With the recent roll out of the covid-19 vaccine all eyes have been on the clinical trial data. In this blog our Senior Research Fellow, Professor Ken Donaldson, tells us more about a very different vaccine trial.
As we have seen with the Covid vaccine, the modern vaccine trial process is complex and highly confidential and the outcomes need extensive analysis before the results can be conveyed to the public. So it’s hard to imagine a vaccine trial being staged in the full glare of a public audience, but that is exactly what happened in 1881 when Louis Pasteur set out to demonstrate to the doubters, once and for all, that anthrax vaccination worked in protecting against anthrax infection.
Anthrax is found all over the world where it specially afflicts domestic animals like sheep and cattle: it can also affect humans although to a lesser extent. In the 19th century anthrax killed millions of animals annually and Robert Koch, for example, reported that in four years anthrax killed 56,000 domestic animals and 528 people in a single German district. Anthrax is caused by a bacterium called Bacillus anthracis which can lie dormant in soil then infect animals that graze on it, even years later. The symptoms of acute anthrax infection in cattle and sheep include fever and hyperactivity followed by depression, stupor then breathing and heart distress, leading to convulsions and death. In humans it causes similar effects along with flu-like symptoms and again is often fatal.
The rise of microbiology
The Frenchman Louis Pasteur (1822-1895) and the German Robert Koch (1843-1910) between them, are seen as the Fathers of microbiology, the science of microscopic-sized living entities, especially in its relationship to disease. In the late 19th century Koch and Pasteur lead the revolution revealing the nature of the infectious diseases which had afflicted humankind throughout time, sickening and killing people. Up till then the fevers, diarrhoea, boils, cough and breathlessness, etc that regularly spread throughout communities, were blamed on magic, evil winds and bad smells. Koch and Pasteur along with their co-workers, set out to systematically look in infected individuals to determine what was going on in diseased organs and in the blood. Using the newly-developed microscope, then later the methods of microbial culture that they themselves developed, they found micro-organisms in infected individuals and in the environment. This enabled them finally to link particular patterns of symptoms, i.e. diseases, to specific microbes.
The chicken disease that showed Pasteur the value of attenuated vaccine
In 1878, by accident, Pasteur’s lab grew chicken cholera bacteria that were normally highly virulent, in a virtually harmless, or attenuated form. Pasteur had asked an assistant to inject the chicken cholera bacteria into chickens, but the assistant forgot and went on holiday for a month. On returning from holiday he injected the old cultures into chickens; to everyone’s surprise, they only developed minor signs of disease and then recovered. Puzzled by this, Pasteur asked that these chickens be injected with fresh bacteria. The chickens did not become ill in response to the virulent bacteria. Pasteur had discovered that prolonged culture weakened or attenuated the organisms to a harmless form that can still infect the individual and importantly produce immunity to the virulent form, the ideal basis for a vaccine! Pasteur subsequently commenced experiments on attenuating organisms as the basis for vaccines and was to have special success in attenuating the organisms responsible for anthrax and rabies and making vaccines against these diseases.
The anthrax vaccination trial
Pasteur published preliminary results with an attenuated anthrax vaccine in a few sheep in 1881 suggesting that it conferred protection against the virulent form of the bacterium. On hearing of this, the Agricultural Society of Melun at Pouilly-le-Fort, 40 km South of Paris challenged him to publicly prove that his vaccine worked. Pugilistic by nature when it came to science, Pasteur saw his chance to counter the people who did not believe in vaccination or that the microbial world even existed. He therefore agreed to stage a public demonstration of vaccination against anthrax. This was a considerable risk since the gains in public acceptance of vaccination would have been put at great risk had the test not succeeded. As scientists know, there are always numerous reasons why an experiment carried out for the first time might fail (since an experiment was essentially what Pasteur intended to do) and failing in full view of the public might set back the cause of immunisation by years.
On May 5th 1881, the animals to be used in the test were assembled in a field on the farm of Mr. Rossignol in the village of Pouilly-le-Fort. Initially the plan was to use 50 sheep and vaccinate half but at the last minute the Agricultural Society asked for a goat to be used instead of the 25th sheep and for six cows to also be used. So finally, in full view of the public, Pasteur and his assistants vaccinated 24 sheep, one goat and 6 cows with the attenuated vaccine. The unvaccinated control group comprised twenty-four sheep, one goat and four cows. On May 17th the vaccinations were repeated as a booster. On May 31st all these animals were injected with a live and virulent culture of anthrax sufficient to kill normal sheep. A crowd assembled to watch on each day but once word got around that the results would be viewed on June 2, more than 200 observers turned up on that day. This included local officials, politicians, doctors, veterinarians, local farmers, and newspaper reporters, as well as the general public. Interest in the trial was prodigious and reporters from the London Times and French newspapers sent reports on the progress of the trial that were published daily.
Here is Pasteur’s published account of the day that the results were announced:-
‘When the visitors arrived on June 2, they were astounded. The twenty-four sheep, the goat, and the six cows which had received the vaccinations of attenuated anthrax, all appeared healthy. In contrast, twenty-one sheep and the goat which had not been vaccinated had already died of anthrax; two other unvaccinated sheep died in front of the viewers, and the one remaining sheep died at the end of the day.’
It was notable that the cows in the unvaccinated group did not die, but it was known that cows were somewhat resistant to death from anthrax infection compared to sheep. All the unvaccinated cows became ill and developed fever and swelling at the site where they had been injected with virulent anthrax; the vaccinated cows did not become feverish or show inflammation at the injection site.
The reaction to the trial
It’s not difficult to imagine the impact that a field of dead, unvaccinated sheep must have had in demonstrating the benefit that anthrax vaccination had produced in protecting sheep from anthrax infection. Although a risky thing to do publicly, Pasteur had successfully carried out a simple yet persuasive demonstration of the power of vaccination. Word of vaccination with an attenuated microbial strain and its potential to protect both animals and humans against disease quickly became apparent. Pasteur was lionised and was on his way to many honours, given to him by France and other nations. Pasteur’s discoveries extend well beyond anthrax, to fermentation, the origins of life, pasteurisation of milk, silkworm disease, rabies vaccination etc. and he is generally considered to be one of the greatest scientists who ever lived.
The emergence of anti-vaxers
In a sad reflection of the situation today, in 1881 a considerable lobby already existed that questioned Pasteur’s revelations that what we now know as infections were caused by a ubiquitous, invisible universe of microbial life. Many of these people were doctors and vets who rejected the theory of microbiological life, despite the fact that vaccination against smallpox had been discovered and widely published by Jenner in the UK in 1796 and that, by 1853, smallpox vaccination was mandatory in the UK. In fact, it’s sad to report that 1 year after the vaccine trial described in this blog, in 1882, the Anti-Vaccination League of America held its first meeting in New York
The success of vaccination
Vaccination is one of the greatest triumphs of Public Health and of medicine in general, saving countless millions of human lives and many more millions from suffering. Pioneers like Pasteur should be considered amongst the greatest benefactors of mankind and the ill-informed and mendacious anti-vax movement should be countered at every stage.