Rabies is widely distributed around the world, and all continents except Antarctica have reported rabies on humans. After entering the 21st century, rabies remains an important public health threat. About 60,000 people die from rabies every year worldwide, making it the most fatal animal-derived infectious disease, and the economic burden caused by this is about US$4 billion each year.

Currently, except for many Pacific island countries, only Australia eliminates carnivorous rabies, Western Europe, Canada, the United States, Japan, Malaysia and a few Latin American countries eliminate dog rabies.

Currently, 99% of human rabies occur in developing countries, mainly distributed in Asia, Africa, Latin America and the Caribbean. Asia ranks first in the world with an estimated annual death toll of 30,000. India is the country with the most severe rabies epidemic. It is estimated that the annual incidence of rabies is 20,000 to 30,000, and the incidence rate is 2.1 million.

The incidence of rabies in China is second only to India. At the peak of the epidemic in 2007, the number of reported cases reached 3,300. From 2004 to 2014, the number of rabies deaths has always ranked among the top three infectious disease deaths in my country. In addition, the survey shows that the underreporting rate of rabies in some areas may be as high as 35%, indicating that the disease burden of rabies in my country may be underestimated.

2. Source of infected animals

The storage hosts of rabies in nature include carnivorous animals and pterocarpus, foxes, wolves, jackals, ferrets, badgers, raccoons, mongooses and bats, etc. are also natural storage hosts of rabies. They can all be infected with rabies viruses and become sources of infection, and then infect livestock such as pigs, cattle, sheep and horses. Rabies susceptible animals mainly include canidae, feline and pterocarpus, avians, fish, insects, oysters, turtles and snakes, etc., which do not infect or transmit rabies viruses.

Globally, 99% of human rabies are caused by dogs, especially in Asia and Africa, where dogs are the main cause of human rabies. The infection sources of dog rabies are well controlled in Europe, North America, Australia and some Latin American countries are wild animals such as bats, foxes, jackals, marmosets, mongooses and raccoons.

Among the host animals, bats are more special. Because bat exposure may be extremely difficult to detect subtle bites or injuries, the risk of exposure is greatly increased. Both the WHO and the US CDC classify bat exposure as severe exposure and require it to be disposed of according to Class III exposure.

Among the 56 human rabies cases caused by bats in the United States and Canada between 1950 and 2007, only 22 cases had a clear history of bites; 9 cases had direct contact with bats without bites; 6 cases had no clear history of contact, and only bats were found in the room; while 19 cases had no direct contact.

The WHO pointed out that large-scale testing of wild and domestic rodents in rabies endemic areas in North America and Europe showed that such animals were rarely infected with rabies, and terminal spillover infection of the rabies virus was only an occasional event, indicating that such animals are not the storage hosts of rabies and are not involved in the epidemic and transmission of the disease.

The US CDC also pointed out that rodents and rabbit-format are rarely infected with rabies, and no evidence of such animals causing human rabies. According to 20 years of monitoring in the United States, although there are occasional records of marmots infected with rabies in areas where raccoon rabies occur, rabies virus has never been detected in small rodents, and there is no evidence of human rabies cases caused by rodents or rabbit-format animals.

3. Characteristics of rabies in my country

Since the 1950s, rabies in my country have experienced three epidemic peaks. The first peak occurred in the mid-1950s, with more than 1,900 deaths reported annually. The second peak occurred in the early 1980s, with 7,037 deaths reported nationwide in 1981, which is the year with the highest number of deaths reported since the founding of New China.

Throughout the 1980s, the national rabies epidemic fluctuated at a high level, with annual reported deaths of more than 4,000, and annual reported deaths of 5,537. The third peak occurred in the early 21st century. After a rapid decline in the rabies epidemic for eight consecutive years, it reappeared a rapid growth trend, reaching its peak in 2007, with the number of reported deaths of 3,300 nationwide that year.

Before and after the third peak of the epidemic, my country has taken a series of measures to curb rabies, including implementing rabies prevention and control measures, establishing a multi-department prevention and control mechanism for rabies, strengthening dog management and animal rabies prevention and control, as well as strengthening the quality supervision of human rabies vaccines and passive immunization preparations, and achieving relatively significant prevention and control results. Since 2008, the rabies epidemic in my country has continued to decline, and by 2014, the number of reported cases has dropped below 1,000, a decrease of 72% from the peak in 2007.

Historically, all provinces in my country have reported rabies cases. In recent years, rabies epidemics are mainly distributed in the densely populated South China, Southwest China and East China, but other provinces have reported epidemics from time to time. From 1996 to 2008, except for Tibet and Qinghai, the remaining 29 provinces had reported rabies cases. The top 10 provinces in the number of reported cases were Guangxi, Hunan, Guizhou, Guangdong, Jiangxi, Jiangsu, Hubei, Henan, Sichuan and Anhui, with reported cases accounting for 86.9% of the total number of reported cases.

Since 2007, the number of regions affected by rabies has shown a downward trend, but the speed is relatively slow. In 2007, a total of 993 counties in 23 provinces across the country reported cases, and 567 counties still reported cases in 2014. After 2007, the rabies epidemic in most provinces showed a downward trend, especially in provinces with severe epidemics, but the epidemic has a trend of expanding to the north and northwest. Hebei, Shanxi, Yunnan, Shaanxi, Hainan, Chongqing and other provinces with fewer reports of previous incidences had once experienced an increase in the epidemic. After 2012, the epidemic in various provinces showed a continuous downward trend.

There are reports of rabies cases in my country every month, with high incidence in summer and autumn, and the peak incidence generally occurs in August. The surveillance data analysis from 2005 to 2011 shows that there are differences in seasonal characteristics in different regions. The higher the latitude, the more obvious the seasonality, and the time of onset of cases is relatively concentrated.

Characteristics of case presentation: There are many cases in rural areas, and farmers generally account for more than 65% of the total number of cases; the number of cases in men is about twice that of women; there are more cases of children under 15 years old and people over 50 years old, and nearly 25% of the cases from 1996 to 2008 were children under 15 years old.

The cases are mainly caused by dog ​​injuries, accounting for about 90%; followed by cats, accounting for about 5%. Other injured animals include horses, squirrels, pigs, bats, monkeys and badgers, but they are relatively rare, accounting for less than 5%. About 50% of injured animals are domestically maintained, and most of the domestic animals have not been vaccinated with animal rabies, and stray animals account for about 25% of the total number of injured animals.

According to the use of human rabies vaccines in my country, it is estimated that the number of exposed populations in the country is more than 40 million. Monitoring in some provinces with high incidence of rabies shows that more than 90% of the exposed patients are Class II and Class III exposure, of which about 40%. Among all exposed patients, about 10% have not been vaccinated throughout the course; among the Class III exposure, only about 15% have received passive immunization preparation injections. The vast majority of cases are caused by rabies virus infection, but there are also reports of small amounts of infection caused by rabies virus-related virus infection.

Rabies vaccine for human use

1. History and status of human rabies vaccine

In 1882, the Frenchman Louis Pasteur successfully invented the human rabies vaccine for the first time. Later, he experienced the early animal neural tissue vaccine, avian embryo vaccine, and crude vaccine for cell culture, and developed to the purified vaccine for primary gopher kidney cells, chicken embryo cells, human diploid cells and Vero cells with increasingly perfect technology.

Early neural tissue vaccines have poor immunization effects, and local and systemic reactions are severe after vaccination. Because the vaccine contains myelin components of animal brain tissue, it may cause neurological paralysis after vaccination. WHO recommended the stopping of production and use of neural tissue vaccines in 1984, and countries have now stopped using them one after another.

Since the 1960s, rabies vaccines produced using cell and tissue embryo culture technology have made great progress. Due to the use of cell culture and purification technology, CCEEVs avoid adverse reactions caused by residual animal brain tissue and cell protein residues in the product, improve vaccine titers and antibody levels after immunization, reduce injection times, and minimize the number of immune failure cases.

It has been proven that CCEEVs can safely and effectively prevent rabies. Currently, widely used include Vero cell purification vaccine, human diploid cell vaccine, purified chicken embryonic cell vaccine and primary gopher kidney cell vaccine.

The human diploid cell vaccine was first created by the Wistar Institute in the United States. Subsequently, the Merieux Institute in France obtained a production license in 1974. After multi-center clinical observation, the incidence of adverse reactions after vaccination was low, the symptoms were mild, and the immune effect was good. However, human diploid cell proliferation was slow, the virus yield was low, the vaccine cost was high, and the price was expensive, so it could not be widely used.

The purified Vero cell rabies vaccine was obtained by the French Meerieux Institute in 1985. The adverse reactions in humans are mild and have good results, and have the same safety and efficacy as human diploid cell vaccine. Moreover, due to the high titer of cultured rabies viruses, the large vaccine yield and low price, it has been widely used worldwide.

According to the clinical observations of different manufacturers, the purified chicken embryo cell vaccine and primary gopher renal cell vaccine have mild adverse reactions, and the immune effect, safety and effectiveness are better.

2. History and current situation of rabies vaccine used in my country

Before 1980, my country has been producing and using carbolic acid-inactivated brain tissue vaccine prepared by sheep brain.

In 1965, my country began to develop a stock solution inactivated vaccine for primary gopher kidney cell culture. This vaccine must be added with aluminum hydroxide 3) as an adjuvant to increase the efficacy of the vaccine. It obtained a production license in 1980. At that time, the effectiveness of the vaccine was determined by the Hael method, with a protection index of ≥10,000, and 14 injections were required. Later, the NIH method was used to determine the titer, and the titer was set at 1.3IU2ml, and the immune procedure was also changed to the 5 injection method.

However, while the purely concentrated vaccine improves its effectiveness, due to the corresponding increase in the content of impurity protein residues, the incidence of adverse reactions increases and the symptoms worsen, and the incidence of serious adverse reactions reaches 5% to 10%. Since then, in order to improve the quality characteristics of the vaccine, purification techniques such as column chromatography were introduced to remove impurity proteins. The vaccine still added aluminum hydroxide adjuvant. The titer of the NIH method can reach more than 2.5IU, reaching the effective vaccine standards set by WHO.

Using the general pre-exposure and post-exposure recommended by WHO, although the addition of aluminum hydroxide adjuvant can increase the immune effect, it will cause the body to respond slowly and produce neutralizing antibodies to delay. Since rabies vaccines are mainly used for post-exposure immunity, the timeliness of vaccine-induced immunity is very important.

In 2005, the State Food and Drug Administration required the removal of aluminum hydroxide adjuvant. Clinical studies show that the early immune response of the deadjuvant vaccine is significantly higher than that of the adjuvant vaccine. The positive conversion rate of neutralizing antibodies in 14 days of primary immunization can reach 100%, and the incidence of adverse reactions is low. Since 1990, my country has developed or introduced Vero cells as a matrix to the market in large quantities. In 2014, domestic diploid cell vaccines were also approved for marketing, and the types of vaccines have been continuously increased. The types of rabies vaccines currently approved for marketing in my country are shown in Table 1.

3. The evolution of immunization procedures for human rabies vaccine

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A simplified vaccination procedure can be used for cell culture vaccines with a titer of more than 2.5 IU doses. Europe was the first to use the 6-dose vaccination procedure for injections of 0, 3, 7, 14, 28, 90 days. With the accumulation of research data, it was found that the vaccination of the sixth shot cannot significantly increase the antibody level, so it was changed to decide whether to vaccinate the sixth shot based on the specific conditions of the recipient's body. Generally, only 5 shots are needed. After that, it was recommended by the WHO and is still widely used worldwide.

In 1984, the Zagre Public Health Institute in the Former Yugoslavia conducted immunization procedures for different types of rabies vaccination and optimized vaccination procedures. The results showed that the neutralizing antibodies produced by the immunization procedure of the upper arm deltoid muscle was vaccinated at about 0 days, and the level of each dose was increased early and the level was also higher. This immunization procedure was called a program. In 1992, WHO was officially recommended at the eighth meeting of the Rabies Experts Committee.

In 2009, the U.S. Immunization Advisory Committee, based on the comprehensive published literature, recommended that healthy adults can adopt the original 5-pill immunization procedure to reduce the last 1 injection under standardized disposal, that is, the immunization procedure injected on 0, 3, 7, and 14 days.

At present, the WHO recommended post-exposure immunization intramuscular injection procedures include, procedures and ACI recommended. The recommended pre-exposure immunization intramuscular injection regimen is 3 doses of vaccines, which are vaccinated on 0, 7 and 21 or 28 days respectively. The post-exposure immunization procedures for rabies vaccines approved by my country include and procedures. The immunization procedures for each vaccine shall be subject to the vaccine instruction manual approved by the State Food and Drug Administration.
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