound dressing/surgical materials/dental and ophthlamic products with bovine ingredients.

4. Products with bovine ingredients administered topically.

5. Products with bovine ingredients administered orally.

6. Products with other animal/fish/insect/bird ingredients administered by injection/topically/oral routes.

7. Products with ingredients derived from animal material by chemical processing (eg stearic acid, gelatine, lanolin ext.

The BSE working group will decide which of these are important, and should be examined more closely, and which categories can be eliminated.

The responses by the companies were presented by Ms Turner and were categorised by MCA standards, the products that were discussed were all low volume usage products eg sutures, heart valves.

8. As the responses included some materials of human origin it was decided that more information should be sought about CJD. There had been 2 recent deaths reported associated with human growth hormone. These were being investigated.

9. Re-editing of the Paper on "Incubation of Scrapie-like Agents"

It was suggested that the document could be sent out to companies with the non-standard sterilization Document. The document could have severe implications on the companies whose products have a high risk factor as decided by the MCA working group....

11. The Need for a list of High Priority Implantables The commitee decided that no list is necessary as all implantables, including ones from a human source are of high priority. Concern was shown over Killingbeck who use human material but had not yet responded. The company will be chased for a response. Concern was shown over the fact that there may be other scrapie-like organisms in other animals and further enquiries should be made.

2334q/RD/4 89/08.21/10.7

BOVINE MATERIAL USED IN THE MANUFACTURE OF SURGICAL IMPLANTS AND BLOOD CONTACT MEDICAL DEVICES

Glutaraldehyde, formaldehyde, and ethylene oxide are used in the sterilization of these devices.

However, glutaraldehyde 4,10,12,19 formaldehyde 5,10,11,13,19 and ethylene oxide 19,23 are all reported to be ineffective methods for sterilization of material infected with the agents of CJD or scrapie.

Previous advice and research using the agents of CJD and scrapie, has concentrated on the decontamination of equipment; protection of health care workers from contaminated human material; human growth hormone; and dura mater. The methods developed may not be directly applicable or transferable to material of bovine origin for use in human implantation.

2334q/RD/7 89/08.21/10.10 BSE11/2 020 SC1337

DEPARTMENT OF HEALTH AND SOCIAL SECURITY Richmood House 79 Whitehall, London SW1A 2NS Telephone 01-210-3000 From the Chief Medical Officer Sir Donald Acheson KBE DM DSc FRCP FFCM FFOM

Mr K C Meldrum Chief Veterinary Officer Ministry of Agriculture, Fisheries and Food Government Buildings Hook Rise South Tolworth Surbiton Surrey KT6 7NG

3 January 1990

Dear Mr. Meldrum,

BOVINE SPONGIFORM ENCEPHALOPATHY

You will recall that we have previously discussed the potential risks of BSE occurring in other Countries as a result of the continuing export from the UK of meat and bone that may be contaminated by scrapie or possibly BSE.

I remain concerned that we are not being consistent in our attempts to contain the risks of BSE. Having banned the feeding of meat and bone meal to ruminants in 1988, we should take steps to prevent these UK products being fed to ruminants in other countries. This could be achieved either through a ban on the export of meat and bone meal, or at least by the proper labelling of these products to make it absolutely clear they should not be fed to ruminants. Unless some such action is taken the difficult problems we have faced with BSE may well occur in other countries who import UK meat and bone meal. Surely it is short sighted for us to risk being seen in future as having been responsible for the introduction of BSE to the food chain in other countries.

I would be very interested to hear how you feel this gap in the present prcautionary measures to eliminate BSE should be closed. We should be aiming at the global elimination of this new bovine disease. The export of our meat and bone meal is a continuing risk to other countries.

Signed Sincerely Donald Acheson

Did the US import fetal calf serum and vaccines from BSE-affected countries? 3002.10.0040: FETAL BOVINE SERUM (FBS) U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date (Customs Value, in Thousands of Dollars) (Units of Quantity: Kilograms)


<--- Dec 1998 ---> <--- 1998 YTD ---> Country Quantity Value Quantity Value



=================================================================


WORLD TOTAL . . . . . . . 2,727 233 131,486 8,502 Australia . . . . . . . . --- --- 19,637 2,623 Austria . . . . . . . . . --- --- 2,400 191 Belgium . . . . . . . . . --- --- 17 32 Canada . . . . . . . . . 900 110 30,983 3,220 Costa Rica . . . . . . . 500 20 4,677 169 Federal Rep. of Germany --- --- 105 21 Finland . . . . . . . . . 1 8 9 83 France . . . . . . . . . --- --- 73 7 Guatemala . . . . . . . . --- --- 719 42 Honduras . . . . . . . . --- --- 1,108 88 Israel . . . . . . . . . --- --- 24 165 Netherlands . . . . . . . --- --- 1 5 New Zealand . . . . . . . 26 5 65,953 913 Panama . . . . . . . . . --- --- 1,195 64 Switzerland . . . . . . . 971 8 1,078 23 United Kingdom . . . . . 329 82 743 756 Uruguay . . . . . . . . . --- --- 2,764 98 ------------------------------------------------------------------ 3002.20.0000: VACCINES FOR HUMAN MEDICINE U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date (Customs Value, in Thousands of Dollars) (Units of Quantity: Kilograms)

<--- Dec 1998 ---> <--- 1998 YTD ---> Country Quantity Value Quantity Value
=================================================================

WORLD TOTAL . . . . . . . 25,702 26,150 550,258 378,735 Austria . . . . . . . . . --- --- 45 225 Belgium . . . . . . . . . 14,311 12,029 248,041 199,036 Canada . . . . . . . . . 1,109 1,527 15,798 16,305 Denmark . . . . . . . . . 80 234 246 682 Federal Rep. of Germany 1,064 4,073 12,001 6,329 France . . . . . . . . . 3,902 4,859 87,879 92,845 Ireland . . . . . . . . . --- --- 120 478 Italy . . . . . . . . . . --- --- 2,359 81 Japan . . . . . . . . . . 445 1,903 11,350 11,298 Netherlands . . . . . . . --- --- 94 6 Republic Of South Africa --- --- 2 1 Spain . . . . . . . . . . --- --- 60 30 Switzerland . . . . . . . 716 353 9,303 4,271 United Kingdom . . . . . 4,075 1,172 162,960 47,148 ------------------------------------------------------------------ 3002.30.0000: VACCINES FOR VETRINARY MEDICINE U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date (Customs Value, in Thousands of Dollars) (Units of Quantity: Kilograms)

<--- Dec 1998 ---> <--- 1998 YTD ---> Country Quantity Value Quantity Value =================================================================

WORLD TOTAL . . . . . . . 6,528 237 87,149 2,715 Canada . . . . . . . . . --- --- 2,637 305 Federal Rep. of Germany --- --- 104 5 Netherlands . . . . . . . 138 64 472 192 New Zealand . . . . . . . 6,390 173 83,882 1,895 United Kingdom . . . . . --- --- 54 318




http://www.mad-cow.org/00/may00_news.html





Procedures Manual

Bovine Spongiform Encephalopathy (BSE)

Ongoing Surveillance Plan

Ongoing Surveillance Plan Implementation July 20, 2006

snip...

Personal Safety

If BSE is transmissible to humans in the occupational setting, the most likely routes would be through contact with infective tissues through wounds or open lesions on the skin, contact with mucous membranes (eyes and mouth), or exceptionally, by swallowing. .....snip...end

http://www.aphis.usda.gov/vs/nvsl/PDFs/BSE%20Ongoing%20Surveillance%20SOP%207-20-06.doc




SO, looks like to me the most likely route of transmission of BSE to humans would be through inoculation i.e., the most likely routes would be through contact with infective tissues through wounds or open lesions on the skin, IF you look at all the successful transmission studies in the lab with TSE, inoculations was the most successful route.



BSE-L@LISTS.AEGEE.ORG

Bovine Spongiform Encephalopathy

BSE-L is a discussion forum for scientists who are interested in Bovine Spongiform Encephalopathy (BSE). BSE-L has been created on 20th July, 1994 by Siegfried Schmitt. Impressum: http://www.kaliv.de/impressum.html

LISTS.AEGEE.ORG ( BSE-L: 484 matches (only the first 50 will be shown).. )


https://lists.aegee.org/cgi-bin/wa?S2=BSE-L&X=1D1B9A2D19721D3331&Y=flounder9@verizon.net&q=VACCINES&s=&f=&a=&b




From: TSS (216-119-138-163.ipset18.wt.net)

Subject: Louping-ill vaccine documents from November 23rd, 1946 Date:

September 10, 2000 at 8:57 am PST


Subject: Louping-ill vaccine documents from November 23rd, 1946

Date: Sat, 9 Sep 2000 17:44:57 -0700

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de

######### Bovine Spongiform Encephalopathy #########

THE VETERINARY RECORD 516 No 47. Vol. 58 November 23rd, 1946

NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND

ANNUAL CONGRESS, 1946

The annual Congress, 1946, was held at the Royal Veterinary College, Royal College Street, London, N.W.I. from September 22nd to September 27th.

Opening Meeting

[skip to scrapie vaccine issue...tss]

Papers Presented to Congress

The papers presented to this year's Congress had as their general theme the progressive work of the profession during the war years. Their appeal was clearly demonstrated by the large and remarkably uniform attendance in the Grand Hall of the Royal Veterinary College throughout the series; between 200 and 250 members were present and they showed a keen interest in every paper, which was reflected in the expression of some disappointment that the time available for discussion did not permit of the participation of more than a small proportion of would-be contributors.

In this issue we publish (below) the first to be read and discussed, that by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E., "Advances in Veterinary Research." Next week's issue will contain the paper on "Some Recent Advances in Veterinary Medicine and Surgery in Large-Animal Practice" by Mr. T. Norman Gold, M.R.C.V.S. In succeeding numbers of the Record will be reproduced, also with reports of discussions, that by Mr. W. L. Weipers, M.R.C.V.S., D.V.S.M., on the same subject as relating to small-animal practice, and the papers by Mr. J. N. Ritchie, B.SC., M.R.C.V.S., D.V.S.M., and Mr. H.W. Steele-Bodger, M.R.C.V.S., on "War-time Achievements of the British Home Veterinary Services."

The first scientific paper of Congress was read by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E. on Monday, September 23rd, 1946, when Professor J. Basil Buxton, M.A., F.R.C.V.S, D.V.H., Prinicipal of the Royal Veterinary College, presided.

Advances in Veterinary Research

by

W.S. GORDON, PH.D., M.R.C.V.S., F.R.S.E.

Agriculteral Research Council, Field Station, Compton, Berks.

Louping-ill, Tick-borne Fever and Scrapie

In 1930 Pool, Browniee; Wilson recorded that louping-ill was a transmissible disease. Greig et al, (1931) showed that the infective agent was a filter-passing virus with neurotropic characters and Browniee & Wilson (1932) that the essential pathology was that of an encephalomyelitis. Gordon, Browniee, Wilson & MacLeod (1932) and MacLeod & Gordon (1932) confirmed and extended this work. It was shown that on louping-ill farms the virus was present in the blood of many sheep which did not show clinical symptoms indicating involvement of the central nervous system and that for the perpetuation and spread of the disease these subclinical cases were probably of greater importance that the frank clinical cases because, in Nature, the disease was spread by the tick, lxodes ricinus L. More recently Wilson (1945, 1946) has described the cultivation of the virus in a chick embryo medium, the pathogenic properties of this culture virus and the preparation of louping-ill antiserum.

Between 1931 and 1934 I carried out experiments which resulted in the development of an effective vaccine for the prevention of louping-ill.* This vaccine has been in general use since 1935 and in his annual report to the Animal Diseases Research Association this year, Dr. Greig stated that about 227,000 doses of vaccine had been issued from Moredun alone.

Dr. Gordon illustrated this portion of his paper by means of graphs and diagrams projected by the epidiascope.

This investigation, however, did not begin and end with the study of louping-ill; it had, by good fortune, a more romantic turn and less fortunately a final dramatic twist which led almost to catastrophe. After it had been established that a solid immunity to louping-ill could be induced in sheep, a group of immunized and a group of susceptible animals were placed together on the tick-infected pasture of a louping-ill farm. Each day all the animals were gathered and their temperatures were recorded. It was anticipated that febrile reactions with some fatalities would develop in the controls while the louping-ill immunes would remain normal. Contrary to expectation, however, every sheep, both immune and control, developed a febrile reaction. This unexpected result made necessary further investigation which showed that the febrile reaction in the louping-ill immunes was due to a hitherto undescribed infective agent, a Rickettsia-like organism which could be observed in the cytoplasm of the granular leucocytes, especially the neutrophil polymorphs (MacLeod (1932), Gordon, Browniee, Wilson & MacLeod. MacLeod & Gordon (1933). MacLeod (1936). MacLeod collected ticks over many widely separated parts of Scotland and all were found to harbour the infective agent of tick-borne fever, and it is probable that all sheep on tick-infested farms develop this disease, at least on the first occasion that they become infested with ticks. When the infection is passed in series through susceptible adult sheep it causes a sever, febrile reaction, dullness and loss of bodily condition but it rarely, if ever, proves fatal. It is clear, however, that it aggravates the harmful effects of a louping-ill infection and it is a serious additional complication to such infections as pyaemia and the anacrobic infections which beset lambs on the hill farms of Northern Britain.

Studying the epidemiology of louping-ill on hill farms it became obvious that the pyaemic condition of lambs described by M'Fadyean (1894) was very prevalent on tick infested farms Pyaemia is a crippling condition of lambs associated with tick-bite and is often confused with louping-ill. It is caused by infection with Staphylococcus aureus and affected animals may show abscess formation on the skin, in the joints, viscera, meninges and elsewhere in the body. It was thought that tick-borne fever might have been a predisposing factor in this disease and unsuccessful attempts were made by Taylor, Holman & Gordon (1941) to reproduce the condition by infecting lambs subcutaneously with the staphylococcus and concurrently producing infections with tickborne fever and louping-ill in the same lambs. Work on pyaemia was then continued by McDiarmid (1946a, 1946b, 1946c), who succeeded in reproducing a pyaemic disease in mice, guinea-pigs and lambs similar to the naturally occurring condition by intravenous inoculation of Staphylococcus aureus. He also found a bacteraemic form of the disease in which no gross pyaemic lesions were observed. The prevention or treatment of this condition presents a formidable problem. It is unlikely that staphylococcal ???oid will provide an effective immunity and even if penicillin proved to be a successful treatment, the difficulty of applying it in adequate and sustained dosage to young lambs on hill farms would be almost insurmountable.

From 1931 to 1934 field trials to test the immunizing value and harmlessness of the loup-ill vaccine were carried out on a gradually increasing scale. Many thousands of sheep were vaccinated and similar numbers, living under identical conditions were left as controls. The end result showed that an average mortability of about 9 percent in the controls was reduced to less than 1 percent in the vaccinated animals. While the efficiency of the vaccine was obvious after the second year of work, previous bitter experience had shown the wisdom of withholding a biological product from widespread use until it had been successfully produced in bulk, as opposed to small-scale experimental production and until it had been thoroughly tested for immunizing efficiency and freedom from harmful effects. It was thought that after four years testing this stage had been reached in 1935, and in the spring of that year the vaccine was issued for general use. It comprised a 10 percent saline suspension of brain, spinal cord and spleen tissues taken from sheep five days after infection with louping-ill virus by intracerebral inoculation. To this suspension 0-35 percent of formalin was added to inactivate the virus and its safety for use as a vaccine was checked by intracerbral inoculation of mice and sheep and by the inoculation of culture medium. Its protective power was proved by vaccination sheep and later subjecting them, along with controls, to a test dose of living virus.

Vaccine for issue had to be free from detectable, living virus and capable of protecting sheep against a test dose of virus applied subcutaneously. The 1935 vaccine conformed to these standards and was issued for inoculation in March as three separate batches labelled 1, 2, and 3. The tissues of 140 sheep were employed to make batch 1 of which 22,270 doses were used; 114 to make batch 2 of which 18,000 doses were used and 44 to make batch 3 of which 4,360 doses were used. All the sheep tissues incorporated in the vaccine were obtained from yearling sheep. During 1935 and 1936 the vaccine proved highly efficient in the prevention of loup-ill and no user observed an ill-effect in the inoculated animals. In September, 1937, two and a half years after vaccinating the sheep, two owners complained that scrapie, a disease which had not before been observed in the Blackface breed, was appearing in their stock of Blackface sheep and further that it was confined to animals vaccinated with louping-ill vaccine in 1935. At that stage it was difficult to conceive that the occurrence could be associated with the injection of the vaccine but in view of the implications, I visited most of the farms on which sheep had been vaccinated in 1935. It was at this point that the investigation reached its dramatic phase; I shall not forget the profound effect on my emotions when I visited these farms and was warmly welcomed because of the great benefits resulting from the application of louping-ill vaccine, wheras the chief purpose of my visit was to determine if scrapie was appearing in the inoculated sheep. The enquiry made the position clear. Scrapie was developing in the sheep vaccinated in 1935 and it was only in a few instances that the owner was associating the occurrence with louping-ill vaccination. The disease was affecting all breeds and it was confined to the animals vaccinated with batch 2. This was clearly demonstrated on a number of farms on which batch 1 had been used to inoculate the hoggs in 1935 and batch 2 to inoculate the ewes. None of the hoggs, which at this time were three- year-old ewes. At this time it was difficult to forecast whether all of the 18,000 sheep which had received batch 2 vaccine would develop scrapie. It was fortunate, however, that the majority of the sheep vaccinated with batch 2 were ewes and therfore all that were four years old and upwards at the time of vaccination had already been disposed of and there only remained the ewes which had been two to three years old at the time of vaccination, consequently no accurate assessment of the incidence of scrapie could be made. On a few farms, however, where vaccination was confined to hoggs, the incidence ranged from 1 percent, to 35 percent, with an average of about 5 percent. Since batch 2 vaccine had been incriminated as a probable source of scrapie infection, an attempt was made to trace the origin of the 112 sheep whose tissues had been included in the vaccine. It was found that they had been supplied by three owners and that all were of the Blackface or Greyface breed with the exception of eight which were Cheviot lambs born in 1935 from ewes which had been in contact with scrapie infection. Some of these contact ewes developed scrapie in 1936-37 and three surviving fellow lambs to the eight included in the batch 2 vaccine of 1935 developed scrapie, one in September, 1936, one in February, 1937, and one in November, 1937. There was, therefore, strong presumptive evidence that the eight Cheviot lambs included in the vaccine although apparently healthy were, in fact, in the incubative stage of a scrapie infection and that in their tissues there was an infective agent which had contaminated the batch 2 vaccine, rendering it liable to set up scrapie. If that assumption was correct then the evidence indicated that:-

(1) the infective agent of scrapie was present in the brain, spinal cord and or spleen of infected sheep: (2) it could withstand a concentration of formalin of 0-35 percent, which inactivated the virus of louping-ill: (3) it could be transmitted by subcutaneous inoculation; (4) it had an incubative period of two years and longer.

Two Frenchmen, Cuille & Chelle (1939) as the result of experiments commenced in 1932, reported the successful infection of sheep by inoculation of emulsions of spinal cord or brain material by the intracerebral, epidural, intraocular and subcutaneous routes The incubation period varied according to the route employed, being one year intracerebrally, 15 months intraocularly and 20 months subcutaneously. They failed to infect rabbits but succeeded in infecting goats. Another important part of their work showed that the infective agent could pass through a chamberland 1.3 filter, thus demonstrating that the infective agent was a filtrable virus. It was a curious coincidence that while they were doing their transmission experiments their work was being confirmed by the unforeseeable infectivity of a formalinized tissue vaccine.

As a result of this experience a large-scale transmission experiment involving the ue of 788 sheep was commenced in 1938 on a farm specially taken for the purpose by the Animal Diseases Research Association with funds provided by the Agricultural Research Council. The experiment was designed to determine the nature of the infective agent and the pathogenesis of the disease. It is only possible here to give a summary of the result which showed that (1) saline suspensions of brain and spinal cord tissue of sheep affected with scrapie were infective to normal sheep when inoculated intracerebrally or subcutaneously; (2) the incubation period after intracerebral inoculation was seven months and upwards and only 60 percent of the inoculated sheep developed scrapie during a period of four and a half years; (3) the incubation period after subcutaneous inoculation was 15 months and upwards and only about 30 percent of the inoculated sheep developed the disease during the four and a half years: (4) the infective agent was of small size and probably a filtrable virus.

The prolonged incubative period of the disease and the remarkable resistance of the causal agent to formalin are features of distinct interest. It still remains to determine if a biological test can be devised to detect infected animals so that they can be killed for food before they develop clinical symptoms and to explore the possibilities of producing an immunity to the disease.

==================================================================


Scrapie Louping-ill Vaccine


‘There has been one instance of inadvertant [sic] transmission of the
scrapie agent to sheep through louping ill vaccine (Gordon, Bronlee and
Wilson 1939). One of the three batches of vaccine made in 1935 at the
Moredun Institute contained the scrapie agent resulting in 7% of the
recipients of the 18, 000 doses in the batch developing scrapie. This
vaccine was made from formalin-inactivated sheep brain, and brought to
the attention of research workers that formalin, at a concentration of
0.35% for at least 3 months, which inactivated conventional viruses, did
not totally inactivate the scrapie agent.


----------------------------


4. Questions we might want to have answered are:


the highest risk would be from parenterals prepared from brain (eg
rabies vaccine). Any species in which transmissible spongiform
encephalopathies have been described would be suspect (“natural”
infections in sheep, goats, cattle, deer, mink, but can be transmitted
to hamster, mouse, guinea-pig etc). Are sterilisation processes
adequate for the most resistant strain of scrapie agent or for CJD
agent? Should companies be asked to include investigation for inclusion
of scrapie agent (eg mouse innoculation [sic]) in at least some batches?
If BSE behaves like scrapie, then we might expect other nervous tissue,
spleen, lymph nodes and placenta to be contaminated. Infection has been
described in other tissues too, eg gut wall, and we can not [sic] be
sure blood is free. Do we know what bovine materials are used in which
products, both as the active ingredient and in production? Bovine active
ingredients in human products include insulin, vasopressin, bone, immune
globulins, fibrin, dermal collagen, albumin. Bovine serum albumin and
fetal calf serum must be used in preparation of very many products. For
each of these products would any “BSE agent” be destroyed or eliminated
in processing? If not, and the product is administered parenterally or
topically into an open wound, might there be a risk? [For oral
products, there would only be a trivially increased load on top of that
taken in food in omnivores/carnivores including man. But for some
herbivores, this might allow the agent to be introduced into yet another
species].


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http://www.whale.to/v/singeltary7.html




Sunday, May 18, 2008

MAD COW DISEASE BSE CJD CHILDREN VACCINES

http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html





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