The rage to conquer rage
Thanks to his international network and the vaccination protocol he devised to distribute a recombinant vaccine to fox populations, Paul-Pierre Pastoret proved that fox rabies could be eradicated.
"L
a rage de vaincre", "vert de rage", "la rage de vivre", "faire rage", "la rage au ventre", "fou de rage"... You only have to look at the number and meaning of expressions that use the word "rage" to understand the extent to which this disease has left its mark on people's minds. And with good reason: when a man declares rabies, it takes him by leaps and bounds within ten days of the onset of symptoms. Death is almost always the only outcome, even if treatment is administered before the onset of convulsions, extreme salivation, hydrophobia, anxiety or delirium.
Rabies is mainly transmitted by foxes, badgers and bats, but also by dogs, cats, cows and deer. If an infected animal bites a human, the virus transmitted in this way travels up the nerves to the central nervous system, reaching it in at least two to eight weeks, and often longer, causing encephalitis. The last fatal case of human rabies in Belgium dates back to 1922, following contamination by a dog bite. But this did not mean that rabies had disappeared from animals in our country. Although sanitary conditions, the development of a preventive vaccine and effective curative treatment (when administered rapidly after the bite) had drastically reduced the number of fatal cases in our regions, the threat of a recrudescence was still very real. " After the Second World War, rabies was widely re-established in foxes in Europe, from East to West, and the animal epidemic arrived in Belgium in 1966," explains Etienne Thiry, Director of Laboratoire de virologie vétérinaire et maladies virales animales (FARAH) at the University of Liège. "The disease remained confined to the south of the Sambre et Meuse furrow, which formed a natural barrier. But rabies was very present in the Ardennes among foxes, cattle, cats, dogs, sheep and so on. Every human being received post-exposure treatment as soon as they came into contact with an animal suspected of having rabies".
A major public health problem
In the 1980s, Paul-Pierre Pastoret, a professor of animal virology at the University of Liège with a long-standing interest in rabies, was given the opportunity to take action. "Paul-Pierre Pastoret is a pioneer of the "One Health" concept, the principle that plant, animal and human health are intimately linked. And the animal virology contexts he studied always had both basic research objectives and medical applications. He liked to ground his research in reality, to solve the problem of infectious diseases that were rampant at the time", says Etienne Thiry. At that time, even if we managed to limit the fatal outcomes of rabies in Europe, it remained a very serious public health problem. And even today, worldwide, 50,000 people die from rabies every year, mainly in Africa and Asia.
"During those years, in an attempt to control epidemics, European authorities had no choice but to resort to gassing fox dens ," continues Etienne Thiry. "But the consequences were disastrous for biodiversity. Fortunately, the same period saw the emergence of molecular virology. New molecular biology techniques enabled virology research to take a quantum leap forward. "This, combined with Paul-Pierre Pastoret's "one health" mentality, led him to think of another solution to eradicate rabies in Belgium and elsewhere. Thanks to his international network, he discovered a French start-up, Transgène, which had developed an interesting vaccine: they used vaccinia, the virus used to vaccinate people against smallpox, into which they inserted genes coding for rabies antigens," explains Etienne Thiry. From there, Paul-Pierre Pastoret imagined the solution that would put an end to rabies in Belgium.
Paul-Pierre Pastoret and Jean Blancou at the Malzéville research station (France), experiment on badgers to demonstrate the harmlessness of the rabies vaccine in this species, which shares the same burrows as foxes.
Immunizing animals to prevent transmission to humans
By developing a rabies vaccine for foxes, we could protect these animals from the disease, thereby preventing transmission to domestic animals and humans. This was Paul-Pierre Pastoret's reasoning in the late 80s. The Transgène company had achieved good results with laboratory animals. But now it was necessary to design and carry out all the tests that would enable this type of vaccine to be used in the field on a large scale. And the task was not an easy one : "First of all, we had to make sure that there was no risk of releasing this recombinant virus into the wild, either for humans or for other animal species, and also find a way of infecting foxes with this recombinant virus, before finally verifying its efficacy ". So it was that Paul-Pierre Pastoret rolled up his sleeves and devised a very special device: a bait made from fish fat, in which was hidden a capsule containing the vaccine virus. From there, and thanks to his contacts with the army, he obtained authorization to carry out trials in the wild on military land. " They were able to confirm that the vaccine was harmless to all the animal species that populated our region," continues Etienne Thiry. "The next step was to produce the vaccine on an industrial scale, so as to be able to carry out real fox vaccination campaigns. And, of course, to convince the authorities in our country of the benefits of vaccination. This exciting project took shape, culminating in a major vaccination campaign in southern Belgium. The results of this operation were published in December 1991 in the prestigious journal Nature (1). In particular, they revealed that the baits were well ingested by the foxes, that a significant percentage of their population was immune to rabies after the campaign, and that the number of rabies cases observed in these animals fell drastically.
Two foxes eating vaccine baits
Two vaccination campaigns a year
Paul-Pierre Pastoret and his colleagues used a marking method to check that the baits - and therefore the capsules containing the recombinant vaccine - had been properly ingested by the foxes. "They incorporated tetracycline into the capsule. It's an antibiotic that leaves a yellowish deposit on the bones of those who ingest it, particularly the jaws," explains Etienne Thiry. "That's how they were able to observe that 80% of the foxes in the area where they had dropped the bait had traces of tetracycline in their system".
The protocol drawn up by Paul-Pierre Pastoret provided for two fox vaccination campaigns a year. One in May, when the young are born, and one in September, when they leave their parents' territory."The problem was that, as it was working so well, the authorities decided around 1996-1997 that the number of vaccination campaigns could be reduced", continues the Professor of Virology."We then witnessed a resurgence of rabies". Paul-Pierre Pastoret recommended "hitting back hard", and the authorities followed his advice, achieving the total eradication of rabies in 2001.
"Proof of concept for oral fox vaccination was given. This major result paved the way for the use of the vaccine in other European countries, and the same concept was developed in other ways elsewhere, such as in North America, where it is still used to vaccinate foxes and raccoons", continues Etienne Thiry. According to Etienne Thiry, who, like his colleague Alain Vanderplasschen, came from the animal virology teaching program founded by Paul-Pierre Pastoret at the University of Liège, veterinary virology and immunology laboratories have inherited Paul-Pierre Pastoret's way of thinking about veterinary virology: in the context of improving animal and human health.
Written by Audrey Binet
(1) Brochier B, Kieny MP, Costy F, Coppens P, Bauduin B, Lecocq JP, Languet B, Chappuis G, Desmettre P, Afiademanyo K, et al. Large-scale eradication of rabies using recombinant vaccinia-rabies vaccine. Nature. 1991 Dec 19-26;354(6354):520-2.
Etienne Thiry
"We don't intervene to determine the sex of angels! Étienne Thiry is a pragmatist. The Director of the Laboratory of Veterinary Virology and Animal Viral Diseases at the University of Liège makes a point of ensuring that the work carried out in his unit has a concrete impact. "We've always been keen to work on themes that have an influence on animal health in the strict sense, or on public health aspects. Whether the research is fundamental or applied, it's important that it tries to contribute to solutions. That's our mission.
He has been working in this field since 1985, when he obtained his doctorate from the University of Liège. This is reflected in his research themes, which generally concern the short-term evolution of viral populations. He has worked on the evolution of herpesviruses, the African horse sickness virus through genetic reassortment, and recombination in noroviruses, the most common cause of gastroenteritis.
It is no doubt his pragmatism that led him to take up the post of Chairman of the Scientific Committee of the Afsca (Federal Agency for the Safety of the Food Chain), where he is involved in assessing animal health and public health risks for the food chain. He also sits on France's ANSES (Agence nationale de sécurité sanitaire) as chairman of the expert committee specializing in animal health and welfare. He is also involved with the French institute Inra, the scientific committee of CERVA (Centre belge d'étude et de recherches vétérinaires et agrochimiques) and the European advisory board on cat diseases.
Alain Vanderplasschen
Alain Vanderplasschen was born on June 27, 1967. In 1985, he began studying Veterinary Medicine at the Cureghem Veterinary School (Brussels, University of Liège). At the end of his second year, he was spotted by Prof. Paul-Pierre Pastoret, who taught immunology at the school. While continuing his studies, Alain Vanderplasschen worked as a research student in Prof. Pastoret's laboratory, which gradually became his spiritual father. After graduating from the University of Liège with a Doctorate in Veterinary Medicine in 1991, he began his scientific career as an FNRS aspirant in Prof. Pastoret's laboratory. D. thesis on interactions between bovine cells and bovine herpesvirus 4 (Immunology-Vaccinology Laboratory, Université de Liège). He then moved to Oxford University, where he completed an honors thesis on vaccinia virus (the virus that led to the eradication of human smallpox) in Prof. G.L. Smith's laboratory (Sir William Dunn School of Pathology, Oxford University). Returning to Liège in 1998, Alain Vanderplasschen pursued his career at the FNRS, becoming the first veterinarian in the history of the FNRS to obtain a permanent position. He then climbed the FNRS career ladder, becoming Senior Researcher in 2002 and Research Director in 2006. At the age of 39, he was the youngest research director at the FNRS. In 2007, he left the FNRS to succeed his Master and became Professor of Immunology-Vaccinology at the Faculty of Veterinary Medicine, University of Liège. His research focuses on the study of host-pathogen interactions, and more specifically on the mechanisms developed by pathogens to protect themselves or even use the immune system of the infected host (a theme known as immuno-evasion). Alain Vanderplasschen's laboratory is also the source of several innovations in the field of animal vaccinology. Alain Vanderplasschen is the promoter of numerous defended doctoral theses, and the author of over 140 listed publications in the fields of microbiology, immunology and vaccinology. He is also the inventor of 6 patents relating to the identification of inhibitors of the complement system in the saliva of the Ixodes ricinus tick, and to the development of various vaccines. He is the recipient of several prestigious scientific awards.
Pr Alain Vanderplasschen is a researcher who accumulates firsts, becoming the first veterinary surgeon to receive the GSK Vaccines prize, created in 1959. This prestigious award, which recognizes a remarkable research career anchored on host-pathogen relationships in the animal world, was presented to him at the Palais des Académies in Brussels on December 10, 2016 in the presence of prestigious personalities. He is a researcher at the FARAH Applied Research Center.
Glossary
Virus: Infectious agent that multiplies inside a cell. Viruses are therefore not considered to be living beings in the same way as bacteria for example, because they have no autonomy: to reproduce, they have to use the cells of living organisms, hijacking them for their own purposes. When a virus is introduced into a cell, the cell's resources are mobilized to ensure that the virus multiplies. New viruses are then introduced into other cells, and so on. This process, known as viral infection, is often accompanied by the death of the host cell. These cell deaths are at the root of pathologies (such as influenza) in infected organisms. Viruses are eliminated by the immune system of infected organisms.
Epidemic: Significant increase in the number of cases of a transmissible infectious disease in a given region over a given period of time.
Rabies: Rabies is an infectious disease of viral origin that is almost always fatal once clinical symptoms have appeared. In up to 99% of human cases, it is transmitted by domestic dogs, but the virus can infect both domestic and wild animals. It is usually transmitted to humans through the saliva of infected animals when bitten or scratched.
