Return to warmwell.com

November 2006 ~ "authorities were not willing to use the U.S. real time PCR test for Foot and Mouth and neither would they use the differential test that discriminates vaccinated animals"

November 2006 ~ "British Intelligence had been made aware of this U.S. technology previously and they were reminded again in February 2001."

November 2006 ~"Did British authorities imagine that the ARS would offer a test that did not exist?"




BTACC Communication: International Veterinary Public Health Consortium

Dear Colleagues:

As per our current discussion associated with molecular detection technologies, I would like to pass on the following reply by Roger Breeze to Alex Donaldson.

In 2001, British authorities were not willing to use the U.S. real time PCR test for Foot and Mouth and neither would they use the differential test that discriminates vaccinated animals from those previously infected: both were rejected for lack of "validation."

As many of you are aware, this was my starting point for engagement during the 2001 UK FMD outbreak (ProMED: Foot & Mouth Disease - EU: Use of Vaccination - 02):

Since antibodies also arise from vaccination, very considerable effort has been made in the 1990s to develop tests [that] distinguish between vaccination antibodies and infection antibodies. At least 5 different tests have been developed and validated (an entire European Union-funded Concerted Action was devoted to this, research summarized in over 15 papers in the supplement of the Vet Quarterly, 1998, 20, suppl 2) and these now transform our ability to identify vaccinated animals that have not been infected. They can also identify the important category of animals that have been vaccinated in an emergency situation and [that] subsequently become infected upon severe virus challenge.


S.M.Apatow
------------------------------------------

November 2, 2006

 

ProMed Mail

 

Dear Sir,

 

In his letter to ProMed of October 2, 2006 (ProMed Archive Number 20061002.2821), my esteemed colleague Dr. Alex Donaldson rightly acknowledges the contributions of the more than 200 scientists who came with warm hearts and willing hands to help Pirbright through its time of need during the 2001 U.K. foot and mouth outbreak.  Unfortunately for British livestock owners, these were all they came with. New technology that might well have made a significant difference to thousands of people was offered by the U.S. government but was not taken up by the British authorities for reasons we shall perhaps never know and can only guess at from subsequent events. In his letter to ProMed over five years after the offer, Dr. Donaldson provides a new explanation for his government's decision, but the most reliable record is that given at the time to the government's Environment, Forestry and Rural Affairs Select Committee (EFRA), presumably under oath, on April 25, 2001 by Dr. Donaldson and Dr. David King, Chief Scientific Advisor to the British government  (testimony available at http://www.warmwell.com/efra25april.html). To put their testimony in context, I must first explain what the U.S. offered.

 

In the aftermath of the First Gulf War, the Clinton Administration asked its scientists to develop means to detect a specific list of potential biological weapons agents in samples of soil, water or air and to distinguish these viruses, bacteria and toxins from all other forms of life present in those samples, whether known or unknown. By 2000, not only was this practical but the analyses could be done by soldiers and non-technical personnel in about an hour on portable equipment at sampling sites anywhere in the world. And the results could be read and verified over the Internet in real time as they were acquired by experts located in the U.S. so that immediate informed action could be taken. Foot and mouth disease virus was on that list. I directed the U.S. Department of Agriculture portion of this effort. Before 2000, the U.S. government began to deploy these portable detectors at home and abroad in a variety of laboratory and non-laboratory situations and there are now hundreds if not thousands of such installations.

 

Real-time PCR was the chosen detection technology. Given that the U.S. government has indicated that use of any biological weapon against its forces or citizenry in war would trigger unlimited U.S responses, meaning the use of nuclear weapons against the aggressor, the scientific basis for detection was to be impeccable to avoid any false positive results. The new detection tests required a much more sophisticated knowledge of the genetic structure of these pathogens and their near-relatives than had previously been the standard for disease diagnostic purposes.

 

When this work began in 1999, there was not one complete genome sequence in the scientific literature for a representative virus from each of the seven foot and mouth disease virus serotypes. A team headed by Dr. Dan Rock at Plum Island determined the complete genomic sequences of 103 foot and mouth disease viruses covering all seven serotypes and subtypes and representative of this disease over time and over geography. These data were later published (1). A state of the art real time PCR test was developed based upon this unprecedented genetic information and this test was validated in vitro and in vivo during 2000 and early 2001 by the Plum Island team: these data were later published (2). Given the comprehensive genomic information that the test was based upon and its application over time in experimentally-infected animals of a number of target species, I think it no exaggeration to say that there was more genomic, in vitro and experimental validation data available on this test in 2001 than for any other diagnostic test in the history of veterinary medicine.

 

The February 2001 U.K. foot and mouth outbreak was the first opportunity to assess and validate this new portable technology and its Internet communications in the field in a country with a foot and mouth disease World Reference Center that could also perform traditional diagnosis as a benchmark. British Intelligence had been made aware of this U.S. technology previously and they were reminded again in February 2001. In March 2001, my boss, the Administrator of the U.S. Department of Agriculture's Agricultural Research Service (USDA ARS), the world's largest and most respected agricultural research organization, asked me to approach British Veterinary authorities to offer them the new foot and mouth PCR test with its devices and Internet technology. It was on behalf of USDA and ARS that I contacted Dr. Donaldson and Mr. Jim Scudamore, the Chief Veterinary Officer, with the intent of first making the Institute of Animal Health comfortable with the technology and its science and then taking the portable devices into the regions of the country where disease was spreading.

 

In April 2001, Dr. David King told the EFRA Select Committee:

  1. "Of course, we have investigated the potential use of this instrument; it is a PCR-based instrument ....... it is a means of detecting the virus. The world's experts in this application of foot and mouth are Dr Donaldson and his team at Pirbright ...." Dr. King was patriotic but wrong. In this application of foot and mouth, Dr. Donaldson and his team at Pirbright were not the world's experts: they did not have the foot and mouth virus genomic information, they had no knowledge of the portable detectors and the U.S program, and had not seen the U.S. foot and mouth disease test data in vitro and in vivo. Neither had Dr. King. The U.S. capability came as a bolt from the blue to all of them.
  2. "Now it is commercially available, but it is an untested machine and there are very serious questions to be asked about the use of that machine in the field, in particular the problem of cross-contamination. Now I have to stress that, if you are under laboratory conditions, Chairman, and you carry out these tests, you do get very accurate results. In the field, it is considerably more difficult to achieve this type of accuracy, particularly if you are going, as you want to do, to analyse a large number of animals, from animal to animal. And that cross-contamination problem has not been answered." Abundant data were available from across the U.S. government on the use of the machine. Extensive data were also available on the foot and mouth test reagents and their performance, which is the most important thing. The test sample is placed in a capillary pre-loaded by the manufacturer with the test reagents and that tube is then sealed and never subsequently opened. Cross-contamination could only come about on the farm if the sample from one animal were contaminated from another animal with foot and mouth in the same herd before it was put in the capillary tube. With or without such a possibility, the test result would be identification of an infected herd, the basis for subsequent decision making. In the event, British authorities chose to kill animals based on their Postal Codes without determining beforehand whether they were infected or not.
  3. "We would like to see very distinct field tests on this instrument; but my final conclusion, from talking to all the experts, including Fred Brown, is that, unfortunately, it will not be available to us for this epidemic." Dr. King did not speak to any U.S. experts on the foot and mouth test except Fred Brown: he did not speak to me even though I contacted his Chief of Staff to explain who I was and my role in the U.S. program. In late summer 2001, the ARS Administrator, who was personally astonished at British failure to use the best technology, took a scientific team directly to Dr. King in his Cambridge University office to demonstrate the technology and share U.S foot and mouth test data but he was uninterested and we never heard from him again.

 

Before the same Committee, Dr. Donaldson said:

1.        "In March, Dr Roger Breeze contacted me and said that he, working with the US military, had this 'smart cycler' equipment available, and he and his team would like to come to the United Kingdom and to test the equipment under field conditions to validate it during an outbreak situation; he was optimistic that it would be very helpful. He did say, in his correspondence, that the machine had not been validated for work with foot and mouth disease. I approached Jim Scudamore, Chief Veterinary Officer, and asked if this could be facilitated. Jim Scudamore's response was that he was very interested in the equipment and he would be very willing to collaborate with the USDA, but he suggested that this should be done after the epidemic had declined because there would be logistic problems in taking such equipment into the field. I sent a reply back to Roger Breeze, saying that the Chief Veterinary Officer was not willing to accommodate him at this particular point in time but would be willing to do so at a future date." As noted above, the test had an unprecedented intellectual basis and extensive in vitro and in vivo validation at Plum Island. What was missing was validation under field conditions (of the practicalities of test performance, not of the test reagents themselves) and further validation on the foot and mouth virus collection that had been accumulated at Pirbright over the years.  Mr. Scudamore missed the point about deploying the test capability immediately to perhaps 10 regional veterinary centers. There would have been logistical problems in driving to these centers from Heathrow airport and finding somewhere to plug in the machine but these would surely have paled beside the subsequent logistical problems of killing, burning or burying millions of uninfected animals, disinfecting hundreds of clean farms and issuing compensation checks to livestock owners for animals that were never infected in the first place.

2.        "I said, meantime, I would be willing to accommodate a scientist from the USDA at the Laboratory in Pirbright to test his equipment under standardised conditions, alongside PCR equipment which we already had and which is up and running and functioning." Please see my earlier response on this matter at http://www.warmwell.com/july18breeze.html.

3.        "The particular attraction of what the USDA have been offering is that their equipment is portable; it is a small device, operated by a battery, which can link to a lap-top computer, and that, in turn, can convey the output of the test result through the Internet. I should point out that the piece of equipment costs in the region of £22,000, and there was no indication of what would happen to the equipment once it had been taken onto an affected farm, in other words, how it will be decontaminated." The samples are placed in capillary tubes that already contain test reagents on the farm and then sealed. Like conventional samples, they are dipped in disinfectant solution as the veterinarian leaves the farm and then examined just beyond the farm gate or in a nearby lab. The machine does not go onto the farm.

4.        "So I expressed that view, that we would be willing to collaborate, sent that back to Roger Breeze. The next communication I had was on a Thursday, saying that he, Roger Breeze, and his team would be arriving the following weekend to test out the equipment. I said that would not be convenient, that we would have to arrange a time to accommodate him in the Laboratory when we could find space and to do it properly. He, in turn, offered to show the equipment to us over the Internet. It was pointed out to me by colleagues that one of my scientific staff was about to make a visit to Plum Island and it would be an opportunity for him to see the equipment, which we understood had been developed in collaboration with Plum Island. That scientist went to Plum Island, he was hosted by Dr Peter Mason, who is the foremost molecular biologist at Plum Island, he asked to see the equipment; the response he got from Dr Peter Mason was that he had heard about the equipment but he had not seen it nor had he been involved in any validation of it." Chairman Mao once said that a journey of a 1000 miles starts with the first step. I might add that a journey of 5000 miles from Pirbright to Plum Island to see the foot and mouth test ends with the last step. I have no explanation as to why the Pirbright representative did not walk the final four steps from Peter Mason's lab to the lab where the new foot and mouth PCR test had been developed and validated on the Plum Island foot and mouth virus collection.  Many others had managed to travel that short distance. Dr. Donaldson's testimony also illustrates the digital divide between the U.S. and U.K. in 2001.  Even under the urgency of an uncontrolled foot and mouth outbreak, given the option of learning the facts and seeing state of the art foot and mouth virus detection immediately over the Internet, he chose to find out a couple of weeks later after his colleague returned - when hundreds more premises might have been infected. And when that colleague failed in his task, weeks later on April 25th Dr. Donaldson testified that he had done nothing about it. Did British authorities imagine that the ARS would offer a test that did not exist?

 

A great deal of discussion has revolved around the issue of "validation." Almost every country has some kind of regulatory process that governs who can practice veterinary medicine and how they do so. Diagnostic tests, drugs, antibiotics and vaccines must meet some regulatory standard of safety and efficacy. In the U.K, how the veterinarian goes about diagnosing and treating the animals in his or her charge is subject to review by the Royal College of Veterinary Surgeons. Despite these standards, governments can do what they wish in extreme situations. In 2001, British authorities were not willing to use the U.S. real time PCR test for Foot and Mouth and neither would they use the differential test that discriminates vaccinated animals from those previously infected: both were rejected for lack of "validation." But because there are no statutory requirements for "validation" and approval, these same authorities then proceeded to use the non-validated techniques of mathematical modeling and contiguous culling that resulted in the slaughter of millions of uninfected animals and made the human, animal and financial costs of the outbreak far greater than they would otherwise have been. Where were the validation data for this foot and mouth control method before 2001 and where are they now?

 

Dr. Roy Anderson has confidently described how unvalidated techniques solved the 2001 foot and mouth epidemic (3). "Second, and perhaps more important, mathematical models have recently been used successfully to inform responses to epidemics that were covered heavily in the media: (1) an epidemic of foot and mouth disease, a viral disease in cattle and sheep, in Great Britain in 2001... and SARS. Thankfully, although both epidemics caused suffering and mortality and much anxiety, they were brought under control relatively quickly... In the past, such planning (for epidemics - RGB) would have been based on the consensus opinion of expert committees, consisting largely of specialists in medicine, infectious diseases, biology and public health. Today, however, calculation and simulation are replacing opinion and consensus..." The name of King Pyrrhus is normally associated with victory announcements of this kind.  Sadly, HAL and the other computers were calling the animal health shots in 2001 A Foot and Mouth Odyssey. Had British authorities used the U.S. portable real time PCR test, someone might have pulled their plugs sooner.

 

Sincerely,

 

Roger Breeze

Centaur Science Group

Washington DC 20007 

 

References

 

  1. Carrillo, C. et al., Journal of Virology, 79, 6481-6504, 2005.
  2. Callahan, J.D. et al., Journal of the American Veterinary Medical Association, 220, 1636-1642, 2002.
  3. Anderson, R.M., The Bridge, 36, 5-9, 2006.