From human pox to vaccinia, human beings open the ＂box＂ of vaccines.

　　Throughout modern history, smallpox has held the top spot in killing human beings.

　　Smallpox is also the first infectious disease eliminated by human beings.

　　When future generations are exploring what killed smallpox, the trekking about how human beings overcome diseases step by step has merged into the long river of human medical history.

　　It is necessary for us to wade into this river at any time, go back to the way we came and find hope for the future.

　　The pockmarked emperor and the milkmaid

　　It is mentioned in Huangdi Neijing that "poison" should be used to treat diseases, and the so-called "fight poison with poison". Traditional Chinese medicine began to use this method to deal with smallpox, which existed during the Tang and Song Dynasties. Doctors take out the serous fluid from the abscess of smallpox patients and implant it into the body of healthy people for prevention and treatment, which is called human pox vaccination.

　　During the Wanli and Apocalypse years of Ming Dynasty, various books about human pox appeared. By the Qing dynasty, the method of preventing smallpox by human pox vaccination was widely promoted. Kangxi, the "pockmarked-faced emperor" who had suffered from smallpox, set up a pox clinic under the Tai Hospital and recruited famous doctors. Also in Beijing, a special "acne check chapter Beijing" is set up to take charge of the Eight Banners’ acne prevention. He specially sent people to welcome Ayla Zhang, a well-known folk vaccinia doctor, into the palace to vaccinate the royal family and banners.

　　Jared diamond, an evolutionary biologist and anthropologist, once revealed how the human body can defeat the virus: in the process of resisting a certain pathogen that infects the human body, the human body will gradually form specific antibodies, which makes it unlikely to be infected by the same pathogen again after recovery.

　　In the thousands of years of confrontation between human beings and smallpox, the latter has occupied an absolute advantage for a long time, and "pockmarked face" is so common that people without pockmarked face become special.

　　The 18th century was the age when smallpox ravaged Europe, and the British doctor edward Cenna (1749-1829) devoted himself to studying the solution. He noticed that almost all the female milkmaids had no "pockmarked faces". The beautiful milkmaid aroused Qinna’s curiosity, and he found one thing in common with them — — Cowpox of a milkmaid.

　　Vaccinia is a virus that can be co-infected by humans and animals, but it does no serious harm to cattle and people. There is a saying in the English countryside that "as long as you have suffered from vaccinia, you will not get smallpox".

　　Since 1788, Qinna began to carry out experiments on animals, using vaccinia of dairy women instead of smallpox patients to fight smallpox. For 8 years in a row, the experiment pointed to the same result, and vaccinia can effectively prevent smallpox.

　　On May 14th, 1796, Qinna conducted the first human experiment. He took the serous fluid Sarah Nelmes, a milkmaid, and inoculated it on the arm of phipps, an 8-year-old boy. Two months later, he inoculated phipps with real smallpox slurry. As a result, the boy was not infected with smallpox, and the previous vaccination seemed to have made him immune.

　　In the following two years, Qinna conducted the same human experiment many times, and the results were the same: all children who had had vaccinia were immune to smallpox virus. In 1798, Chennault announced that smallpox could be prevented by vaccination.

　　Vaccinium vaccination spread rapidly around the world. In 1977, Ethiopia recorded the last case of smallpox in human history. On October 26, 1979, WHO officially publicized that smallpox was eradicated all over the world.

　　This is the first time in human history to win the battle against infectious diseases.

　　Fatal bacteria and life-saving bacteria

　　Although the practical application of vaccinia technology is very successful, scientists are not satisfied. People need to explain theoretically why vaccinia can fight smallpox.

　　In the 1950s, chemist Louis Pasteur confirmed the relationship between diseases and germs, and found that specific microbial pathogens could cause specific diseases. Moreover, he found that the long-term growth toxicity of bacteria on artificial culture medium would be weakened, but the immunogenicity still existed.

　　According to this theory, in 1881, Pasteur artificially attenuated Bacillus anthracis with strong immunogenicity and inoculated it into sheep, which finally proved that sheep inoculated with Bacillus anthracis vaccine would not get the disease again.

　　Rabies virus can not be isolated and cultured like bacteria, but Pasteur confirmed that the pathogenic microorganism causing rabies exists in the spinal cord or brain tissue of sick animals. Therefore, he chose rabbit brain for subculture to obtain attenuated strains, and then successfully made live vaccines.

　　With the development of microbiology and immunology, vaccine is really defined as active immunity preparation for preventing infectious diseases, which is made of pathogenic microorganisms (such as bacteria, rickettsia, viruses, etc.) and their metabolites by artificial attenuation, inactivation or genetic engineering.

　　Based on this method, more vaccines can appear. Attenuated live vaccine made by heating inactivation of Vibrio cholerae; After 13 years and 213 generations of continuous culture on the culture medium, attenuated BCG was obtained.

　　With the development of the discipline, some traditional classical vaccine varieties have been further transformed into new vaccines, and some vaccines that cannot be developed with classical technology have found ways to solve the problem.

　　In 1972, recombinant genetic engineering contributed a lot of technical support and gave birth to recombinant gene vaccine. By using DNA recombinant biotechnology, natural or synthetic genetic material which can induce immune response in protein of pathogen shell can be directionally inserted into bacteria, yeast or mammalian cells, and the vaccine can be made after expression and purification. Nowadays, BCG, recombination vaccines, SARS vaccine, HIV vaccine and highly pathogenic avian influenza vaccine are being studied.

　　Conjugate vaccine appeared in 1980s. Scientists linked sugar molecules with protein (toxoid of Clostridium tetanus or diphtheria) by chemical methods, and developed a conjugate vaccine. Vaccines against pneumonia and meningitis are made in this way.

　　Looking at the present, the vaccine that has attracted much attention is none other than nucleic acid vaccine. Nucleic acid vaccine, also known as gene vaccine or DNA vaccine, transports DNA vaccine to human cells through some carrier (such as nanoparticles), which will guide the cells to produce immune active components, and then the cells will "spit out" these active components to stimulate the human body to obtain corresponding immunity, but it will not cause disease.

　　Nucleic acid vaccine can even transfect food cells, such as inserting hepatitis B virus nucleic acid vaccine into the genome of tomato cells, and inoculating the vaccine when eating tomatoes.

　　Scientific and technological progress brings infinite possibilities, and the new exploration of vaccination methods is also the tireless pursuit of scientists. In addition to traditional injection methods, oral administration, skin patch, nasal spray and improved fruit are all targets.

　　A never-ending struggle

　　With the development of immunology research, people have more and more expectations for vaccines, hoping that they will not only "prevent diseases". Researchers are already in action, trying to achieve the effect of treating diseases or preventing diseases from worsening by inducing specific immune responses. Such vaccine products are therapeutic vaccines.

　　There are many therapeutic vaccines that have been studied all over the world: tumor vaccines used for tumor treatment use tumor antigens for active immunization to stimulate the body’s active specific immune response to tumors to prevent the growth, spread and metastasis of tumors; Vaccines used for the treatment of cardiovascular diseases aim at intervening the immune process to prevent the occurrence and development of atherosclerosis (AS). A Swiss biotechnology company said that CYT006-AngQb, a vaccine used to treat hypertension, has a good clinical development prospect … …

　　On the other hand, when human beings are struggling to move forward, the "perpetrators" of infectious diseases are not willing to be silent. Since 1970s, more than 40 infectious diseases have been discovered in the world, such as HIV virus, avian influenza virus, SARS virus, mad cow disease prion, monkeypox virus, Lyme virus, Ebola virus, Legionella, Vibrio cholerae O139 and so on. People’s common influenza viruses are constantly innovating. For example, after the "Spanish flu" caused by H1N1 virus, the "Asian flu" and the "Hong Kong flu" were staged by H3N2 subtype virus. Or a lower-grade flu, it is staged almost every few years in Europe, America and Asia. There are also new viruses that have never met each other, eyeing and hiding in the dark.

　　"The only competitor competing with humans for the dominance of the earth is the virus." The words of lederberg, the winner of the Nobel Prize in Physiology or Medicine in 1958, sounded like an alarm bell. In the past two hundred years, the confrontation between human beings and germs was the fiercest. For the first time, we turned the tables, stood in a pre-emptive position, and seized the throat of the biggest killer of human beings. Compared with the end of the 19th century, the average life expectancy of human beings has been extended for several decades.

　　We have opened the "box" of vaccines. Overcoming the challenge of disease again and again makes us believe that disease creates problems and also provides understanding.

　　Huaxi Dushi Bao-cover journalist Li Yuanli

　　[References]

　　1. zhangfang, from human pox to cowpox [J], Science World, 06, 2018;

　　2. [America] jared diamond, Guns, Germs and Steel, Shanghai Translation Publishing House;

　　3. Huang Jiandong, the milestone of human conquest of smallpox — — Jenner’s Invention of Vaccinium Inoculation [J], Invention and Innovation, 2003, (9): 42-43;

　　4, Liu Xueli, China’s ancient immune thought and human pox vaccination [J], Medicine and Philosophy, 1993 (11);

　　5. Kou Yi, Brief Introduction of Three Vaccine Revolutions [J], Chinese Journal of Medical History;

　　6. Plotkin, Vaccine Science (5th Edition) (Fine), People’s Health Publishing House, 2011;

　　7. Xie Zhongping and Li Qihan, Fighting Infectious Diseases: Application and Development of Vaccines, 2007.