Prewar Vaccines for Human Use

▶ Pasteur Vaccine

 Before discussing the development of vaccines in Japan, we should mention the development of the first rabies vaccine in the world.

 In 1881, Galtier was the first to vaccinate animals against rabies by intravenously injecting the saliva of a rabid dog into goats, and later devised a method of intravenous vaccination using diluted and filtered rabid dog medullary emulsion.

 In 1883, Louis Pasteur produced a fixed rabies venom that was attenuated by repeated passages in rabbits, whose period of time before disease onset was stabilized. The fixed venom was attenuated by drying the spinal cord of infected rabbits with potassium hydroxide.

 On May 2, 1885, the attenuated rabies venom was injected into Gilard, a 61-year-old man suspected of rabies. On June 22, 1885, Julie Antoinette Pougon, an 11-year-old girl suspected of rabies, received it. This record remained in Pasteur’s laboratory notebooks, and it is assumed that there may have been some aspects that were not suitable for publication regarding diagnosis and prognosis after injection. For this reason, these patients are said to be “Pasteur’s private (secret) patients,” the first to receive the human rabies vaccine.

 On July 6, 1885, Pasteur’s team initiated rabies prophylaxis with the vaccine against a 9-year-old bite victim, Joseph Meister, and succeeded in preventing the onset of the disease. This is the first officially documented administration of rabies vaccine to a human being. The specific methods used were as follows.

  • Post-exposure vaccination was initiated approximately 60 hours after multiple rabid dog bites.
  • Rabbit spinal cord suspension (air-dried and emulsified for 14 days) infected with rabies virus was used as the vaccine.
  • 13 doses of 47 cc of spinal fluid were administered over 11 days from July 6 to July 16.

(Image:Louis Pasteur)

 Following the success of human vaccination, a prophylaxis using this fixed venom was developed by Pasteur himself and Höyges et al.

 Pasteur created a less dangerous mutant strain of rabbit fixed venom, and then used a staircase drying process on the infected spinal cord in order to further weaken the virulence. This led to the development of a suitable attenuated strain of dried spinal cord, the so-called Pasteur vaccine. This method was used for more than half a century until major changes were made in the manufacture of rabies vaccines.

▶ Kurimoto Vaccine

 From March 1893, an epidemic of rabies broke out in Nagasaki City, Nagasaki Prefecture. A vaccine was developed by Dr. Tomei Kurimoto, then chief of internal medicine at Nagasaki Hospital of the Fifth Higher School of Medicine, using cerebrospinal cord obtained from beaten dogs. He studied its effectiveness using domestic rabbits by the following procedure (intracerebral inoculation method).

  1. In order to ensure uniformity in the amount of spinal cord-containing venom, rabbits weighing between 450 and 500 monme (1 monme = 3.75 g) are prepared.
  2. After measuring weight and body temperature, the rabbits are placed on a table and their four legs are fixed.
  3. The head hair is cut off into the size of a two-cent coin, the cranial skin is incised with a small knife about 2 cm in the anterior-posterior direction, the scalp along with the periosteum is eliminated on both sides to expose the bone, and a round hole is made with a puncture technique about 5 mm in diameter to avoid damaging the brain dura mater.
  4. Inoculum prepared from rabid dog brain or infected rabbit brain is injected into the cranial cavity using a syringe.
  5. After injection, the cranial skin is pulled back, sutured with 2 stitches, and iodoform is applied.

▶ Demonstration of effects on animals and humans

 In addition, an immunization proving test was conducted to examine whether the animals had acquired immunity from the pre-exposure rabies vaccine. A 0.5 g dose of attenuated injectable solution was injected daily into the right and left buttocks of two rabbits over a period of 15 days, with the toxic potency being increased momentarily, and the vaccination was considered complete on the 15th day. The injection-treated group (n=2) and the non-treated group (n=2) were inoculated subdurally with rabies venom, and only the treated group tolerated the injection. The untreated group developed characteristic symptoms. Furthermore, healthy rabbits developed rabies symptoms and died when injected with solution prepared from the intestinal tract of rabbits that had died after no treatment. This showed that animals that received attenuated injections acquired immunity to rabies and that the toxicity remained even after the rabies-affected rabbits died.

 As for the maintenance of rabies toxicity after individual deaths, Kurimoto’s “intracerebral inoculation test” (a study in which rabies venom was implanted in six rabbits 27 days after a rabid dog was beaten to death, and five rabbits died 14-18 days after the onset of rabies) also showed that rabies toxin maintained its toxicity for nearly one month after individual deaths.

 He also reported that the vaccine can be used not only for post-exposure immunization, which is administered after a bite, but also as a prophylactic injection for those who have not yet been bitten, since the vaccine passed without abnormal reaction disorder when administered to healthy humans (n=5) before exposure.

(Image : Grave of Dr.Kurimoto)

▶ Example of vaccination for humans

 In 1894, the first post-exposure vaccination of bite victims was conducted in Japan. Fourteen injections were administered over a 20-day period from October 18 to November 6 to a patient who was bitten on August 12 of the same year.

 Post-exposure vaccination was administered to 32 patients bitten in Nagasaki Prefecture between February 28 and July 8, 1895. 25 patients, excluding 7 who dropped out, did not develop the disease after 5 months, demonstrating that the vaccine was successful in preventing the disease. Confirmed side effects included hyperemia and swelling at the injection site, minor pain, and inguinal lymphadenopathy, all of which were mild.