The history of vaccines
How do we talk about people? Will it be like what astronomers see, just a little dust, crawling helplessly on an unimportant planet? Or, as chemists say, a bunch of chemicals are skillfully fiddled together? Or, as seen in Hamlet's eyes, is man noble in intelligence and infinite in talent? Or both? -Russell's Wisdom of the West
Since the birth of mankind, looking back on the course that mankind has gone through, mankind will always suffer from one disease or another inadvertently. However, despite suffering from various diseases, human beings did not yield and retreat, but embarked on a tragic journey again and again in bursts of pain. Because of this, human beings can survive, continue and develop!
Disease and life coexist, but infectious diseases directly and irresponsibly threaten anyone. When infectious diseases come and human beings find themselves ignorant, when human beings can't control the spread of diseases, fear arises. Human beings regard disease as the power of ghosts and gods and as the arrangement of fate. The occurrence of diseases is also considered to be that God wants to punish guilty people, so it will come. Rulers, politicians and wizards used people's fear of disease to strengthen their rule, whether in the tribal era or in the birth of civilization. With the decline of Greek and Roman civilization in 400 A.D. and the beginning of the dark ages, infectious diseases, parasites and other disasters began to threaten the European continent, and human beings began to realize that the root of the plague epidemic was people, not ghosts and gods.
From 65438 to the beginning of the 8th century, people in China were inoculated with pus from smallpox patients to prevent diseases and introduced to Europe. At the same time, Chen Na, a British village doctor, also found that the milkmaid who had been exposed to vaccinia would not suffer from smallpox, so he improved the inoculation method and succeeded in human trials. This gave birth to vaccinology and immunology.
Vaccination is a complex interdisciplinary subject, which depends on both theoretical research and experience. Its purpose is not only to study the basic theory, but also to study how to obtain the results with practical application value. Throughout the development history of vaccinology, its development process can be roughly divided into development stage, experience stage and modern stage. Among them, the modern stage is the productive period of vaccines, and many new vaccines and technologies have been developed and are still in use today.
A period of great energy
/kloc-At the beginning of the 9th century, vaccinia vaccination became a global epidemic prevention work, especially in Europe and North America, during which no new vaccines appeared. The past 25 years have been a period of hard work, and meaningful vaccinology has emerged. After that, it lasted for 40 years and entered the First World War. The research objectives of this period mainly focused on bacteria, medical application and experimental immunology of antibodies, represented by Pasteur, Koho, Von Beilin and Eric.
Pasteur found that under the condition of laboratory culture, the virulence of bacteria causing poultry plague was weakened, so that more tolerant and toxic bacteria could be induced. Further research enabled him to effectively develop vaccines against anthrax, cholera and rabies virus. As the first medical scientist to win the Nobel Prize, Feng Beilin immunized diphtheria and tetanus with soluble toxins, and established passive immunotherapy, which played an important role in the development of anti-infectious disease treatment methods. However, the most far-reaching influence in this period was Eric's discovery.
Eric found that dyes and other chemical components have specific affinity with cell structure. Based on this principle, he developed the world's first synthetic chemical drug, namely 606 complex, which can be used to treat syphilis. At the same time, Eric developed a special antibody quantification method, which made Feng Beilin's passive immunity really practical. He believes that cell side chains are particularly complementary to chemical substances and other protein (hereinafter referred to as special receptor-ligand binding), and his views enable us to have a deeper understanding of immune specificity, cytochemistry and special drug treatment methods.
19 19 At the end of World War I, human beings discovered humoral immunity. The titer of live or inactivated vaccine (in serum reaction, the maximum dilution of antibody or antigen preparation with obvious visible reaction between antigen and antibody is called titer. ) has been greatly improved. In addition to the vaccines mentioned above, vaccines for typhoid fever, Shigella dysentery, tuberculosis, diphtheria, tetanus and whooping cough have also been successfully developed.
The 1930s-1950s, spanning the whole World War II, was an era of great changes, which became the transition period from vaccine development to prolificacy. A breakthrough in this period was that Goodpeste proved in 193 1 that the virus could grow in fertilized chicken embryos, so Taylor produced a safe and effective chicken tissue vaccine against yellow fever, which was widely used in tropical countries.
During this period, many vaccines were studied for military purposes. Researchers such as Hillman of Walter Army Research Institute in the United States have developed typhus vaccine in the yolk of chicken embryos. After this achievement was put into use, a large number of vaccines were produced, which saved many wounded and sick people during World War II and made them reborn. In addition, they also developed an influenza vaccine, which was purified by continuous flow centrifugation, creating a precedent for purifying virus vaccines.
During the flu, Hillman also found adenovirus. Through his colleagues, he obtained fresh tracheal samples from a dead recruit and obtained tracheal ciliated epithelial cells after culturing tracheal endothelial tissue in vitro. Three new viruses, adenovirus, were isolated from throat specimens of patients in some areas, and the effective rate of adenovirus vaccine was proved to be 98% in large-scale clinical trials from 65438 to 0956. Inactivated adenovirus vaccine was approved for marketing in 1958, and used to vaccinate children. 1946, Enders discovered that poliovirus can reproduce in embryonic tissue cells, which opened the way for virus culture in cells.
productive cycle
After 1950s, it entered the modernization period of vaccine development, which was a period of high vaccine production. However, after 1985, the number of cases in which new vaccines were developed and licensed decreased rapidly, and a few vaccines were not licensed until 1980 ~ 1990.
Vaccines in this period can be divided into whole-bacteria vaccine, semi-bacteria vaccine, virus recombinant subunit vaccine, live virus vaccine cultured in vitro and inactivated virus vaccine. Bacterial vaccines are mainly subunit capsular polysaccharide preparations, but attenuated whole bacterial vaccines have also made great progress.
As early as 1946, pneumococcal whole-cell vaccine appeared and obtained the production license. However, its application was soon interrupted by sulfonamides and other antibiotics. Although antibiotics have achieved remarkable results in reducing bacterial infections, drugs have not completely prevented patients from dying. Therefore, at the insistence of Dr. Austrone in Australia, the research on pneumococcal vaccine was restarted. Pneumococcal vaccines with titer of 14 and titer of 23 were licensed in 1977 and 1984 respectively.
Polysaccharide vaccine, especially Haemophilus type B vaccine, will not produce immunity to children. However, animal experiments show that the combination of polysaccharide and protein can stimulate T cells and make newborn animals immune, which opens the door for Hillman and other researchers and many biological preparation companies to develop efficient combined vaccines. Several effective combined Haemophilus vaccines have been licensed, and this technology has been used to improve the immunity of meningococcal and pneumococcal vaccines.
During this period, viral vaccines have also developed greatly, and anti-polio vaccines have also been developed. The breakthrough of inactivated polio vaccine comes from Enders' research, that is, polio virus can reproduce in non-nerve tissue cell culture. Up to now, live vaccines still retain a small amount of neurotoxicity, but rarely cause polio to vaccinators or contacts. Nevertheless, active polio vaccine is still a model to prevent polio and eradicate the global polio virus.
However, in the process of virus vaccine development, the research and development of children's live virus vaccine is facing many obstacles, among which the main obstacle is how to develop and manufacture a large number of qualified vaccines with different generations and commercial quality. Although chicken yolk was used as the original cell culture medium for measles vaccine production, the common avian leukemia virus pollution in chicken yolk once troubled researchers. It was not until the successful cultivation of anti-leukemia chickens that this problem was fundamentally solved.
In addition, the original measles virus vaccine is particularly toxic to children, and it needs to be injected with measles antibody at the same time to solve this problem. Scientists quickly developed measles and rubella vaccines through attenuated treatment. The combined vaccine showed good safety and effectiveness in all aspects, and the technology of combining bivalent and trivalent vaccines for measles, mumps and rubella came out soon. The application of triple vaccine has become the main product of children's immunity today. Great progress has also been made in the development of varicella vaccine, hepatitis A virus vaccine and hepatitis B virus vaccine.
The first licensed anti-cancer vaccine in the world was also produced during this period. Marek's disease is a lymphoma that occurs in the nerves and viscera of chickens. The turkey herpesvirus cultivated by Bermeister and his colleagues shows that it can fight Marek herpesvirus without making chickens sick. Hillman Laboratory developed Marek's vaccine on 197 1 and obtained permission, and developed a purified dry virus vaccine on 1975. After a long and complicated study, it has been proved that it can produce protective titer to chickens, and it is very safe, and humans will not be affected by eating immunized chickens, so there is a vaccine.
Future days
Contemporary vaccinology, especially viral vaccines, is very complicated, and the current research mainly focuses on viral subunits. Except Lyme disease vaccine and hepatitis B vaccine, none of them are registered in recombination vaccines. All existing and inactivated virus and bacterial vaccines still need to be explored and studied.
With the development of society, many new infectious diseases have appeared. In the future, we are eager for new vaccines to prevent more than 20 diseases, such as tuberculosis, malaria, hepatitis C and AIDS. Since 1985, the research and development of new vaccines has always been barren, but it seems to bring hope, and there are not many overall successes. The real development of vaccine needs the maturity of many theories.
Scientists' understanding of the importance of cell regulation and humoral influencing factors in immune response has opened a new era of vaccine research, which is more worthy of our expectation than anything in the past. The development of new vaccines depends on the identification of suitable antigens and antigenic determinants. More importantly, the development of vaccines must depend on the content and way of presenting antigens to the immune system. What to present for vaccines (such as AIDS vaccine) will be the main problem, and the discovery and identification of antigens and antigenic determinants will accelerate the process of vaccine development.
With the technical breakthrough of recombinant hepatitis B vaccine, the research on how the body presents antigens is full of new and exciting possibilities. Molecular genetics will focus on this and carry out the continuous evolution of eukaryotic cell expression. The internal expression and presentation of transfected dendritic cell antigen has created a great opportunity for developing anti-infection vaccine and treating persistent infection and cancer. Transgenic plants provide a new research direction for developing countries that need cheap and simple vaccines. With the development of synthetic chemistry, linear string compounds or the combination of multiple antigens and antigenic determinants may play an important role in the future. The knowledge platform of the 20th century has provided a good support for the development of vaccines in the 20th century. We should be optimistic about the future of vaccines and believe that this will come true. -
(Editor Wang Caixia)
The process of vaccine
Pneumococcal vaccine
1946
The hexavalent vaccine was licensed, but it was replaced by antibacterial agents.
1964 ~ 1968
Effective chemotherapy can't prevent death, so vaccine research should be carried out again.
1977
14 valent vaccine is licensed.
1984
The 23-valent vaccine was licensed.
Haemophilus vaccine
1985
Older children have obtained permission to use polysaccharide vaccine, but the immunity of polysaccharide vaccine is insufficient in younger children.
1987 ~ 1990
Different Haemophilus combinations are licensed.
1992
Conduct extensive research on all polysaccharide vaccines.
1998
Schmeizhan Company has obtained the license of a new subunit Lyme disease vaccine.
measles vaccine
Chicken embryo cell culture. Reduce the reaction and use it at the same time with immunoglobulin.
Further attenuated (no globulin). An experimental leukemia-free chicken was developed by removing chicken leukemia virus from the culture medium. Efficient and safe vaccine production.
mumps vaccine
Chicken embryo cell culture. High-efficiency non-response vaccine production of Jerry Lynn virus strain without neurotoxicity.
German measles vaccine
Found to reproduce in duck cells.
Fast and reliable attenuation.
It will not be transmitted to vulnerable adult contacts.
Bivalent and trivalent formulations
Acceptable titer and reactivity.
The clinical trial was very successful.
The main immunogen of children.
Varicella vaccine
Generate 198 1 KMcC virus strain. When applying attenuated procedures, viruses cannot achieve an acceptable balance between reactivity and immunogenicity. Replaced by OKA virus strain.
Vaccine type
1. Inactivated vaccine: a preparation prepared by killing pathogenic microorganisms by physical or chemical methods, called inactivated vaccine.
Type: typhoid, cholera, whooping cough, epidemic cerebrospinal meningitis, Japanese encephalitis, typhus and leptospirosis vaccine.
Features: Immune function is weak, so it must be injected many times, and the amount should be large. But easy to preserve.
2. Live vaccine: A preparation made of live attenuated or nontoxic pathogenic microorganisms artificially mutated or screened from nature, called live vaccine, also known as attenuated live vaccine.
Types: BCG, measles, polio vaccine, rubella and other vaccines.
Features: strong immune function, small inoculation amount, generally only one inoculation. But it is unstable and not easy to store.
3. Subunit vaccine: a vaccine prepared by extracting antigen components from pathogenic microorganisms that can stimulate the body to produce protective immunity. For example, the blood-borne vaccine of hepatitis B is made by separating and purifying the small spherical particles HbsAg of hepatitis B virus.
4. Synthetic vaccine: A vaccine made by combining a synthetic antigen peptide that can induce the body to produce protective immunity with a carrier and then adding an adjuvant. The amino acid sequence of the active ingredient must be obtained first.
Features: once synthesized, it can be produced in large quantities, and there is no possibility of blood-borne infection.
5. Genetic engineering vaccine: The antigen gene (target gene) encoding protective immunity in pathogenic microorganisms is recombined with the vector and introduced into the host cell, and the expression of the target gene produces a large number of corresponding antigens, so the vaccine prepared from this is called genetic vaccine. Such as hepatitis B gene vaccine.
6. Toxoid: After bacterial exotoxin is treated with 0.3% ~ 0.4% formaldehyde, it loses its toxicity and retains its antigenicity, which becomes toxoid.
Type: diphtheria, tetanus toxoid, etc.