1. Introduction
  Over forty years have already elapsed since Japan became free of rabies. It seems that most of the Japanese consider that rabies is a sickness of the past. However, rabies is, still endemic all over the world except in some island states and peninsular countries. Each year a great number of people fall victim to this disease notably in the Asian region. Given the current expansion of the transportation means, the risk that rabies may invade into Japan from neighboring countries and that Japanese may become infected with rabies virus in endemic regions is growing more than before.

2.Characteristics of rabies
  Rabies is a typical viral zoonosis. It is also called "hydrophobia" given its characteristic clinical profile. Rabies virus belongs to the genus Lyssavirus within the family Rhabdoviridae.(1) The epidemiological features of rabies are as follows. As started above, the disease occurs all over the world except in certain island states and peninsular countries. Virtually almost all mammals can contract it. There are urban type outbreaks which occur in a rabies virus infection cycle among stray dogs in urban areas such as in Asia and sylvan type outbreaks caused by infected wild animals as observed in Europe and North America. Furthermore bats on the North and South American Continent are vector of the rabies virus, and certain bats living in Europe, Australia and Africa are infected with a Lyssavirus that is similar to the rabies virus.
  Clinically rabies is characterized by a mortality of almost 100% after onset and a lengthy incubation period, usually lasting one to three months. There exists no testing method to know whether rabies virus has been contracted before onset. There is no effective treatment against rabies, and only six cases of survival amid rabies patients have been reported so far. Post-exposure treatment for protection against onset through the inoculation of rabies vaccine repeated at specified intervals is the only means to avoid death caused by this disease after having been bitten by a rabid animal. Indeed rabies is a disease that can be prevented but cannot be cured.

3.Human rabies vaccines
  The rabies vaccine was put to application in 1885 by Louis Pasteur of France. It is hard to know whether Pasteur's vaccine was an inactivated or live vaccine. This vaccine caused a certain number of fatalities. Afterward a rabies vaccine in which a brain homogenate of goats or sheep infected with a fixed virus was completely inactivated with formalin was made (Semple type vaccine). Since this vaccine contained a large amount of nerve tissue components, serious neurological adverse reactions such as demylienating encephalitis occurred. A suckling mouse brain-origin rabies vaccine was manufactured in 1955 in order to prevent contamination by myelin regarded as the major cause of adverse reactions of the nervous system. However, adverse reactions of the nervous system such as the Guillain-Barre syndrome occurred also with this vaccine. Later the incidence of adverse reactions decreased after reducing the number of injections. The suckling mouse brain-origin vaccine is still used primarily in South and Central America. A vaccine prepared by growing rabies virus in cell culture and inactivating the virus emerged in the 1970s. The cell culture derived lyophilized inactivated rabies vaccine that is almost free of adverse reactions is now the standard rabies vaccine. In this category of vaccines, a human diploid cell vaccine (HDCV), a purified Vero cell rabies vaccine (PVRV) and a purified chick embryo cell vaccine (PCEC) are currently marketed. These vaccines use a different rabies vaccine strain and different types of cell culture. Incidentally a locally manufactured purified chick embryo cell vaccine (PCEC-K) is on the Japanese market.

4.Post-exposure Prophylaxis(PEP)
  The WHO gives the following recommendations in case of bites by rabid animals in rabies endemic areas: (1) copious washing of the wound site with water and soap; (2) disinfection with a disinfecting solution such as alcohol or povidone-iodine; (3) administration of tissue culture inactivated rabies vaccine on days 0, 3, 7, 14 and 30, taking day 0 as the day of the first inoculation, and injection of rabies immune globulin (RIG) on day 0 (Essen regimen). Incidentally it is difficult to have access to RIG in Japan, since it is not marketed in this country.
  In case the inoculation dose of the rabies vaccine made locally in Japan, 1.0 ml, is divided into three and injected intradermally into two sites and subcutaneously into one site (intradermal-subcutaneous combination method), a high antibody titer can be obtained more rapidly than in case of a single 1.0-ml dose given subcutaneously into one site. Therefore PEP treatment to prevent onset using the intradermal-subcutaneous combination method can be regarded as the second best option in case an injection of RIG is not available.
  It is preferable to use the same rabies vaccine for PEP of rabies onset. However, since it is difficult to have access to foreign rabies vaccines in Japan, it is next to impossible for a victims bitten by dogs or other animals in a foreign country to continue after he comes back to home country to have PEP with the same type of vaccine after having received one or several injections of a cell culture rabies vaccine manufactured abroad. They should receive without hesitation the rabies vaccine made locally in Japan, since it has been determined that PEP may be continued effectively and without danger with the rabies vaccine manufactured in Japan. However, since the inoculation schedule is totally different from the Essen regimen (See Note) for the victims of animal bite who received the suckling mouse-brain derived vaccine, it is impossible to continue simply PEP. In addition as there are few health care facilities capable of PEP in Japan, it is not always easy to look for a medical institution to continue PEP carried out abroad. The homepage of the Narita Quarantine Station should be useful in such instance (http://www.forth.go.jp).

5.Pre-exposure immunization
  Since a cell culture inactivated rabies vaccine practically free of side effects has been developed, the vaccine may be used for its original purpose, namely prophylactic vaccination before being bitten by a rabid animal (pre-exposure immunization). People assigned to work or residing in rabies-endemic areas for a long period, notably in developing countries, should be advised to be vaccinated against rabies before their departure.
  The WHO recommends a regimen of three shots of the rabies vaccine on days 0, 7 and 28, while the US recommendation is a course of three injections given on days 0, 7, 21 or 28. On the other hand, in Japan, two doses of tissue culture rabies vaccine are given at a one month-interval, and a third dose is administered six months later to complete primary immunization. In many cases, since there is a gap of about two months between the decision to go abroad for work and the date of departure, it is difficult to complete primary immunization under the Japanese system. Although the preventive efficacy given by two shots of the current rabies vaccine manufactured in Japan is insufficient, the formation of antibodies production will begin early enough if the subject receives the rabies vaccine immediately after having been bitten in the country of residence. Since the preventive efficacy against rabies onset can be fully expected even if an injection of RIG cannot be given, it will be preferable to leave the country even after only two injections. Besides animal handlers and people who plan to carry out field surveys in rabies-endemic areas should go abroad to take up their post after having completed the WHO's pre-exposure rabies vaccination schedule.

6.Conclusion
  Rabies is a typical viral zoonosis that is preventable but cannot be cured even with modern medical care once it has been clinical event. One should be aware that even now hundreds or thousands of people fall victim to rabies each year in regions a few hours far away from Japan by plane. Therefore one should take full precautions against this sickness when traveling to regions where rabies frequently occurs and receive at least two shots of rabies vaccine before leaving the country. Likewise one should undergo PEP in a local health care institution if bitten by an animal in a rabies-endemic area. As repeatedly mentioned above, though rabies is preventable, it cannot be cured, and it is by no means a disease of bygone years.
Note - Essen regimen: international standard method for post-exposure prophylaxis of rabies onset.