On May 25, 2011, the International Organization of Epizootics (OIE), something like the WHO of veterinary medicine, declared eradicated an infectious disease that killed millions of animals and also ended the lives of millions of human beings.
This article has been conceived to show that animal health and human well-being are intimately connected. Also to share the history of a terrible disease that caused enormous suffering, to narrate the global race that led to its eradication and, finally, as a tribute to those that made this feat possible.
Today, rinderpest along with smallpox are the only two infectious diseases eradicated worldwide. Let’s hope polio soon is next.
I would like to start with a travel back in time: Rome A.D. 1713:
Nothing could appease Pope Clement XI. The recent signing of the Treaty of Utrech had caused him to lose territories and influence. France, with the Jansenist heresy and its king, that arrogant Louis XIV did nothing but give him headaches.
All this, although annoying, fell within the logic of the struggle for power. Something much more serious was keeping the Bishop of Rome awake. It was not sin or the works of the evil one that tormented him but something much more prosaic: his cattle were dying. Not even the procession to St. Peter’s Basilica, followed with zeal by the faithful, who also lost their animals, gave the expected results. The Lord seemed to have turned his back on him. 1714 began with the worst omens, the cold did not contain the epidemic and the fields were covered with dead animals. Hunger lurked. There was no milk, no meat, and much worse: no animals to plow the fields. Without them it was impossible to cultivate the land and obtain crops. As the year progressed, their losses were approaching 25,000 head: a catastrophe.
So, the Supreme Pontiff, to save his flocks, put his trust in the same person who took care of his health. His personal physician: Giovani Maria Lancisi.
Portrait of Giovani Maria Lancisi. The Pope’s physician
The doctor put to work and obtained the papal favor to – against the criteria of many cardinals – promulgate a series of norms among which the following consideration stood out:
“It is better to kill all the sick and suspicious animals, rather than allow the disease to spread in order to have enough time and the honor to discover a specific treatment that is often sought without success.”
To the sacrifice of all sick animals and those that had been in contact with them, he added a strict control of the movements of livestock (and other animals such as dogs) as well as the obligation to bury the corpses in quicklime and not take advantage of anything, skin nor meat, to avoid future infections.
In addition, those who did not comply with these norms paid it well with the punishment of galleys in perpetuity (if they were ecclesiastical) or were directly executed (all others). There were no exceptions of degree, social class or economic position.
In nine months, the epidemic was under control.
The success of the Italian doctor did not go unnoticed in the European courts and his standards were imposed in much of the continent. He also served to lay the foundations for the study of the principles that had controlled the epidemic and that resulted in the creation of the world’s first veterinary college, founded in the French city of Lyon in 1761 with the royal support of Louis XV.
Royal document of approval of the first veterinary college in the world. Lyon France 1761
Although in a very timid way, the rulers began to realize that this evil could not be overcome without cross-border collaboration. Historical enemies would have to work together to fight this cattle plague.
Today we know that the disease that ruined Pope Clement XI’s finances was cattle plague (also known by its German name of Rinderpest). A highly contagious and highly deadly virus (over 90%) that preyed on both domestic and wild ruminants. It arrived in Europe with the Asian armies and it was, later, the local armies that spread the infection since the logistics and transport of war materials made it necessary to use the traction force of the oxen who, together with the weapons, carried the infection. With the arrival of the railroad, the cattle trade grew exponentially and with it the transmission of the virus accelerated throughout the continent, arriving in waves mainly from Russia, where it was endemic.
The virus belongs to the genus of morbilliviruses such as canine distemper or measles. The latter appeared as a Rinderpest mutation that was adapted to humans around the 11th or 12th century AD. It is a highly contagious RNA virus. After infection, the animal began to show the first symptoms 3-6 days later: fever, lethargy, nasal and eye discharges, mouth sores and a foul odor. Later, diarrhea appeared, and the animal died a few days afterwards.
Symptoms of the disease and an actual photo of ocular discharge
The high animal mortality became a death sentence for the communities. Without cattle, milk and meat were lacking. But worse still, the driving force that allowed the fields to be plowed disappeared without oxen, it was the people who had to tie themselves to the plows and drag them to try to obtain a meager harvest, always insufficient. Those who could afford it bought horses or mules – immune to the disease – but high demand drove prices up.
Thus, in the successive epidemics that have been documented in the England of the SXIV, a draft horse went from a cost of 12 shillings to 35 in full epidemic. Hunger reached the villages, and it was not uncommon that hunger pushed people to eat carrion and even to commit acts of cannibalism.
Horse prices sharp increased in impacted communities. It took years to bring prices back to normal
Rinderpest accelerated historical events of first magnitude. Thus in 1749 the French physician Blondet described the situation in the countryside of his country: “desolate pastures, uncultivated lands, abandoned farms, everything testifies to our misfortune.” In the Limousin region alone, 4,000 people died of hunger in March 1770. In addition to the mortality caused by the disease, there were also the shots that the soldiers had been ordered to fire on any animal suspected of having been in contact with sick cattle. Although the king paid for the shot animals, the new prices of healthy cattle, always on the rise, made the royal compensation worthless. With no ploughing force, no manure, and without key food sources, it is not surprising that spirits were stirred and that discontent, as some historians point out, contributed to the breeding ground that led to the French Revolution in 1789.
Without oxen, people had to plough the fields. Exhausting work to obtain poor results
The horror was not limited to Europe, Africa suffered the plague as a result of successive imports of European cattle. At the end of the 19th century, the Ethiopian Emperor Menelik lost more than 250,000 cattle. Thus began the great Ethiopian famine of 1888-1892, which a French missionary described as follows: “wherever I go I come across walking skeletons or corpses half-eaten by hyenas, of the hungry who have fallen from exhaustion.”
One third of the Ethiopian population died because of this famine.
But not only domestic livestock were involved. Wild animals also suffered from the disease: buffalo, giraffe, antelope, all ungulates fell prey to the infection.
Livestock is deeply rooted in many African cultures for which animals are the only way to have capital, cattle constitute an economic system in themselves: dowries, inheritances and loans are paid with livestock. Animals’ death meant the death of entire cultures.
Cattle plague deaths in South Africa
Something had to be done and a good number of countries came to an agreement to put aside their quarrels and try to join forces and fight this disease.
In 1871, the Austrian government launched the first international conference for rinderpest control. Governments agreed to alert each other by telegraph when there was an outbreak of disease to interrupt the trade in animals, they promised to compensate farmers for their losses, as well as to implement stringent disinfection measures in the event of any positive diagnosis.
Following these rules, the German authorities alerted their British counterparts – in 1877 – that the animals that had just arrived in their territory from Hamburg could be contaminated as in the German city an outbreak of rinderpest had just been diagnosed. Rapid communication enabled English veterinarians to immobilize and slaughter the cows, and prevent the disease from spreading across English territory. The immobilization of German animals was quickly established, as well as the prohibition of importation into Dutch, Belgian, Swiss and French territory, among others. The efforts made it possible to stop the disease in Europe.
But although the virus saw its expansion in the old continent short-circuited, it began its wide expansion in other latitudes thanks to the colonizing activity of the European powers.
As an example, the importation of cattle to feed the Spanish military contingent located in the Philippine Islands introduced Rinderpest in the archipelago. But where the virus was rampant was on the African continent. In South Africa, the plague preyed on cattle and no preventive measure seemed to work. So serious was the situation that the government of the Cape province requested the services of Robert Koch who years before had established his famous postulates that allowed a disease to be attributed to a specific germ. Koch knew his trade and was certain that a micro-organism caused the plague. Vaccination experiences against rabies and smallpox made him optimistic about finding an effective prophylaxis against rinderpest.
After many tests with different body fluids, he ended up recommending that healthy cattle be inoculated with bile from animals that had died of the disease. The method was unsuccessful, but it allowed local scientists to create another alternative: injecting serum from infected animals. It was not an ideal solution, many other infections were transmitted trying to avoid the plague, but the inoculated animals developed some immunity against the virus. Mortality in treated cattle dropped from 77% to 44%. Colons of European origin had more access to this remedy and inoculated more, hence we can know the difference between cattle that did not receive prophylaxis -mainly from native cattlemen- versus those of owners of European origin.
In 1902, Turkish researchers proved that the agent behind plague outbreaks was a virus.
A few years later, in 1910, the Japanese invaded the Korean peninsula and Japanese veterinarians set out to create an immune belt between Korea and China to protect the Korean herd from rinderpest. To do this, the veterinarian Chiharu Kakizaki was able to inactivate the viral agent in blood and spleen samples by mixing them with glycerin: The first vaccine against rinderpest was born.
International coordination efforts to fight the plague took another big step with the signing of 28 countries for the creation, in 1928, of the OIE, the International Organization of Epizooties, still active today and which played a leading role, together with the FAO, in eradicating the rinderpest from the Earth.
A few years later, in the Philippines, an American military veterinarian, Raymond Alexander Kesler, used chloroform to inactivate the virus present in macerated spleen, lymph nodes and liver. The vaccine required multiple doses and provided immunity for a limited period of time, but the important thing was that it helped, along with quarantine and slaughter measures, to limit the disease. The Philippines launched a vaccination campaign that between 1924-1931. It was administered at a rate of 300,000 heads/year.
Raymond Alexander Kesler
Dead vaccines do not cause infection because the virus is inactive, but they are capable of “alerting” the immune system and generating defenses. The major drawback is the need to repeat the doses to maintain their prophylactic capacity, which is often prohibitively expensive and labor intensive.
The next battle was to get live vaccines, which could stimulate long-term immunity without causing the disease or led to an attenuated form, with mild symptoms. Previous experiences with rabies virus and smallpox invited to test the attenuation of the virus by passage in non-target species. Thus, it was tested on different animals with varying success. The first successful experience was obtained by passing in goats and gave rise to the vaccine called Kabete O, very effective for African cattle (although it produced a mild disease) but still fatal for 50% of the European herd, so the the old continent should continue with the administration of the dead vaccine.
Kabete O could easily be transported in previously immunized live goats. Once slaughtered, between 500 and 800 doses could be obtained from each goat. It was a tremendously efficient mode of transport in the conditions of the African continent.
We thus arrive in the 1940s. Quite surprisingly, the Second World War was, de facto, a boost in the fight against rinderpest.
American President Roosevelt knew firsthand the consequences of an infection. At the age of 40, he suffered a paralysis that he would live with for the rest of his life. Polio preyed on the little ones, but adults were not safe, either.
Now the war was his main concern and the dossier that had just arrived from the defense staff convinced him that he must act quickly. American intelligence knew that the Japanese were successfully developing biological weapons. In Manchuria, Unit 731 of the Japanese Army experimented with typhus, plague and cholera. His victims numbered in the hundreds of thousands.
It was essential to have vaccines and medicines that could neutralize a Japanese biological attack. And the US military got down to work and not only to defend itself from attacks on its human population but also to protect animals.
The island of Grosse is a small point on the map in the enormity of Canada. Located on the Saint Lawrence River, this island was the entry and quarantine point for the thousands of Irish emigrants who arrived on the coast of the country fleeing the great famine of 1845-49 due to the poor potato harvest. Many died there of typhus and cholera. It is the largest cemetery due to the great famine outside of Irish territory. It closed its doors in 1932, but reopened them ten years later to, this time, deal with rinderpest.
The Americans knew that if the virus reached their territory, the cattle lacked defenses completely, so it was imperative to immunize them with a vaccine, but to do so, the responsible virus had to be brought to American soil, with the risks that this entailed. The solution? Focus all the investigations on an isolated space such as the Island of Grosse.
The US Army was successful, in 19 months they had a new vaccine ready.
We have already seen how the Japanese knew about the disease and had not stopped making progress on its control: the veterinarian Junji Nakamura managed to attenuate the virus after repeated passage through a non-target intermediate species: the rabbit. Protecting cattle in Japanese territory was critical to the war effort. The American soldier was the best fed of the war, not so the Japanese. Protecting the herds was extremely important. The use of lapinized vaccine (passed more than 100 times per rabbit) was widespread in Asia. The reproduction of the plague virus had no secrets for the Japanese.
On his part, Hitler ruled out biological warfare altogether from the start, and although his lieutenant Himmler toyed with the idea, there were no real efforts to make it happen. This was not the case with the Empire of the Rising Sun.
The Japanese accelerated with their tests and the Americans, on the Island of Grosse, tried to beat them with an effective vaccine, and above all, easy to produce and administer. Work began with the chloroform-inactivated vaccine, but when injected into the calves, they produced only about 350 doses per animal. In 1943, to produce 100,000 doses, 270 bovids were needed. Virologist Richard Shope, in charge of the Canadian facility, estimated that to protect the North American herd, which then numbered about 60 million animals, it would take 170,000 calves and about 60 years of work at the current rate. Obviously, other solutions had to be found. The vaccine could stop small outbreaks, but not protect all livestock.
Shope decided to try a different route: grow the virus in bird eggs. Previous experiences with the flu virus had been successful, so that route was explored. He used the Kabete O strain. The process required passing the virus through a suspension of bovine spleen and then passing it through the chorioallantoic membrane of the egg for 8-12 times. From there it went to the yolk. At that point, the virus replicated with enormous speed invading the embryo and all the fluids that surround it within 24 hours.
This avianized vaccine conferred complete protection within 10 days after administration. And 3-4 doses were obtained per egg. In addition, frozen and vacuum packed, it retained its properties for 15 months. With this vaccine, in 1944, the US was prepared to neutralize a Rinderpest attack by the Japanese.
And the threat was absolutely real. At the forefront of the Japanese effort to infect American cows was the Japanese veterinarian Noboru Kuba. The plan consisted of adding viral preparations to hot air balloons that were built to bomb North American soil (some did hit and one caused the death of 6 people, the only casualties in the American continent from this war). Kuba prepared a mash of infected organs, dried it and obtained 50 grams of highly contagious powder. He did a test with a rocket that after exploding in midair, spread infectious dust around. 10 cows had been placed in the vicinity. The experiment was successful as all 10 cows developed symptoms and died of Rinderpest. The project arrived at Unit 731 (known after the war for its many atrocious experiments, mutilations, tests with the bubonic plague, etc.) with the idea of producing 20 tons of infective powder. The idea reached General Tojo who, although retired, still had an important influence on military decisions. Tojo was convinced that if rinderpest plan succeeded, the Americans would wipe out the rice crop, driving hunger to the heart of the Japanese empire. The plan was aborted.
Japanese war balloon
After the end of the war, the nations collaborated again to end the plague as it continued to rage. Thus, the Chinese herd lost 200,000-300,000 heads each year due to the infection, which condemned many farmers – children included – to pull the plows to get some grain from the land. Starting in 1947, millions of egg vaccine doses arrived from Canada. A network of local laboratories was established to produce the vaccine on site. Unfortunately, it was impossible to multiply the virus in eggs, the goat vaccine produced too severe symptoms in Asian cattle so, finally, the lapinized vaccine was chosen. Each rabbit provided between 300-600 doses, was easy to transport and to replicate. The lagomorph was injected and 3-6 days later it could be sacrificed to procure more vaccines. The program was an absolute success and the last Rinderpest case was declared in China in 1955.
At the international level, nations joined forces (with notable exceptions) to fight hunger. Thus in 1945 the FAO was created, an agency dependent on the UN created for this purpose. FAO took responsibility (in collaboration with the OIE) to help the poorest countries. Provide resources, but above all technical collaboration to eliminate rinderpest. Their performance was key to addressing joint prevention programs, providing vaccines, developing new versions of them, and validating the results once the campaigns had been implemented.
FAO and OIE worked together to control cattle plague
Thailand had carried out many vaccination campaigns but was repeatedly re-infected due to cattle smuggling from neighboring Cambodia. These situations underscored the need for an international effort. With assistance from FAO, Thai technicians developed a lapin vaccine that was adapted to pigs. Much more abundant than rabbits in the region and with a higher yield since up to 800 doses were obtained from each animal.
In 1957, the greatest success, according to the then FAO Secretary-General, was the practical eradication of the disease in Asia and its control, although much remained to be done in Africa.
The 1960s gave another great boost to the fight against the disease. British veterinarian Walter Plouwright was able to reproduce the virus in cow kidney cell cultures. This finding made it possible to dispense with live animals or eggs to keep the virus alive in a laboratory. The new TCRV (Tissue Culture Rinderpest Vaccine) vaccine was safe for all species of livestock, of all ages, conferred lifelong protection, and was cheap and easy to produce.
The only downside is that it needed to be refrigerated. This point was not minor, since reaching remote areas, in Africa, often zones of armed conflict, was not easy. But as this vaccine did not cause the disease or casualties, the farmers allowed the vaccination of their animals without reluctance.
Here is a short video that explains his findings in detail:
The immunization and control of this virus had two factors that facilitated its success. It was fortunate that the characteristics of the virus helped control it, namely:
– The virus has 3 lineages: Asian and African I and II. Immunity against one viral strain conferred protection against all the others, allowing the same vaccine to be used in different areas of the world.
– The reproductive rate (R0) of the virus (the number of animals that an animal carrying the virus can infect) is relatively low. It ranges from 1.5 (lineage II) to 4.6 in Sudan (lineage I). To determine the minimum herd immunity, it is calculated with this formula 1-(1 / R0), which gives a herd immunity requirement ranging from 33 to 78%. In fact, the disease was eradicated from the Somalian region with herd immunity never exceeding 50%.
To give a different example, measles virus has an R0 of 18, therefore it requires a very high immunization rate, over 95% of the population to be effective.
Starting in 1987, FAO established a surveillance program in which, after two years of no cases, the countries stopped vaccinating. It was the only way to verify that the virus was not active since the serology did not distinguish the animals that had antibodies due to the vaccine or to natural infection. If there were no clinical cases in two years after the vaccine was discontinued, FAO determined that the country was free of rinderpest.
Also, towards the end of the 80s another twist came to corner the plague: the veterinarian Jeffrey C. Mariner, together with scientists from the Plum Island research center in NY, after passing the virus through Vero cells (from African green monkey kidney ), got a thermostable vaccine, that is, it did not need refrigeration for 30 days. The TRV or ThermoVax.
Jeffrey C. Mariner
The shepherds, ranchers, nomads, veterinarians, authorities, all absolutely all collaborated to vaccinate the animals. New diagnoses also allowed a simple swab applied to one eye to determine in 10 minutes whether or not an animal had antibodies.
Like dominoes, countries were receiving plague-free status: India in 2004, Pakistan in 2007, Ethiopia in 2008, Somalia in 2010. So, it was on May 25, 2011, when the OIE declared all countries free and rinderpest was declared the second disease ever eradicated from planet Earth after smallpox in 1980. A month later the FAO would ratify the OIE declaration.
The efforts to achieve this eradication had an approximate cost of $ 610 million. The benefit is incalculable: millions of people who can escape hunger, avoid suffering and death of millions of animals, the protection of wildlife from a threat that caused countless deaths, in addition to the many learnings obtained to mitigate the impact of other animals and human diseases as well.
Both FAO and OIE have passed resolutions for member countries to destroy their stocks of plague virus that are still stored in various laboratories. 24 countries still have viable virus. The risks are enormous, in case of escape millions of cattle would die, the wild fauna would be in danger, the cost of eradication would be exponential, the paralysis of the cattle trade would slow down livestock development, there would be a certain risk of lack of food, millions of small producers would see their existence and viability compromised.
Furthermore, there is no objective need to maintain virus samples. If a new epidemic were to appear today, it would be possible to gather the genetic information of the virus that is available at GenBank a genetic database that contains the complete sequences of the Nakamura III and Kabete O strains in case it becomes necessary to develop vaccines again.
Today we can celebrate an event like few others in history: the elimination of a virus that caused unimaginable suffering. Thanks to science, today it is part of the past.
A few scientists, with very limited resources, defeated rinderpest. It is only fair that their feat is known and recognized as it deserves.
I hope this article has served that purpose.