Surveillance and training key to cattle plague endgame
One of the most devastating animal diseases known to man looks set to be officially consigned to the history books. As the World Reference Laboratory for rinderpest, staff at the Institute for Animal Health, an institute of BBSRC, have played an important role towards eradicating the disease, which has helped to reduce famine and poverty in rural communities and increase agricultural production throughout the developing world.
On 15 October, the Food and Agriculture Organisation (FAO) of the United Nations declared the end to field operations as part of the Global Rinderpest Eradication Programme (GREP). Rinderpest has been described as the most dreaded of all animal diseases, which, in its most virulent form, can result in more than 80% mortality of cattle, buffalo, yaks and many cloven-hoofed wildlife species.
FAO estimates that additional production due to rinderpest's eradication from India alone between 1965 and 1998 added up to $289 billion, and the benefits in Africa have been estimated at around $1 billion per year during the same period (ref 1).
"Most importantly, the protection of cattle in sub-Saharan Africa, the Near East and Asia has improved both food and income streams for hundreds of thousands, if not millions, of pastoral people and small farmers, and helped avoid famine and the loss of draught power in agricultural communities," says Felix Njeumi of the GREP Secretariat at FAO.
Vaccination against the disease has been at the heart of rinderpest eradication campaigns throughout the 20th century, supported by the development of appropriate technologies.
"One of the biggest problems in an eradication campaign is the delay between actually getting a sample and a diagnosis - getting a sample from the field to the laboratory - during which time the disease is still progressing and spreading," explains Dr John Anderson, former Head of the World Reference Laboratory for rinderpest at the Institute for Animal Health's (IAH) Pirbright Laboratory.
Meeting user needs
IAH researchers have played a central role in the development of new technologies appropriate to key stages of rinderpest eradication. The early stages of the campaign, prior to GREP, involved extensive vaccination. The available vaccine was heat sensitive and required a 'cold-chain' to retain its efficacy under field conditions. Post-vaccination testing was essential to determine if the vaccination had been successful or not.
"We needed a new assay to handle the large number of samples that were generated throughout affected regions, and this had to give reproducible results across the network of laboratories in these countries," says Dr Anderson.
Researchers at IAH Pirbright developed a simple 'indirect ELISA' for the detection of antibodies to rinderpest which was field trialled extensively by Dr Anderson in Tanzania before being introduced into the FAO/International Atomic Energy Agency Rinderpest Laboratory Network in the 1980s. IAH staff provided support, training and 'technical backstopping' for those countries either just starting testing or encountering problems in their laboratories. The use of a single test and a single supplier, Biological Diagnostic Supplies Ltd., ensured test reproducibility. In fact, when IAH carried out blind-testing to validate the network's results they found a 98% agreement between all African laboratories involved, a figure much higher than was shown at the time for AIDS testing.
Image: Stockbyte/Thinkstock 2010
In the later stages of the campaign, tests were needed that could differentiate between antibodies to rinderpest and the closely related virus peste des petits ruminants (PPR) across a range of susceptible animal species. IAH Pirbright responded to this need and in 1990 scientists there developed a 'competitive ELISA', which had increased sensitivity and specificity compared to the earlier indirect ELISA. The new test was based on a monoclonal antibody, which facilitated test kit standardisation, quality assurance and reproducibility. It was used throughout GREP where it greatly assisted in the interpretation of results and gave increased confidence in the quality of these results during regional and border-harmonisation meetings.
Once the mass vaccination stage of the programme had ended, the focus moved to disease surveillance. Clinical surveillance would not detect mild strains of the virus therefore the emphasis was on antibody detection. Again the competitive ELISA proved invaluable due to its high sensitivity and, more importantly, its high specificity. In Ethiopia, the test's specificity was shown to be greater than 99.5%. This considerably reduced the number of false positive results and consequently the number of field investigations. The test proved essential in the Somali Ecosystem - the last area of the world to report suspected rinderpest - to demonstrate that there was no serological evidence that rinderpest was still present.
Throughout the 1990s, as GREP moved into its closing stages, rapid diagnosis was essential since delays in submitting samples to national laboratories could result in further spread of disease. To overcome this problem, IAH researchers developed a field-based test, using the same 'lateral flow' technology as the widely-used home pregnancy test, which gave a result using a simple eye swab within 5-10 minutes. This provided field veterinarians with a powerful yet low-tech tool, the results from which could not be ignored by officials. From its first trials in Pakistan, the test has proven highly valuable. And during an outbreak in Tanzania in 1997, when a clinically mild virus strain was present, the pen-side test proved to be the only means to detect it. It was also used very successfully to identify the few remaining pockets of rinderpest in Pakistan and led to an announcement from the FAO that Pakistan was free from the disease.
A place in history
For centuries, rinderpest has been feared by man. Wherever it has occurred, rinderpest has caused terrible destruction of cattle, damaging livestock agriculture, rural livelihoods and bringing famine and starvation. Rinderpest epidemics have preceded the downfall of the Roman Empire and the French Revolution.
The disease has also defined modern veterinary science: it was instrumental in the founding of the world’s first veterinary schools, the establishment of the World Organisation for Animal Health (OIE) in 1924, and the FAO Animal Health Service in 1946.
Following previous attempts to control the disease, the FAO launched GREP in 1994, to co-ordinate international efforts to promote eradication and provide a mechanism to verify freedom from the disease, as well as technical guidance, through its reference laboratories, on how to achieve these goals.
The FAO and OIE are expected to make a joint statement declaring rinderpest freedom in June 2011. This would make rinderpest the first animal disease and the second infectious disease, after smallpox, to ever be eliminated.
Creating skilled workers
Throughout the rinderpest eradication campaign, including the forerunners of GREP (PARK and PACE) IAH staff have acted as advisors to the OIE and FAO. They have provided training for scientists in rinderpest diagnosis and antibody detection as well as on-the-spot training for lab technicians and vets working in diagnostic labs in countries where the disease was present or suspected. Dr Anderson also instigated the formation of the Advanced Veterinary Information System (AVIS) - a consortium consisting of IAH, FAO, OIE and multimedia specialists Telos Aleff Ltd who provided interactive programmes in all aspects of rinderpest from clinical diagnosis, field control, laboratory diagnosis, epidemiology and public awareness.
"The success of our technology transfer programme was realised in the late 1990s when IAH expertise was no longer needed for troubleshooting in diagnostic techniques. Many African experts had been trained and were available to assist not only in Africa but also in Europe and Asia," he says.
At the same time, an initiative funded by the Department for International Development (DfID) and Save the Children led to the training of community-based animal health workers (CAHWs) who, as trusted local herdsmen, achieved high levels of disease surveillance and vaccination in 'no go' areas where war made it impossible to operate state veterinary services.
According to Dr Anderson this approach had a big pay off, "When we received samples from Southern Sudan, an area of civil unrest with no functioning veterinary services, we were able to provide evidence that CAHWs had achieved greater levels of immunity than the state vets had in adjacent areas."
The dawning of the molecular era
It was also during the 1990s that the late Professor Tom Barrett, the then head of rinderpest research at IAH, developed a procedure for the genetic fingerprinting of rinderpest virus, which provided a real breakthrough in understanding the epidemiology of rinderpest outbreaks. For the first time, researchers were able to identify the source of the virus in an outbreak, and the likely means by which the disease had arrived in a region. This enabled more precise detective work to be carried out, in order to better understand why pockets of infection remained. In 1993 this RT-PCR technique, followed by DNA sequencing, was used to show that an outbreak of the disease on the Russian-Mongolian border had originated in Asia. In the following year there was an unexpected outbreak of rinderpest in buffalo and kudu in south Kenya. Analysis revealed that the virus was from a lineage that had been thought to be extinct, revealing the presence of another, previously hidden, endemic focus in the region.
African scientists. Image: Institute for Animal Health
With the ability to generate genetically modified forms of rinderpest, research at IAH also paved the way for genetically defined 'marker' vaccines against rinderpest that would have had the important feature of allowing animal health workers to distinguish between animals that had been vaccinated and those which had had disease. As it turned out, these marker vaccines were not used as part of GREP, as they were developed too late in the campaign. But the reasons for developing such vaccines are applicable to other diseases, including rinderpest's close relative, another Morbillivirus, pestes des petits ruminants (PPR).
"PPR is a growing problem in the developing world, causing enormous losses to sheep and goat herds, the mainstay of the poorest livestock keepers. The existing PPR vaccine is a weakened form of the virus. Once you start using it you can't distinguish vaccinated and infected animals, so it is nearly impossible to survey for active infection in areas where there is a lot of vaccination happening," explains Dr Michael Baron, current head of Morbillivirus research at IAH. "This has serious implications for controlling the spread of the disease through trade."
Dr Baron is currently leading a joint BBSRC/DfID-funded project at IAH to create and test a marker vaccine for PPR.
Where do we go from here?
If rinderpest is a disease of the past, PPR is a disease of the present. There is some evidence that the cross protection conferred by exposure of sheep and goats to circulating rinderpest kept PPR in check until recently. But, over the same period that eradication of rinderpest was completed, the geographical distribution of PPR expanded.
"What we know is that PPR has spread further south in Africa than rinderpest ever did. It is now endemic in most of Western and Eastern Africa; it's in central Asia and is also present in Turkey and Morocco where it threatens to push into continental Europe," says Dr Chris Oura, current Head of the WRL for rinderpest.
The experts at FAO are in agreement that it should be possible to eradicate PPR using the same tools and strategies that were put into practice to eliminate rinderpest.
"One of the great tragedies would be if we allowed all of the people who were involved in the eradication of rinderpest to retire and their expertise to disappear before we have captured it all - we need to look at the lessons that were learnt from rinderpest to see how they can be applied to future challenges," says Dr Baron. "The knowledge we acquired through our work on rinderpest has enabled us to develop new vaccines, techniques which we are now applying to PPR."
Dr Anderson concludes, "I think we should look back at the success of global rinderpest eradication and see it as a blueprint. It won't necessarily work with all diseases, or all animal virus diseases, but it could work as a basic format to approach eradication programmes. For too long, I think, people have been involved in controlling diseases and not actually dreaming that it is possible to eradicate a disease from the world, but with rinderpest we have!"
Emergency response faculties
As the FAO World Reference Laboratory (WRL) for rinderpest, scientists at the Institute for Animal Health’s (IAH) Pirbright Laboratory have provided expertise to organisations such as the FAO, OIE, and the EU, and also to the UK and foreign governments, to advise on disease control policy. Today, the WRL continues to provide rinderpest diagnostic kits and receive samples for testing. They supply standardised reference strains and reagents that are used to calibrate diagnostic test systems and as research tools by research institutions around the world.
IAH Pirbright is home to reference laboratories, and provides diagnostic services, for eight other ‘List A’ diseases: African horse sickness, African swine fever, bluetongue, foot-and-mouth disease, lumpy skin disease, peste des petits ruminants, sheep and goat pox, and swine vesicular disease.
The Pirbright site is currently being redeveloped to provide state-of-the-art, specialist facilities that will strengthen our strategic capability to protect UK livestock and other animals – including people – from devastating diseases. This new international centre of excellence will act as a hub for researchers across the UK and abroad. It is expected to open its doors in 2013, following an investment by the Department for Business, Innovation and Skills of over £100M.
- Develop improved vaccines against PPR for use in disease control
- Develop strategies for the progressive control and eventual eradication of PPR
- Dr Chris Oura, Institute for Animal Health
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