AN ELECTRON MICROGRAPH of the rinderpest virus.
EXACTLY 300 years after Giovanni Maria Lancisi, the chief physician of one of the oldest public health facilities in Rome, wrote the first book-length manuscript on rinderpest – the animal disease that had been a scourge for millennia, devastating cattle and their keepers and destroying local or even national economies – and 250 years after the first veterinary college opened in Lyons, France, spurred on by Lancisi's writings, the viral disease has been eradicated from the face of the earth.
On June 28, the Food and Agriculture Organisation (FAO) of the United Nations declared in Rome through a resolution of its 192 member-states that the world had “achieved freedom from rinderpest in its natural setting”. About a month before this formal announcement, the Paris-based 178-member World Organisation for Animal Health (OIE) – formerly the Office International des Epizooties – which has closely partnered with the FAO's Global Rinderpest Eradication Programme (GREP), had adopted a similar resolution after the final report of the Joint FAO/OIE Committee on Global Rinderpest Eradication had been released.
On the basis of the OIE's detailed archived dossiers of country-wise information on their progress to rinderpest-free status, the report had concluded in January that rinderpest “as a freely circulating viral disease” had been eliminated from 198 countries of the world. Accordingly, in February, OIE experts gave the green signal to recognise the remaining countries as rinderpest-free, and this was done in May.
This is only the second disease to be completely eradicated, after smallpox in 1979. This is no mean achievement given that even up to the 1950s the infection was widely spread over large swathes of Europe, Asia and Africa. It is a demonstration of what globally mounted strategies backed by advances in veterinary science, with well-planned epidemiological studies, sustained and focussed vaccination campaigns, constant disease surveillance and monitoring and, most importantly, political commitment and cooperation among countries and their veterinary health programmes can achieve.
The GREP itself was launched by the FAO only in 1994 when it was recognised that a single, cohesive approach, combined with technical and financial help, was needed to overcome, isolate and eliminate the disease. There were gaps in the international efforts until then, which found that the disease had re-emerged in regions that had been rendered rinderpest-free. Rinderpest-free countries bordering countries with the infection faced the constant threat of transboundary incursion. Once endemic pockets in different parts of the world were identified and appropriate measures, including trade barriers, put in place, the two organisations could set 2010 as the target year for complete eradication. Although the last reported outbreak was in Kenya in 2001, the FAO halted all activities only in October 2010 after completing the elaborate process of certifying countries not historically rinderpest-free and susceptible regions as rinderpest-free, thus paving the way for the May-June 2011 declaration.
Rinderpest is a German word meaning cattle plague and is perhaps, historically, the most important animal disease. It was referred to as the steppe murrain as it was regarded as a disease from the Steppes between Europe and Asia. The disease spread west to the Atlantic and east to the Pacific and is believed to have been carried by marauding Mongol armies. It was a scourge throughout Asia, Africa and Europe, with war, trade and rail transport aiding its spread up to the mid-20th century.
Sir Gordon R. Scott and A. Provost wrote in their background paper on rinderpest eradication for the FAO in 1992: “[Rinderpest is] the most dreaded bovine plague known, belonging to a select group of notorious infectious diseases that have changed the course of history…. [F]rom its homeland around the Caspian Basin, rinderpest, century after century, swept west over and around Europe and east over and around Asia with every marauding army, causing the disaster, death and devastation that preceded the fall of the Roman Empire, the conquest of Christian Europe by Charlemagne, the French Revolution, the impoverishment of Russia and the colonisation of Africa.”
Interestingly, the Americas have remained unaffected by the infection throughout history except for its introduction from Asia into Brazil, along with Australia, in the early 20th century. But both incursions were quickly contained and stamped out. Europe was constantly infected. In the 18th century, Pope Clement XI, alarmed by the number of deaths in the papal herds, ordered his physician Lancisi to take action and control the situation.
Lancisi, after his study, concluded: “The disease was caused by exceedingly fine and pernicious particles that pass from one body to another.” He ordered the slaughter of infected animals, the burial of whole animals and the inspection of meat, and restricted the movement of cattle, in order to reduce the spread of the disease. The penalties for violators were drastic, including death by hanging. During the 1714 outbreak in Britain, the royal surgeon, Thomas Bates, adopted Lancisi's methods but without the draconian penalties and also included financial compensation to the devastated farmers. Much of Lancisi's principles are still valid for pandemic epizooties.
The pandemic of Africa in the 19th century was perhaps the most destructive. The epidemic is believed to have started in north-eastern Africa with the import of infected cattle from either Yemen or India to feed the Italian army based there. In the next decade or so, the disease caused unprecedented devastation, killing 80-90 per cent of susceptible animals. Similarly, in the late 1980s, supplies for the Indian Peace Keeping Force in Sri Lanka included live goats, and it is believed that local cattle got infected with rinderpest. It was not until 1999 that Sri Lanka was declared “provisionally rinderpest free”, and only in 2011 was it granted the final “free from rinderpest” certification.
The historical spread of the disease, however, had the salutary effect of leading to the growth of veterinary services in various parts of the world. The massive losses of cattle in France led to the founding of the first veterinary school in Lyons in 1761, and soon nearly all of Europe followed suit and institutionalised Lancisi's ideas though Britain and its colonies like India had to wait another 100 years for veterinary services to be established.
The OIE itself was established in 1924 following a new incursion of the rinderpest virus (RPV) in Europe via the port of Antwerp in Belgium. A group of veterinarians decided to found an international organisation that could inform its member-countries of epizootics and provide them with scientifically founded animal disease control measures.
The RPV is related to the human measles virus (MeV), most likely the latter's precursor, and belongs to a group of closely related, yet distinct viruses called morbilliviruses. Besides the RPV and the MeV, the morbillivirus genus includes peste des petits ruminants virus (PPRV), canine distemper, phocine distemper, and a recently recognised virus in aquatic mammals. The RPV infects cloven-hoofed beasts, including domesticated cattle and buffaloes and large antelopes, deer and even giraffes and wildebeests in the wild. It is a highly contagious disease that is characterised by necrosis and erosions throughout the digestive tract. The mortality rate in infected animals is high, generally 50-80 per cent, and in its severest form the disease can kill up to 95 per cent or more of infected animals. Affected animals develop fever, discharges from eyes and nose, mucosal erosions from the mouth to the anus, diarrhoea, dysentery and eventually death. The infection leads to rapid protein loss, weight loss and dehydration and can result in death typically in 10 to 12 days. Animals that survive are debilitated and take a long time to recover.
Surviving an exposure to wild strains or attenuated live vaccines confers a sterile lifelong immunity. When the virus is introduced into a formerly unaffected but susceptible population, the impact is marked by high mortality. In 1994, for example, as many as 50,000 cattle and yaks died within a few months in the valleys of northern Pakistan. However, in endemic areas, which serve as reservoirs of infection, much of the population will be protected either through earlier exposures or through vaccination. In such areas, it has been found that mild strains of the virus also exist, and these are difficult to detect clinically. But, most interestingly, mildness is not a fixed characteristic and can get modulated to high virulence under certain circumstances and when the virus is transferred to a distant susceptible population. The biological basis of this modulation is, however, not yet fully understood.
Using the technique of reverse transcriptase-polymerase chain reaction (RT-PCR), the existence of three different phylogenic lineages of the virus was identified by the FAO World Reference Laboratory for FMD and Rinderpest at Pirbright, United Kingdom. Two of these originated in Africa and one in Asia. According to the present understanding, African lineage 1 has generally been restricted to East Africa, stretching from Egypt, through Sudan to Ethiopia, Kenya and Uganda. On the other hand, historical evidence suggests that Africa lineage 2 was much more widely distributed, covering both West and East Africa. Livestock trading resulted in the spread of the only Asian lineage virus westwards into Oman, Saudi Arabia, the UAE, Yemen and even Turkey, rendering some of the regions endemic.
Strict control of animal movement caused a decline in the disease in most of Europe, but it was the development of vaccines in the late 19th and 20th centuries that made global eradication of the disease a distinct possibility. All the RPVs belong to a single serotype, and therefore one vaccine can provide protection against all existing forms of the virus. Further, there is no carrier state in the host, and exposure to the virus gives lifelong immunity. These factors render rinderpest a good candidate for global eradication.
Era of vaccine
The era of the rinderpest vaccine began with the discovery in the late 1880s, by E. Semmer in Russia and Arnold Theiler and Herbert Watkins-Pitchford in South Africa, that a mixture of infected blood and immune serum from a recovered animal confers immunity. While the immune serum conferred passive immunity, the animal's own immune system mounted an active response against the virus in the infected blood, providing lifelong immunity. This led to the serum-virus method of immunisation, which was used throughout Africa and in India up to the 1930s. However, vaccinated animals were potentially infectious and needed to be physically separated from unvaccinated ones. Despite this drawback, it was effective, and the method was used to eradicate rinderpest from the entire European Russia by 1928.
In 1927, J.T. Edwards fortuitously modified the RPV by growing it serially in goats. After 600 passages, the virus was found to be attenuated, and mass immunisation with this attenuated goat tissue virus (GTV) became possible. From 1931, this came to be increasingly used in India. Freeze-drying of the material gave a powdered vaccine with a prolonged shelf life, but such a (caprinised) GTV had its limitations: it was found to result in fever, mouth lesions and diarrhoea in some cattle breeds.
With advances in virology, it became possible to grow specific cells in tissue culture. W. Plowright and R.D. Ferris succeeded in growing the virus in bovine kidney cells, which led to the development of the tissue culture rinderpest vaccine (TCRV). This was found to be safe and immunogenic for cattle of all breeds. The only problem with the vaccine was its heat instability and the attendant need to maintain an effective cold chain. A more thermostable variant of the TCRV, called Thermovax, was developed in the 1990s by J. Mariner. It could be used in the field for up to four weeks at ambient temperatures as long as it was sheltered from sunlight and excessive heat. This was widely used in mass vaccination programmes in Africa.
Mass vaccination constituted a central tool in the early strategies adopted by the global rinderpest eradication effort, and it is the worldwide availability of the TCRV that made eradication possible. As early as the 1960s, mass vaccination campaigns, accompanied by conventional control measures such as quarantine and trade restrictions, led to a substantial global decline in rinderpest, which, however, made a devastating reappearance in Africa 20 years later.
This led to the OIE recommending standards for the establishment of rinderpest epidemiological surveillance systems, which contained what is now known as the “OIE Pathway”. This was to be used by countries that wanted to be officially recognised as rinderpest-free. In essence, it set out a three-step process (“provisional freedom from rinderpest disease”, “freedom from disease” and “freedom from infection”) that constituted a series of verifiable epidemiological objectives against which progress towards eradication could be measured over a period of six to seven years from the last detected case. Most significantly, cessation of vaccination was integral to the OIE Pathway, and completing all the steps of the Pathway (disease- and serosurveillance) was far less costly than continuing with endless rounds of mass vaccination. India was declared “provisionally free from disease” in March 1998, “free from disease” in May 2004 and “free from infection” in May 2006.
In parallel, in 1994, the FAO spearheaded the GREP in collaboration with the OIE, the International Atomic Energy Agency (IAEA) and other institutional partners, governments, regional organisations and communities worldwide. The international cooperation, coordination mechanisms and funding by developed nations have been fundamental in achieving eradication, particularly in the poorest countries. The partnership with the OIE was particularly noteworthy in aiding national authorities to seek accreditation from the OIE.
One of the most difficult elements in the eradication process was making the transition from mass vaccination to serosurveillance. Until the 1990s, vaccination campaigns tended to be an institutionalised national activity. For instance, many countries in Asia and Africa continued to implement vaccination campaigns even after rinderpest had been eliminated from a territory. The inability to differentiate between antibodies induced by vaccination and the wild virus infection created doubts about the rinderpest status, and therefore, vaccination campaigns were continued.
The GREP coordinated with national authorities to withdraw mass vaccinations following successful vaccination campaigns, which allowed epidemiologists to identify reservoirs of endemic rinderpest and carry out focussed vaccinations to move towards eradication.
The GREP was also instrumental in overcoming instances of lack of communication among countries on their rinderpest status. Even though the RPV was isolated from Landhi Dairy Colony in Karachi in 1984, Pakistan did not implement an eradication programme for over a decade. Here was a case of two neighbouring countries each of which had the virus circulating. But, while one had embarked on a major eradication programme, the other lacked the requisite resources to tackle the spread, in particular to fight the commercial pressure.
In 1994, the RPV spread from central Pakistan to the north, causing an outbreak among an unexposed population, which turned out to be one of the worst in many years before it was brought under control through the GREP. Throughout this episode, there apparently was no communication between the veterinary authorities of India and Pakistan, but India maintained a 30-kilometre buffer zone with 100 per cent vaccination along the border, obviously at a cost. Subsequently, the infection spread to Afghanistan.
The Indian experience thus provided several lessons for the GREP in its efforts at rendering difficult endemic pockets around the world rinderpest-free. Indeed, during the celebration of global freedom from rinderpest, Malleshappa Rajasekhar, former head of the Project Directorate on Animal Disease Monitoring and Surveillance of the Indian Council of Agricultural Research (ICAR), was awarded a medallion by the FAO on June 27 in Rome for his outstanding contribution to global eradication of the disease.
Now that the world is free of rinderpest, what next? According to Juan Lubroth, Chief, Animal Health Service, FAO, exhaustive searches for the RPV have been done under the GREP. “We are confident that the virus really has been removed from its natural setting and we know of no wild or domestic reservoirs of this disease,” he said.
But the virus is still there in many laboratories around the world, and these have to be guarded against accidental or deliberate release. “We have to be sure that this virus, or these tissues, are kept securely or even destroyed to be sure that it doesn't escape. This is one of the key responsibilities facing countries in the post-eradication phase,” he added.
The GREP, according to him, will, therefore, continue for the next five to 10 years. National authorities are expected to communicate any suspicion of a rinderpest outbreak to neighbouring countries and to the FAO, whose referral laboratory at Pirbright will provide free diagnostic services to all countries. This also means that countries should maintain budgetary allocations towards national rinderpest programmes.
Following the FAO/OIE report, a mechanism has been developed to arrive at an international agreement on a list of laboratories where viruses and sera could be maintained for research purposes and where vaccine master seeds and vaccine banks could be established under proper biosecurity conditions. The post-eradication strategy recommended by the report includes the declaration that all RPVs, biological samples and vaccines have been destroyed in all locations except the agreed upon laboratories. Guidelines for the sequestration of all biological material in recognised laboratories and for the granting of authorisation for research on the material are in the process of being evolved. Given its bio weapons implications, this too could elicit a controversy as has happened in the case of the small pox virus, and a case for the complete destruction of the RPV could be made.
Since the virus genome is known, the function of the encoded proteins involved in replication of the virus are known and the virus can be rescued from its constructive genes, says M.S. Shaila of the Indian Institute of Science, Bangalore, who has been engaged in RPV research for 32 years. “There are many unanswered questions on the molecular basis of its pathogenesis vis-a-vis the host cells,” she says. Shaila herself has been using only recombinant clones expressing viral proteins either in E. coli or in a baculovirus expression system in recent times, and so her research work will not be affected, she says.
Post-eradication activities under the GREP will include study of the potential sources of latent RPV reservoir species, possible re-emergence of the RPV, or a reversal of virulence of attenuated mild strains, and ensuring emergency vaccine and diagnostic kit availability and distribution. Most significantly, the future programme includes formulation of a control/eradication strategy for the PPRV, a virus close to the RPV, using the lessons of the GREP. In theory, the PPRV or any other member of the morbillivirus genus could mutate into the RPV. “But this could accidentally happen over many hundreds of years or more and such a possibility is very unlikely,” points out Shaila.
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