Calf link raises new BSE fears
Europe's hidden mad cow scandal
Prof Lacey argues for both vertical and horizontal transmission
Establishment argues otherwise

Calf link raises new BSE fears

Steve Connor Science Correspondent
SUNDAY TIMES ... June 30 1996

SCIENTISTS have uncovered the first evidence that "mad cow" disease can be passed from mother to calf, raising the prospect that BSE may be more difficult to eradicate than currently envisaged.

A new analysis of the 27,000 cattle with BSE that were born after the 1988 ban on contaminated animal feed has revealed a small but significant transmission from some pregnant cows to their calves.

Until now, the official view has been that there is no evidence for such vertical transmission and that the presence of BSE in cattle born after the ban was the result of contaminated feed still being used on beef and dairy farms after 1988.

The new findings have not yet been given formally to the spongiform encephalopathy advisory committee (Seac), the government's advisers on the BSE epidemic, but one member aware of the research said the implications were important.

"This information might influence our advice if we now have certain evidence of vertical transmission rather than having no evidence," he said.

It could also have far-reaching implications for other European countries which have not established an effective way of identifying cattle with BSE or calves born to BSE cows on their farms. Where British scientists are confident their measures should eradicate vertically transmitted BSE, less rigorous approaches on the Continent may lead to it spreading.

The "slight" vertical transmission from BSE cow to calf has been identified through sophisticated computer modelling by a team of Oxford University scientists. However, the researchers also found the vast bulk of the 27,000 cases have resulted from exposure to contaminated feed.

It is understood the scientists have concluded that the current targeted culling policy of the government will eradicate BSE in the long term, although the task may be made more difficult because some pregnant cows that were incubating the disease may have passed it on to their offspring.

The scientists do not believe other countries where BSE is thought to be indigenous will be able to eradicate the disease so easily. One scientist close to the Oxford team said: "Other countries with BSE do not have a good enough reporting system and still do not pay full compensation to farmers with BSE cattle, so eradication by targeted culling will be a problem for them."

Vertical transmission is also being investigated by the Ministry of Agriculture. Its experiment, set up in 1989, is not due to be finished until next year but it has come under pressure to publish preliminary results.

Ministry scientists are monitoring 315 calves born from BSE cows and another 315 from cows certified BSE-free. It is a "blind" experiment with the code that identifies the calves kept secret to prevent any bias in how they are treated during the research.

So far there have been 47 cases of BSE in the herd of 630 but scientists have up to now believed that this could be accounted for by the unwitting exposure of some of the animals to contaminated feed prior to the experiment.

The scientists still believe they can disentangle BSE in the herd caused by feed and BSE caused by vertical transmission and are preparing to analyse the brains of about 400 of the experimental cattle, which have already been slaughtered.


EUROPE'S HIDDEN 'MAD COW' SCANDAL

Steve Connor Science Correspondent
SUNDAY TIMES ... June 30 1996

The great unwritten assumption about the export ban on British beef is that beef produced in other European countries is completely free of "mad cow" disease. A closer look fails to deliver this reassurance. Consumers in Europe are less protected against BSE than beef-eaters in Britain.

There is no denying that BSE is primarily a British problem. We have nearly 170,000 confirmed cases compared with just over 400 in the rest of the world. Many cases overseas can be linked directly to either the export of British cattle or British-made meat and bone meal. However, there is now a growing acceptance that there is a hidden epidemic of indigenous BSE in many European countries that, unlike Britain, have failed to institute the most basic measures for protecting public health.

One of the strongest pieces of evidence to suggest that the rest of Europe has significantly under-rated its BSE problem comes from an international team of scientists who are shortly to publish their report on the unacknowledged problem. As The Sunday Times revealed two weeks ago, this report concludes that EU countries failed to report more than 1,600 cases of BSE in the 57,900 British breeding cattle they imported between 1985 and 1990. Only 29 cases of BSE were reported in this group of animals.

A second piece of evidence to show that some European countries have been economical with the BSE truth comes from an analysis of the meat and bone meal exported from Britain at the end of the 1980s. This was a legal trade because the UK allowed it to be fed to pigs and poultry even after it was banned in 1988 as a feed for British cattle and sheep. Thousand of tons were exported through brokers in Holland. France bought 15,000 tons in 1989 alone and sold some to Switzerland: which has the highest incidence of BSE outside Britain, with 220 confirmed cases.

All the BSE cattle in Switzerland were born in that country and they undoubtedly developed the disease through eating this imported feed. The question Swiss scientists are asking is why France and other countries that imported the same feed do not have as big a problem. "We are an island of BSE in Europe," says Marc Vandevelde, Switzerland's BSE expert at Bern University. "The disease stops at our border."

Vandevelde says that "if" the dairy practices in France and the Benelux countries were similar to those in Switzerland, there should be several hundred cases instead of the mere 20 in France and none in Belgium, Holland and Luxembourg.

Meat and bone meal exported from Britain was almost certainly mixed with meat and bone meal made in other countries. Even if the British feed was intended for French poultry and pigs, it would have contaminated feed destined for French cattle in the French mills where both products were processed. British scientists accept that this kind of contamination caused thousands of BSE cases in cattle born after the feed ban in 1988. If it happened here, why not in France and other European countries?

What happened to the many hundreds, and possibly thousands, of cattle with BSE that "disappeared" in mainland Europe? Many, if not all, would have been rendered into meat and bone meal and fed to other animals. We know the British ban on feeding cattle protein to cattle and sheep (ruminants) was not totally effective. We also know that some European countries continued the practice until very recently.

Few scientists believe that countries in Europe have been able to escape the deadly cycle of ruminant contamination. Truly indigenous BSE (created by the feeding of home-made feed to home-bred cattle) is very likely, according to Bram Schreuder of Holland's Institute for Animal Science and Health: "There is a risk that if a local rendering plant is not fully effective, countries that were continuing to feed meat and bone meal to cattle were creating their own indigenous BSE. I think there are countries in Europe that have had such cases."

Scientists at the Institute for Animal Health here have shown that many rendering processes used in Europe fail to destroy the agent that causes scrapie, the brain disease in sheep. This finding should be particularly worrying for the French because even though the EU asked them in 1993 to set up an official system for notifying cases of scrapie, they failed to do so until this year.

Many sheep with scrapie must therefore have been rendered in a system that failed to eliminate the scrapie agent, which is how BSE in Britain is thought to have developed.

All this could, perhaps, be overlooked if France and other European countries had set up an effective barrier against BSE to protect public health. Central to this strategy would be a well-policed ban on bovine offal in the human food chain, particularly brain and spinal cord matter where the BSE agent thrives. However it was only in this year, for instance, that the French introduced such a ban. The moral of the tale is that if British consumers ever faced a risk from BSE, consumers elsewhere now face a bigger risk from their own beef industries.


BSE Transmission: From Cow to Calf?

Adapted from memo of English biostatistician Stuart Neilson ... 10 June 1996

The vertical transmission study was set up in 1988/9 with the purchase of 315 calves born to BSE-affected dams and 315 control calves (from the same farms) born to unaffected dams. The calves are to be kept until the age of seven years (November 1996) and all survivors will be autopsied for signs of BSE. So far about 150 have died, 51 confirmed BSE. The trial is blind, so no conclusions can be drawn from the deaths alone, only when the trial ends will the maternal status be revealed. All calves were apparently exposed to contaminated feed at some point. Epidemiological surveys to date have shown somewhat elevated odds-ratios in the offspring of BSE-affected cattle.

The calves.were up to six months old and all were weaned. The period selected is dangerously close to the feed ban in July 88. As a result a 10% infection rate could be expected, or if most of the calves were weaned after the ban (allowing for feed stocks etc) then one would expect a very much lower figure.

Note control calves may have been born to cattle that developed BSE at a later date -- perhaps 20% of them. If there is genetic predisposition to BSE, the calves from sick cows would have a greater penetration of it. These calves were also exposed in utero to a cow with a more advanced stage of disease than controls (whose mothers may not have been sick at all). BSE cases are expected in both groups, but 51 BSE cases (possibly more at autopsy) may be enough to show a statistically significant effect if there is one.

A statistical significance of 5% would be possible now [from chi-squared test] if there were twice as many affected case calves as control calves, but an elevation of 50% over control calves would be significant if a further 40 BSE cases turn up. [More cases give better statistical resolving power.] If maternal status is a factor then this study should show it. The autopsies should also show how many clinically asymptomatic animals have BSE at seven years of age.


51 cases of BSE so far; 90 cases expected by November 1996
excess at risk control stat. sig. at risk control stat. sig.
10% 27 24 0.66 47 43 0.65
20% 28 23 0.47 49 41 0.36
50% 31 20 0.11 54 36 0.04
100% 34 17 0.01 60 30 0.001


There are demands for the trial to be ended now (including some from individual members of SEAC), rather than wait for November.The incidnce of BSE amongst seven-year-old cattle in 1994 was 4.75%, which equates to a further 15 cases of BSE or 2.5 cases PER MONTH in the 630 cattle in the study. The table shows how rapidly significance rises with additional cases of BSE. Unblinding the trial will not affect significance, but ending it most certainly will.

The vertical transmission study achieves greater statistical resolving power than previous epidemiological surveys by a balanced design. The large number of affected mothers ensures that a much lower ratio of experimental to controls is likely to be significant. Conversely, the selection process and large numbers involved ensure that a spurious correlation is less likely. "Maternal status" in this trial is whether or not the calf's mother had been diagnosed with BSE.

If there is an excess of BSE among calves with BSE-affected mothers, it would indicate that maternal status is associated with calf status. In the absence of any other transmission route, this would imply a causal association and maternal transmission. Because these calves were also exposed to BSE-infected feed (and equally so because both cases and controls come from the same herds) it will not be possible to conclude that maternal transmission occurred, only that the maternal status was a factor in the status of the calf. This is the real hypothesis that the study will test: BSE occurs more frequently in the calves of dams with BSE.

It is not clear how genetic predisposition is disentangled from in utero infection. Dependent on the inheritance pattern (and on what proportion of the dams of control calves were truly BSE-free), there are likely to be between twice and three times as many BSE-susceptible animals amongst calves of affected dams. My rough guess was that 20% of bulls are BSE-susceptible, leading to a BSE susceptibility rate of 60% (rather than 100%) in the case calves. The fact that both cases and controls were exposed to contaminated feed is unlikely to significantly alter the findings.

The numbers of case and control cattle with BSE may become available to the public long before the formal publication of results (indeed announced recently by the BBC Newsnight team, not the researchers). This experiment is very significant to lifting of the EU beef ban, because maternal transmission could make the currently proposed eradication scheme wholly inadequate. If there is ANY excess of BSE in case calves, some will say: "the study demonstrates maternal transmission, therefore blood leukocytes are infective, therefore all parts of the cow (including milk) are infective, therefore the human dimension is beyond measure." The final report is due officially in mid 1997.




Calving in the UK by month of birth 84-90. Dairy only.Calving rate in % per month.
88 89 90 91 92 93 94
Jan 10.0 8.5 8.9 8.7 8.0 7.8 8.1
Feb 6.8 6.5 7.1 6.8 6.5 6.3 6.7
Mar 5.3 5.3 5.8 5.8 5.9 5.6 5.9
Apr 4.8 4.8 4.8 5.0 4.8 5.0 5.6
May 3.4 3.6 3.7 4.0 4.2 4.5 4.9
Jun 3.1 3.5 3.8 4.4 4.9 5.6 5.8
Jul 4.4 6.1 6.5 6.9 8.4 9.3 9.4
Aug 8.6 9.8 9.9 11.1 11.8 11.6 11.6
Sep 13.3 13.7 14.1 14.4 12.8 12.6 12.3
Oct 15.9 14.6 14.0 12.8 12.3 12.1 11.7
Nov 13.4 13.5 11.7 11.0 11.3 10.7 9.8
Dec 11.1 10.2 9.7 9.0 9.0 8.9 8.3
Tot(k) 2362 2488 2570 2482 2460 2570 2630


Infectedness by calving month. Cases per *thousand* calvings.
84 85 86 87 88 89 90 MA %
jan 1.7 2.4 3.4 7.0 10.0 4.2 1.35 10.0 87
feb 1.7 1.7 3.5 6.6 9.9 2.3 0.87 9.9 91
mar 2.3 3.0 5.2 9.7 9.2 3.7 0.94 9.7 90
apr 2.0 1.6 3.8 9.1 9.9 2.3 0.75 9.9 92
may 1.6 2.6 4.5 10.1 11.6 2.1 0.79 11.6 93
jun 1.9 2.7 6.8 13.9 15.6 5.6 1.24 15.6 92
jul 2.6 5.4 9.5 20.8 12.6 5.6 1.56 20.8 92
aug 4.0 6.8 12.1 27.6 12.4 7.0 1.47 27.6 95
sep 6.3 8.6 14.2 25.7 10.3 5.2 0.95 25.7 96
oct 4.0 5.5 9.8 15.9 5.8 3.1 0.52 15.9 97
nov 3.2 4.4 7.9 13.1 3.9 2.0 0.31 13.1 98
dec 2.5 3.8 6.9 10.9 3.6 1.8 0.37 10.9 97

BSE maintained by vertical and horizontal transmission

British Medical Journal 1.20.96
R W LACEY
Professor of clinical microbiology
Department of Microbiology
University of Leeds

EDITOR, - In their article looking at the possibility of maternal transmission of spongiform encephalopathy R M Ridley and H F Baker analyse previously published information and conclude that natural sheep scrapie has a genetic basis.[i] Of course this is so. Because of the absence of nucleic acid within the infective particle, host genome is required for the pathogenesis of the disease,[ii] and it follows that such genes are inherited in various ways. This in no way negates the well established observations that the transmissible spongiform encephalopathies are due to infectious agents which are acquired by vulnerable hosts in a variety of ways, including maternal transmission.[iii] Maternal transmission cannot sustain the disease in a species in the long term, but it will occur in association with horizontal transmission due, for example, to several lambs or ewes eating or having contact with an infected placenta.[iv]

Ridley and Baker omit to provide any of the evidence supporting the occurrence of vertical and horizontal transmission of the infectious agent for bovine spongiform encephalopathy under farm conditions. This evidence includes the following.

By early 1989 bovine spongiform encephalopathy had been carefully studied for three years, and it was predicted that the total number of cases would be 17,000-20,000, on the assumption that neither vertical nor horizontal transmission occurred.[v] By 26 October 1995 the number of cases of bovine spongiform encephalopathy that had been confirmed in the United Kingdom was 154,150.[vi]

Because of the belief that recycled animal remains was the cause of bovine spongiform encephalopathy[v] this practice was made illegal from 18 July 1988 after extensive consultation. Indeed, in early 1989 this ban was considered to have been implemented effectively.[v] From September 1988 to April 1989, newborn calves were removed from 600 dams by the Ministry of Agriculture, Fisheries and Food and were reared on fresh grass so that the extent, if any, of vertical transfer could be quantified.[v] By January 1995 more than 30 of these animals had died of bovine spongiform encephalopathy,[vii] although the details of the experiment have not been published.

Furthermore, since the ban on cannibalistic feeding was imposed in 1988 over 22,000 animals have been born that have subsequently developed bovine spongiform encephalopathy; one was born as recently as June 1993. Interestingly, the range of ages at which the disease was diagnosed in these animals is virtually the same as that in animals born before the ban (table).


Distribution of ages of animals with conformed bovine spongiform encephalopathy born before and after feed containing recycled animal remains was banned in July 1988 Figures are numbers (percentages)
Age (years) Born before ban,disease diagnosed 1989[iii]*Born after ban, disease diagnosed 1990-5**
1- 1 (0.02) 1 (0.004)
2- 28 (0.52) 81 (0.38)
3- 586 (10.81) 2824(12.44)
4- 2138 (39.45) 9820 (43.24)
5- 1874(34.58) 7966 (35.08)
6- 667 (12.30) 2008 (8.84)
7-8 125 (2.31) 9 (0.04)
*England and Wales.
**Data given in letter from A Browning (minister for food. Ministry of Agriculture, Fisheries and Food) to D Hinchcliffe (member of parliament), Nov 1995.


These figures show that bovine spongiform encephalopathy is now endemic and is being maintained by vertical and horizontal transmission. However, the Ministry of Agriculture, Fisheries and Food maintains that all the affected animals that were born after the ban were exposed to remnants of contaminated feed (data given in letter from A Browning (minister for food) to D Hinchcliffe (member of parliament), Nov 1995),[vi,vii] with the implication that those involved in the production of feed and also farmers have been breaking the law on a massive scale. But if traces of infectivity from the feed were responsible for the disease in these animals, the animals would be expected to be older, as the incubation period of transmissible spongiform encephalopathies is inversely related to the infecting dose.[iii]

R W LACEY
Professor of clinical microbiology

Department of Microbiology University of Leeds Chapel Allerton Hospital Leeds LS7 4SA

References
i. Ridley RM, BAKER HF The myth of maternal transmission of spongiform encephalopathy. BMJ 1995;311:1071-6. [With commentary by RG Will (21 October.)

ii. Beuler H, Aguzzi A, Sailor A, Greiner RA, Autenried P, Aget M, et al Mice devoid of PrP are resistant to scrapie. Cell 1993;73:1339-47.

iii. Dealler SF, Lacey RW Transmissible spongiform encephalopathies: the threat of BSE to man. Food Microbiology 1990;7: 253-79.

iv. Dickinson AG, Young GB, Stamp JT, Renwick CC An analysis of natural scrapie in Suffolk sheep Heredity 1965;20:485-503.

v. Southwood R. Report of the working party on bovine spongiform encephalopathy. London HMSO, 1989.

vi. Hinchliffe D, parliamentary question to Browning A. House of Commons official report (Hansard) 1995 Oct 31;265:cols219-23 (No. 154.)

vii. Hinchliffe D, parliamentary question to Browning A. House of Commons official report (Hansard) 1995 Jan 31;253:cols 645-7. (No 42.)


No evidence so far for maternal and horizontal transmission

H F BAKER 
Senior scientific officer
BMJ  ediltorial 1.30.96

EDITOR - R W Lacey admonishes us for failing "to provide any of the evidence supporting the occurrence of vertical and horizontal] transmission of the infectious agent for bovine spongiform encephalopathy under farm conditions." [i]The data from commercial farms regarding the occurrence of bovine spongiform encephalopathy in the offspring of cows that themselves developed the disease can be found in Hoinville et al's paper.[ii]

These veterinary epidemiologists carried out a case-control study of 477 animals with bovine spongiform encephalopathy and 1,294 matched, unaffected animals all born after the ban on feed containing recycled animal remains was introduced in 1988 and retained in the same 349 farms. The results showed that 94.4% of the animals with bovine spongiform encephalopathy and 95.7% of the control animals were born to dams that did not subsequently develop the disease. This difference is not significant, and the data provide strong evidence that maternal transmission is not a risk factor. The possibility of horizontal transmission is being assessed by looking for bovine spongiform encephalopathy in the indigenous members of herds that have never been exposed to the foodborne source of infectivity but into which purchased animals that subsequently developed bovine spongiform encephalopathy have been introduced. This assessment is incomplete but to date provides no evidence for horizontal transmission.[iii]

i. Lacey RW. Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. BMJ 1996;312:180-1. (20 January)

ii. Hoinville LJ, Wilesmith JW, Richards MS. An investigation of risk factors for cases of bovine spongiform encephalopathy born after the introduction of the "feed ban." Vet Rec 1995;136:312-8.

iii. Wells GAH, Wilesmith JW. The neuropathology and epidemiology of bovine spongiform encephalopathy. Brain Pathol 1995;5:91-103.

iv. Fraser JR, Foster JD, Fraser H. Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. BMJ 1996;313:181. (20 January.)

v. Davis T. General view of the agriculture of Wiltshire. London: Richard Phillips, 1811:140-9.


Other studies and assertions of cow-to-calf transmission of BSE:

  • The 1995 SEAC Progress Report: a 1.9:1 (357:185) ratio of BSE amongst calves of affected cattle was given in . Again this was not statistically significant due to the small number of affected animals involved. Of all BSE issues, vertical transmission is the issue that seems to provoke the greatest hostility. Earlier associations are probably real, but masked by the high levels of infectivity to which cattle have been exposed in the past. A statistically significant association can be expected in the forthcoming trial too.

  • LJ Hoinville, JW Wilesmith and MS Richards
    An investigation of risk factors for cases of bovine spongiform encephalopathy born after the feed ban
    Veterinary Record (1995)136:312-318

    This article shows a statistically non-significant excess of BSE in 81 mothers of BSE-affected cattle (5.6% of mothers of BSE cases, n=25; 4.3% of mothers of unaffected animals, n=56). The results section states that "Although 5.6% of the cases and 4.3% of the controls were offspring of animals subsequently affected by BSE, the odds ratios did not attain a high level of statistical significance, and provided no evidence for a statistically significant association between maternal status and the occurrence of the disease".


    Correspondent in NZ:

    Tomai's case of the Japanese woman with the prion in the colostrum and the umbilical lymphocytes suggested that all prion diseases have a vertical capacity.