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Home , Attenuated vaccine, Charles Chamberland, Edward Jenner, Louis Pasteur

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MILESTONE 3 The first live attenuated

Awareness of ’s pioneering COVID-19 treatment trials, 24 sheep, 1 Despite failing to culture the -caus- studies of (MILESTONE 2) goat and 6 cows were inoculated twice with ing organism outside animal hosts or to view led (1822–1895) to propose Pasteur’s , on 5 and 17 May it under a microscope (because, unknown to that vaccines could be found for all virulent 1881. A control group of 24 sheep, 1 goat and Pasteur, rabies is caused by a rather than . 4 cows remained unvaccinated. On 31 May a bacterium), Pasteur discovered that the Pasteur began to study cholera all the animals were inoculated with freshly of his rabies stocks, maintained by in 1877 and by the following year had suc- isolated anthrax bacilli, and the results were serial intracranial passage in dogs, decreased ceeded in culturing the causative organism, examined on 2 June. All vaccinated animals when the infected material was injected Pasteurella multocida. In 1879, Pasteur into different species. Starting with a highly discovered by chance that cultures of this virulent rabies strain serially passaged many bacterium gradually lost their virulence times in rabbits, Pasteur air-dried sections over time. Before leaving to go on a holiday, of infected rabbit spinal cord to weaken the Pasteur had instructed an assistant to inject virus through oxygen exposure, as explained the latest batch of with fresh cultures in Pasteur’s 26 October 1885 report to the of P. multocida. The assistant forgot to do this, French Academy of . All 50 dogs however, and then himself went on holiday. vaccinated with this material by Pasteur were On his return, Pasteur’s assistant inoculated successfully protected from rabies , the chickens with the cultures, which by this although we now understand attenuation to time had been left in the for a result from viral passage through dissimilar month, stoppered only with a cotton-wool species, rather than air exposure. plug. The inoculated chickens developed mild Up to this point, however, Pasteur had symptoms but recovered fully. no proof that his vaccines, a term coined by Another scientist might have concluded Pasteur to honour Jenner’s work, would be that the cultures had (mostly) died, but effective in humans. Reluctantly — as Pasteur Pasteur was intrigued. He injected the recov- was not a licensed and could have ered chickens with freshly cultured cholera been prosecuted for doing so — on 6 July . When the birds remained healthy, 1885, Pasteur used his , in the Pasteur reasoned that exposure to oxygen presence of two local doctors, to treat 9-year- had caused the loss of virulence. He found old Joseph Meister, who had been severely that sealed bacterial cultures maintained their bitten by a neighbour’s rabid dog. Joseph virulence, whereas those exposed to air for Meister received a total of 13 differing periods of time before over a period of 11 days, and survived in showed a predictable decline in virulence. good health. Pasteur’s reluctance might also He named this progressive loss of virulence be accounted for by posthumous analysis of

‘attenuation’, a term still in use today. Louis Pasteur holding rabbits, which were used to help his laboratory notebooks, which revealed that Pasteur, along with develop the vaccine for rabies. Credit: World History Archive / Pasteur had vaccinated two other individuals and Emile Roux, went on to develop a live Alamy Stock Photo before Meister; one remained well but might for anthrax. Unlike not actually have been exposed, and the other cultures of the chicken cholera bacterium, remained healthy. The unvaccinated sheep and developed rabies and died. cultures exposed to air read- goats had all died by the end of the day, and all By the end of 1885, several more desperate ily formed spores that remained highly viru- the unvaccinated cows were showing anthrax rabies-exposed people had travelled to lent irrespective of culture duration; indeed, symptoms. Chamberland’s private laboratory Pasteur’s laboratory to be vaccinated. During Pasteur reported that anthrax spores isolated notebooks, however, showed that the anthrax 1886, Pasteur treated 350 people with his from soil where animals that died of anthrax vaccine used in these public had rabies vaccine, of whom only one developed had been buried 12 years previously remained actually been attenuated by potassium dichro- rabies. The startling success of these vaccines as virulent as fresh cultures. However, Pasteur mate, using a process similar to that developed led directly to the founding of the first discovered that anthrax cultures would by Pasteur’s competitor, Jean Joseph Henri in 1888. grow readily at a temperature of 42–43 °C Toussaint. Caroline Barranco, but were then unable to form spores. These In 1881, Victor Galtier (who had already Nature Reviews Cross-Journal Team non-sporulating cultures could be maintained demonstrated transmission of rabies from at 42–43 °C for 4–6 weeks but exhibited a dogs to rabbits) reported that sheep injected ORIGINAL ARTICLES Pasteur, L. An address on vaccination in marked decline in virulence over this period with saliva from rabid dogs were protected relation to chicken cholera and splenic fever. Br. Med. J. 2, 283–284 (1881) | Pasteur. L. Méthode pour prévenir la rage when inoculated into animals. from subsequent inoculations. These surpris- après morsure. C. R. Séances Acad. Sci. (Séance du lundi 26 Accordingly, in public experiments at ing observations piqued Pasteur’s interest and octobre 1885) Pouilly-le-Fort, , conducted under a he went on to develop the first live attenuated FURTHER READING Jackson, A. C. (ed.) Rabies: Scientific Basis of the and Its Management (Academic Press, 2013) media spotlight reminiscent of that on today’s rabies vaccine.

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