From: Alvin W. Smith, DVM, PhD Professor, Oregon State University College of Veterinary Medicine Laboratory for Calicivirus Studies Corvallis, Oregon 97331 Fax 541 737 2730
October 4, 1996
Mrs. Marguerite Wegner
16 Montes Square
Riverton
Western Australia 6148
Dear Mrs. Wegner:
Thank you for your inquiry of 3 October 1996 regarding whether or not the concerns which I expressed to the Honorable John Howard, the Honorable John Anderson, and others involving the host specificity of the rabbit hemorrhagic disease virus had been addressed in the August 1996 BRS document entitled "Rabbit Calicivirus Disease". The answer is a resounding NO. In fact, now it becomes an even more obvious case of an orchestrated "cover-up" of key data.
Recently, I had delivered into my hand a very incriminating letter addressed to all VPC members telling them to inform all state ARMCANZ ministers that the Honorable John Anderson would reply to my concerns AFTER the unanimous decision of all ministers to release rabbit hemorrhagic disease was publicly announced and that the Honorable John Anderson would then make the BRS report available to me. This 12 September letter, signed by G.W. Eggleston Program Manager Agriculture Protection, then went on to instruct the state ARMCANZ ministers to respond to me as follows:
1. "Thank Dr. Smith for his letter.
2. Indicate that you understand Minister Anderson has received and has responded to his letter and has provided a copy of the BRS report to him.
3. And that we should say no more than this."
The final decision approving the release of rabbit hemorrhagic disease was announced on 16 September 1996; my letter and BRS report from Minister Anderson were written and posted on 23 September 1996, and arrived on 30 September 1996, right on cue. All the data was kept under wraps until after a "lock-step" decision had been carried out.
This may be politics at it's best but it does not solve the real and pending problem of potential threat to the livestock, wildlife and people of Australia. Next week (9 October 1996) there is to be a scheduled release of the rabbit hemorrhagic disease agent in New South Wales at 50 different sites. The problem is that the BRS data provides even more reasons suggesting the potential for cross-species infectivity of this agent. Let me point this out by briefly answering your specific questions.
1. You ask if the Australian scientists' test of the rabbit hemorrhagic disease agent were adequate to prove that it infects only a single species, the European rabbit. The answer is no and in fact their test data suggests quite the opposite, that perhaps 20% or more of the species tested may have become infected (see specifics below).
2. You ask for specifics from the test data presented on pages 37-42 in the BRS report. These are serum antibody tests to determine whether infection occurred when animals were given a 1000 rabbit lethal dose50 of virus. Drs. Westbury and Lenghaus have repeatedly stated that this was a dose intended to be so low it would not in itself stimulate antibodies unless the virus replicated in the test animals. Using this criteria, any increase in antibody should be interpreted as probable infection (AAHL criteria, not just an A.W. Smith opinion). Next, the tests themselves were adjusted up to readings of 0.3 for the indirect ELISA and 30% inhibition for the competitive ELISA. This was done because of pre-existing calicivirus-like antibody activity already existing in Australian rabbits (1994) which cross-reacted with the rabbit hemorrhagic disease agent antibodies. In other words, there appeared to be other caliciviruses infecting Australian rabbits that are unknown but resemble rabbit hemorrhagic disease in their protein structure. This explains 1) Why the tests were required to have such high values (0.3 and 30% or above) to be declared positive and, 2) also explains why some animals tested positive before being innoculated. The upshot of this is that overall these test reagents and the tests were simply inadequate even when pushed to the outer limits in attempts to rank obvious antibody response to rabbit hemorrhagic disease injection as negative.
In summary, virus doses were kept low in an attempt to prevent any antibody responses, and antibody tests were "rigged" to require that very high antibody responses would be needed before the test would be graded as positive. This can be likened to avoiding tea leaves (contaminants) by never drinking tea from the bottom third of the cup. The bottom 30% may be all tea or all leaves, you won't know so to be safe you avoid the bottom third of the cup. The same is true for the tests. You never know whether the bottom third is all rabbit hemmorhagic disease antibody or all background so you just don't use it. Even rabbits that survived rabbit hemorrhagic disease infections did not become positive to the competitive ELISA test before 20-30 days after injection and 29 of 32 Australian species were killed and tested on day 14 after injection, ie well before they were expected to develop a positive test even if infected. The tests were set up to get a negative response but that didn't always happen.
a. 4 of 4 chickens were positive even before they were injected. The tests are meaningless.
b. 3 of 4 mice had obvious antibody increases. One was high enough to be ranked positive even by the "rigged" testing cut-off value of 0.3.
c. 4 of 4 bush rats developed an antibody response but did not reach the cut-off level by day 14 so were called negative.
d. 4 of 4 hares appeared not to respond, but hares in Europe and Asia are routinely reported to have rabbit hemmorhagic disease antibodies. This gives some verification of how very low and subimmunogenic the 1000 RLD dose of virus really was.
e. 2 of 4 Brown falcons were postiive. One was positive before injection, the other became positive after injection.
f. 3 of 4 ferrets had increasing antibodies on day 7 and even higher on day 14, yet were killed while the levels were still going up, but had not reached 30%, so they were called negative.
g. 4 of 4 pigeons had increasing levels of antibody and 2 raised to over 29% ie less than 1% below the 30% cut-off.
h. 2 of 4 Silver gulls became strongly positive 46 & 38%, but then began to decline. This same pattern was detected in pigeon whose values, started up a second time from their lowest level on day 14 and their highest level on day 28. The gulls were killed on day 21.
i. 1 of 3 Blue-tongued lizards was positive before testing began.
j. 2 of 4 Northern brown bandicoots had antibody increases. The highest level reached on day 14 was 25%. This is considerable higher than occurs with infected rabbits by day 14.
k. 2 of 4 Koalas died soon after injection (less than one week). Was this poor animal care or rabbit hemorrhagic disease?
l. 1 of 4 wombats was positive and reached the 30% cut-off level on day 7.
m. 4 of 4 Echidnas had 2 to 10 fold antibody increases. All were increasing at 7 days, and increased even higher at 14 days, but again they were all killed while their antibody levels were going up at an even faster rate than occurs with rabbits.
n. 4 of 4 Kiwis were positive.
o. All bats (7), including 2 that were exposed by contact but not injection, appeared to have antibody increases (missing data). One had a documented increase at 14 days that exceeded the value for infected rabbits at 14 days.
Please note that if any of these results were suspected of being due to a simple protein reaction as occurs with virus vaccines, the experiments could have been repeated by giving the same amount of killed virus in the same solutions as was carried out with the live virus and the result compared. If the results were the same there was probably no virus replication. If the animals getting live virus developed higher levels of antibody than the "killed virus" controls then the virus is most probably replicating in the test animals. If these very easy and simple tests were done, the results were not reported. One rather suspects they were not done because they may have demonstrated that some or all of the species listed with the above positive reactions had supported viral replication. This is to say they had been infected. If the BRS report shows anything, it shows non-target species are being infected by rabbit hemorrhagic disease injections using low amounts of virus.
3. The third question you asked "does the BRS report show that humans will not be infected"? Again, the short answer is NO! What the BRS report does not deal with is the known fact that 4 of the 5 calicivirus taxonomic groups do cause disease in humans. To my knowledge, only two human populations have been examined for rabbit hemorrhagic disease antibody; one in Australia and a small sampling in Mexico. Consequently, citing lack of human infection in 41 other countries on four continents is misleading; no one has looked. In Mexico, one out of this small sample had rabbit hemorrhagic disease antibody. In Australia, we see a remarkable "dance" taking place. On page 53 of the BRS report we read Chief Medical Office A.I. Adams' statement with five (count them) hedges and back doors in a single two sentence paragraph which concludes by him not endorsing the rabbit hemorrhagic disease release but instead not finding grounds to oppose it. Is anyone going to get a good night's sleep after reading this?
" 1) While at this stage 2) there is no guarantee of human safety with respect to exposure to rabbit calicivirus 3) I am satisfied that the above findings do not provide evidence that rabbit calicivirus is associated with infection. 4) On this basis and 5) with the limitations of the study in mind, I have no objection to the controlled release of rabbit calicivirus as a means of rabbit control".
None of the laboratory test values on the human serums are included in the BRS report, and for good reason. The indirect and competitive ELISA tests reportedly used are very likely to have shown a great deal of pre-existing calicivirus antibody activity which cross-reacts in the two AAHL tests just as was seen in the animal test serums. Because of the withheld data and because the same evasive misleading "tobacco company" language that is used by tobacco industry officials when addressing lung cancer and cigarette smoking is also used here by Australian government officials to describe the human risk of rabbit hemorrhagic disease, one can justifiably guess that the human serology data are open to interpretations that are not compatible with government policies on rabbit hemorrhagic disease release. Phrases like "no significant difference" between rabbit hemorrhagic disease exposed and non- exposed people are meaningless. What is called significant? Where are the numbers? Can we conclude there were differences but some mystery person somewhere using some unknown statistic, or no statistic at all, decreed "no significance"? This evasiveness raises suspicions because of all the other false statements that have already been made.
The carry home lesson for Australia is that now, today, with rabbit hemorrhagic disease loose in the country if any serum samples from any species including human is tested with the now standard tests (ie the indirect and competitive ELISA) and found to be reactive at any level it will not be known whether this is background reaction or low level rabbit hemorrhagic disease antibody. How then do the Australian's intend to reliably determine whether rabbit hemorrhagic disease has jumped, switched or otherwise infected non-rabbit species or even certain rabbits when the background levels of reactivity to the rabbit hemorrhagic disease antibody tests shown and alluded to in the BRS report range from near zero to above 0.5 and 50% and known infected animals (at least rabbits) will have had the disease for a month before their competitive ELISA tests go this high. How many infected animals including rabbits never get test levels this high? We simply don't know and the available diagnostic reagents will not tell us. This entire program is now a high stakes crap-shoot where all the players are blind including the government and no one knows who has the dice or where they are.
All in all, Mrs. Wegner, the BRS report did not address any of my concerns regarding host non-specificity and the possible human health considerations. Instead, because of the abuse of scientific methods and deception to the point of dishonest reporting, and interpretation of results, and the results themselves (flawed as they are), I am more concerned than ever.
If the Australian authorities really do believe in their data and the test interpretations they have made public, they should jump at the suggestion of convening an internationally recognized expert panel of calicivirologists to help interpret the data and solidify their position. This was first recommended to the then Prime Minister Keating and the Biological Control authority on Page Two of the 30 December 1995 submission filed by Dr. Matson and myself. Instead of welcoming such a suggestion, officials have stridently resisted the concept for nine months and instead substituted some statement about their data being reviewed by experts who remain nameless and anonymous. Why the resistance? I believe the answer is obvious. The data is flawed and very poor, to the point of embarrassment, but even beyond that, it would be impossible, in my opinion, for any responsible scientist to conclude that these data show the rabbit hemorrhagic disease virus to be species specific and that it will not infect humans.
The Polymerase chain reaction data which is also being used to proclaim abscence of virus in the tissues of potentially infected animals is equally as flawed as the serum antibody data, we could discuss that if needed.
As a measure of the reliability of the research data being cited to justify rabbit hemorrhagic disease release in Australia, Dr. Anthony Robinson presented an overview of the Australia rabbit hemorrhagic disease program at an international scientific meeting last month. When questioned pointedly in front of 65 calicivirologists from 12 countries concerning the manipulation used to arrive at his reported conclusions on the antibody results of the 28 species tested and the use of this as evidence that rabbit hemorrhagic disease would not infect any species except the European rabbit, he abandoned the defense of the tests and stated that "the serology wasn't very important." With that single statement, virtually all the scientific support for the purposeful spread of rabbit hemorrhagic disease has been wiped out.
Highest regards,
Alvin W. Smith, DVM, PhD
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