Vertical and lateral transmission of TSEs

This review was kindly provided on 10.8.96 by:
Phil Rogers MRCVS
Work Fax: 353-46-26154
Work Tel: 353-46-25214
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The question of vertical and/or lateral transmission of TSEs is unresolved. Scrapie is almost certainly transmitted laterally and vertically (Constantin 1994).

MAFF workers (Bradley & Wilesmith 1993; Bradley 1994; Taylor 1994; Wells & Wilesmith 1995) state that the feeding of contaminated MBM was the only proven source of BSE in the UK and that lateral or vertical transmission of BSE in cattle is not proven. However, in June 1995, the UK Subgroup on BSE (chaired by Bradley) stated that "maternal and horizontal transmission cannot be excluded".

Lateral transmission may occur in some species: since 1970, a small herd of kudu at the London Zoo derived from 3 individuals. TSE was diagnosed in 5/8 kudu born in this herd since 1987. With the possible exception of the first confirmed case, none of these is thought to have been exposed to feeds containing ruminant-derived protein. Greater kudu are very susceptible to TSE and natural lateral transmission may have occurred among them (Kirkwood et al 1993).

Dealler & Lacey (1994) suggested vertical transmission of BSE. Ridley & Baker (1995) disagree: "The probability of maternal transmission of TSE in any species should be viewed with the greatest scepticism". No maternal or paternal transmission of was found in the progeny of mice inoculated with the agent of CJD (Taguchi et al 1993). However, research in MAFF (UK), released on Aug 10th 1996, has confirmed vertical (maternal, or cow-to-calf) transmission rates of about 10%, or about 1% per infected cow per year (Anon 1996).

Anon (1996) BSE research results suggest "enhanced risk" of
       maternal transmission.  Vet Rec AUG 10;139(...):126-127.

Baker,H.F.  & Ridley,R.M.  (1996) CJD and BSE:  Study so far
       provides no evidence for maternal and horizontal
       transmission.  Brit Med J MAR 30;312(7034):843.  HF Baker,
       Sch Clin Vet Med, MRC, Compart Cognit Team, Dept Exptl
       Psychol, Cambridge CB3 0ES, England.

Bradley,R.  (1994) Embryo-Transfer and Its Potential Role in
       Control of Scrapie and BSE.  Livest Prod Sci
       MAR;38(1):51-59.  R Bradley, MAFF Cent Vet Lab, New Haw,
       Addlestone KT15 3NB, Surrey, England.  
BSE is a new TSE of cattle resulting from consumption of a Scrapie-like agent in MBM of concentrate rations. There is evidence of a decline in the epidemic following the introduction of a feed ban in July 1988. Cow to cow transmission is not proven. Scrapie is an endemic disease of sheep known for over 250 years where maternal and horizontal transmission are responsible for the difficulty in controlling the disease.

Embryo transfer (ET) is a valued method of moving genetic material around the world with negligible risk of transmitting infectious diseases provided the International Embryo Transfer Society protocols are used. Data on ET and the control of SE in sheep and cattle is being investigated in the USA and the UK. In regard to sheep there are conflicting results. Washed embryos from experimentally infected sheep in the USA have not transmitted Scrapie to recipients though no account was taken of the genetic susceptibility of the embryo or recipient.

In contrast in the UK, using Sip and PrP genotyped experimentally-infected sheep and unwashed embryos, Scrapie resulted in the homozygous susceptible (sAsA) offspring within 979 d. The question as to whether ET can be used to control natural Scrapie in sheep is thus unresolved. Further studies to investigate the effect of washing embryos are in progress. In the UK, 1000 embryos have been collected from confirmed BSE cows and some have been transferred into 347 heifers imported from New Zealand as calves and subsequently held under quarantine conditions. Some embryos and uterine flushings have been inoculated into susceptible mice. No disease has resulted but the experiment will not be completed until 2001.

Constantin,A.  (1994) A Short-Story of TSSEs.  Bull Acad Natl
       Med MAY 3;178(5):859-871.  A Constantin, Intervet SA,
       F-49125 Briollay, France. 
Sheep Scrapie, the archetype of TSSE, has been described for more than 200 years but the first scientific papers appeared 60 years ago. The link between doctors and veterinary surgeons enabled our knowledge to develop. First, a Slow Virus was evoked, then Hadlow DVM (USA) suggested using brain filtrates from deceased patients of Kuru in order to inoculate primates or small rodents; this was carried out by Gajdusek's team.

The complete absence of an immune reaction has made the label "Slow Virus" give way to Unconventional Transmissible Agent (UTA). The few human cases of TSSE have all been transmitted to mice, rats, hamsters. Prusiner (San Francisco) has given us an enormous boost with the notion of prion, a protein molecule derived from an ordinary small membrane protein. Having recourse to transgenic mice has enabled American and European teams to demonstrate the essential role of genetics in the formation of the UTA. Those responsible for the Health of Cattle in U.K. will not contradict us. Future Research will be fascinating and will open a new chapter in the Medical Science concerning Mammals.

Dealler,S.F.  & Lacey,R.W.  (1994) Suspected Vertical
       Transmission of BSE.  Vet Rec FEB 5;134(6):151.  SF
       Dealler, York Dist Gen Hosp, Dept Microbiol, York YO3 7HE,
       N Yorkshire, England. 
A female Friesian-Holstein cow aged 4 years with clinical signs suggestive of bovine spongiform encephalopathy (BSE) was slaughtered. Histological examination of the brain revealed findings typical of BSE with severe spongiform change. It is suggested that since the cow was born after the ruminant feed ban and since its dam had been a confirmed case of BSE the history is suggestive of vertical transmission of BSE.
Dealler S (1995) Vertical transmission of BSE: epidemiological
       evidence. Prion meeting at Gottingen, November 1995.
       Burnley General Hospital, UK.

He made it clear that various statistics in the epidemiology of BSE did not fit with the epidemiology that was expected for a disease that was passed purely through feed. What fitted much better was the model that it was the mothers that ate the infective material and they infected their offspring. The appearence of cattle in Portugal with BSE that were the offspring of exported UK cattle, the slow decay in the cases of BSE after the feed ban, the increased likelyhood of a herd that has had a case of BSE to have another compared with unaffected herd, the steady in-herd rate at approximately 25% (why not 100%?), and the apparent 2 peaks in the age distribution of cattle developing BSE.

A lot of ifs and buts were needed to fit the MAFF model to the epidemiology but it could be done. However, the vertical transmission model fitted it well. The added risk from BSE to a UK adult that continues to eat beef products is now less than 5% of the risk that has already been taken. Dealler S and Kent J. When the difference in risk for people stopping eating beef at specific dates is compared with the risk for those continuing it is seen that there is little difference by the time we reach 1996. By this time little difference is seen but only applies for people that have eaten beef throughout the epidemic until that point. It is also made clear that the apparent difference was quite wide in 1989. The statistics only used the human diet as liver, kidney, meat (and the nerves they contain).

Dealler S (1996, Internet): Aetiology of scrapie in cetain
       circumstances is not evidence against another aetiology in
       different circumstances. BMJ 20 Jan 1996 p 180. Ros Ridley
       and Harry Baker, Dept of Exp Psychology University of
       Cambridge. This is the continued argument that the findings
       of various groups that suggest vertical transmission of
       scrapie can be explained in a genetic manner.

Dealler S (1996, Internet): BSE is being maintained by vertical
       and horizontal transmission. BMJ 20 Jan 1996 p 180.
       Professor Lacey, University of Leeds He explains that the
       epidemiological models used by MAFF had one by one been
       shown not be be adequate to explain the huge number of
       cattle that have developed BSE after being born after the
       feed ban. He says that the recycling of remains would cause
       the rapid rise of the disease but could not be the only
       cause for the number of cases remaining so high.

IFST Bovine Spongiform Encephalopathy (BSE): Position Statement,
       14 September 1996.
Placental transmission has been proposed as a likely route for vertical transmission for scrapie in sheep, although the existence of vertical transmission of scrapie has been disputed [Ridley and Baker (1995)]; but placental transmission has not been demonstrated with BSE in cattle. Until recently, there has been no evidence of maternal transmission in cattle.

A large-scale epidemiological study [Hoinville et al (1995)] should have brought to light the occurrence of vertical transmission if it occurred, but it did not, which was strongly suggestive of no significant occurrence. Preliminary results from the long-term experimental trials started in 1989, involving 315 calves born to BSE-infected dams (nearly all born within 13 months and many within 5 months before clinical onset of BSE in the dams) and 315 controls born of healthy dams, were the subject of a MAFF announcement and a SEAC report on 1 August 1996 [when the research paper is published, the reference will be given in an Editorial Footnote].

Some 550 animals, having reached their seventh birthdays had already been slaughtered and their brains histologically examined. BSE occurred in 15% of the test animals and 5% of the controls [presumed to be due to exposure to infected meat-and-bonemeal feed in their early years]. SEAC assumed that this represented 10% risk of maternal transmission in the trials, and, by assuming further that the risk is negligible in calves born through the earlier part of the dams' incubation period, estimated a risk of 1% in the field. However, the latter is unsubstantiated speculation, based on an unverified assumption, although some support for it may or may not be implicit in the results of a subsequently-published computer study [Anderson et l (1996)] [see later].

What the trial showed was a statistically significant association between BSE-infected dams and occurrence of BSE in the calves, but, on information currently available, did not establish the cause of that association. That cause may be maternal transmission or, for example, inherited genetic disposition coupled with exposure to infected feed. If it is in fact maternal transmission, that would raise the question of the mode of transmission, as yet unanswerable in the light of current knowledge and methodology.

Fortunately, whether the real risk was 10% or 1% or somewhere in between, will have no significant bearing on the continuing rapid decline in the number of new BSE cases and in the virtual eradication of the disease. Whatever the level of risk was, it has been operating throughout the period of rapid decline and is thus also, as the stock exchange analysts put it, already discounted in the epidemiological forecasts of further decline [e.g. Stekel et al (1996)]. Moreover, in the absence of horizontal transmission, of which there is no evidence, and in enforced absence of infected MBM feed, the effect found in this trial would be the only route for future infection.

Taking the figure actually found in the trial, 10%, and assuming the worst case situation that it applied throughout the calving lives of the dams, it means occurrence in one in ten of the offspring of BSE cows in 1989 (for the trial results are, of course, the belated findings on what actually happened in 1989).. Even assuming that, of that second generation (now 7 years old), all of the calves inheriting BSE survived and became dams for a full calving career (and it must be borne in mind that all are culled at 30 months, but even ignoring that), that means that there will have been occurrence in one in a hundred of the second generation's offspring. And in one in a thousand in the third generation's offspring, and so on. Of course, the geometric reductions in numbers of transmissions does not happen in large several-year-jumps like that, but in a smoother descending curve, because "generations" overlap and one must think in terms of annual cohorts, but over time the numbers must at least decline in that way.

Narang,H.  (1996) Origin and implications of BSE.  Proc Soc Exp
       Biol Med APR;211(4):306-322.  H Narang, Ken Bell Int, 22-40
       Brentwood Ave, Newcastle Tyne NE2 3DH, Tyne & Wear,
This is a review of TSEs. All animal and human SEs are slow-developing infectious diseases. The current working theory links the origin of BSE to the feeding of cattle with MBM prepared from the remains of scrapie-infected sheep. Recycling of cattle MBM essentially resulted in the selection of a single strain from the "wild type", a mixture of 20 strains. The BSE agent is easily transmitted through ingestion, with some evidence of vertical transmission.

Paradoxically, cattle have selected a major new strain which appears to be more virulent than an unselected strain found in scrapie sheep. The same strain of BSE agent is implicated in the occurrence of SE in domestic cats, tiger, and some exotic species of ruminants in zoos. The properties of BSE and its spread into cattle are still disputed. Since our understanding of the disease and its transmissibility in humans must await observations that will be made over some years to come, it is important to keep a reasonable perspective and ensure that any speculative comment is consistent with fact.

In risk assessment in such circumstances, it is tempting give too much credence to persuasive parallels when direct relevant information is not available. On the other hand, it would also be unwise to assume that the disease will die by itself and will have no effect on humans.

Ridley,R.M.  & Baker,H.F.  (1995) The Myth of Maternal
       Transmission of SE.  Brit Med J OCT 21;311(7012):1071-1075.
       RM Ridley, Sch Clin Vet Med Cambridge, Innes Bldg,
       Cambridge CB3 0ES, England.  
It has long been accepted that the pattern of occurrence of Scrapie, the form of SE associated with sheep, is determined mainly by maternal transmission. This view has had a profound influence on policy decisions in the control of BSE and on public concern over the risk to human health from this disease.

The occurrence of maternal transmission is, however, not predicted by modern knowledge of the aetiology of SE, and even though claims of maternal transmission have been reiterated frequently in the literature, re-examination of the source data reveals that they are extremely scanty, unreplicated, and probably subject to ascertainment bias. The probability of maternal transmission of SE in any species should be viewed with the greatest scepticism.

Taylor,K.C.  (1994) Suspected Vertical Transmission of BSE.  Vet
       Rec FEB 12;134(7):175.  KC Taylor, MAFF, Govt Bldg, Toby
       Jug Site, Surbiton KT6 7NF, Surrey, England.
Taguchi,F., Tamai,Y.  & Miura,S.  (1993) Experiments on Maternal
       and Paternal Transmission of CJD in Mice.  Arch Virol
       130(1-2):219-224.  F Taguchi, Kitasato Univ, Sch Hyg Sci,
       Dept Microbiol, Sagamihara, Kanagawa 228, Japan.  

No transmission of CJD in mice was observed in 75 offspring born to CJD agent-inoculated females or to normal females mated with inoculated males and in 19 normal offspring maintained by foster nursing with the inoculated mothers. The fertility of young adult female mice was lost by d 57 after the inoculation, whereas the reproductivity of male mice was maintained over 106 d after the inoculation.
Wilesmith,J.W., Wells,G.A.H., Hoinville,L.J.  & Simmons,M.M.
       (1994) Suspected Vertical Transmission of BSE.  Vet Rec FEB
       19;134(8):198-199.  JW Wilesmith, MAFF Cent Vet Lab,
       Addlestone KT15 3NB, Surrey, England. 
The research which has been undertaken into potential sources of Infection and means of transmission is briefly described. Results of this research which are not yet complete, will estimate the risks of infection from feedstuffs, dams and as a result of horizontal transmission.

The results of monitoring histopathological changes in the brains of clinically suspect bovine spongiform encephalopathy have shown a remarkable consistency of lesion pattern which has confirmed that the diagnostic method currently used remains valid. Research on the pathology of the disease showed that mean lesion scores in all brain regions increase with clinical duration but there is no correlation between short clinical duration and mild or equivocal histological changes.

Will,R.G.  (1995) The Myth of Maternal Transmission of SE:
       Commentary:  Scrapie Revisited.  Brit Med J OCT
       21;311(7012):1075-1076.  RG Will, Western Gen Hosp, Dept
       Clin Neurosci, Natl Ct CJ, Dis Surveillance Unit, Edinburgh
       EH4 2XU, Midlothian, Scotland.
Will RG & Wilesmith JW. Response to the article: "Vertical
       transfer of prion disease" by Lacey and Dealler. Human
       Reproduction 1994; 9(10): 1792-1800.