From smallpox to coronavirus
Vaccines: what are they and why are they needed
Nikolay Nikitin, Post-science
Whooping cough, polio, measles are just some of the diseases that are practically not found today thanks to vaccination. Modern people now know about smallpox and typhoid epidemics only from books.
Vaccination forms the body's defense mechanisms for resistance to the disease and makes the immune system stronger. Most often, vaccines are made from weakened forms of the pathogen in order to prepare the immune system to face a real threat – a virus or a bacterium.
According to WHO, vaccination can prevent from 2 to 3 million deaths annually, and people's distrust of vaccines is included in the list of the top ten health problems that WHO worked on in 2019. For example, in 1958, more than 750 thousand cases of measles were registered in the United States – 552 people died. But when measles vaccination became mandatory, the number of cases dropped to several dozen per year.
The first vaccines. How doctors defeated smallpox
Viruses and bacteria have been living next door to humans throughout history. More than once they caused epidemics, the victims of which were hundreds of thousands of people. Black (natural) smallpox – a severe viral infection – for sixteen centuries passed through the lands of Europe, India, China and Persia.
There were no medicines for the misfortune, but doctors were looking for a way to stop the disease – that's how variolation appeared. Pus from the pustule was taken from the patient and rubbed into the skin of a healthy person. The idea was simple: to cause a mild illness in order to prevent a serious one later. After variolation, a person suffered from smallpox in a mild form, but this was enough to form immunity.
In 1718, this technique was brought to Europe by Mary Wortley Montague, the wife of the British ambassador to Constantinople. She learned about variolation in Turkey and was not afraid to vaccinate her own five-year-old son. After "clinical trials" on criminals and children from church shelters, the method was adopted by British doctors.
Mortality from variolation was only 2% – a good indicator for the XVIII century. But the technique did not always work smoothly and sometimes caused epidemics: doctors estimated that 25 thousand more patients died in 40 years of clinical use in London alone than in the same number of years before the introduction of vaccinations. By the end of the XVIII century, variolation began to be gradually abandoned.
By this time, the British rural doctor Edward Jenner had come up with a new way to fight the disease. He noticed that local milkmaids were often infected with cowpox. The disease passed in a mild form, and then immunity to smallpox was formed.
Jenner suggested that the causative agents of natural and cowpox belong to the same family and therefore, having had one smallpox, the second person will not get sick. For about thirty years, the doctor observed natural cases of cowpox and in 1796 decided on a public experiment. In the presence of doctors and spectators, Jenner took a smallpox crust from a milkmaid and "vaccinated" her eight-year-old boy James Phipps: the doctor took some fluid from the milkmaid's abscess and made incisions in the boy with the same lancet. The disease began, but developed only on the vaccinated sites and proceeded without complications. A few weeks later, Jenner vaccinated the child with natural human smallpox, but even that did not take root, and the boy remained healthy. No one will allow such experiments today: the risk was too high, and the boy could die. But Edward Jenner's expectations were met. The method was called "vaccination" (from the word vaccinia – "cow").
In fact, attention was paid to this before Jenner, but only he was able to sum up the theoretical basis and prove his hypothesis experimentally.
More recently, the scientific community started talking that Jenner used not only cowpox virus, but also horse pox. They began to think about this after an experiment by a scientific group from the Canadian University of Alberta, which was able to recreate in laboratory conditions the same horse pox virus. The recovered virus does not pose a danger to humans, but is biologically close to the smallpox virus. This model virus was supposed to help get a new, safer vaccine, but caused public concern about using it as a biological weapon.
In the XIX century in Europe, vaccinations against smallpox by the Jenner method gradually became ubiquitous, and after his visit to In 1814, the smallpox vaccination committee was established in Russia. After the revolution in 1919, the Soviet authorities made vaccinations against smallpox mandatory, and then, in the 1960s, the USSR achieved from WHO launched a program for mass vaccination of mankind, and in 1980 this disease was officially ended.
Modern vaccines
At the same time, the vaccination process gradually became more and more secure. The fact is that Jenner's method, in which pus was taken from the pustules of cows, assumed the risk of infection with other diseases. Therefore, his followers came up with the idea of first rubbing the contents of the pustule with glycerin, which relieved the suspension of bacterial impurities. This dramatically reduced the number of side effects, but still did not reduce them to zero.
Modern vaccines are much safer and originate from drugs Louis Pasteur is a French chemist and microbiologist who studied fermentation processes in the second half of the XIX century. At that time, there was a theory that considered fermentation a purely chemical process. Pasteur proved that this is not the case. Having established the biological basis of fermentation, he immediately assumed that the results of his research could eventually be useful in medicine.
Pasteur argued that the creatures that cause fermentation and disease may be similar. It was a completely new idea for that time. Physicians of the mid-XIX century assumed that diseases occur from a combination of an unhealthy environment, an imbalance in the vital processes of the body, the influence of heredity and the action of "miasma" – these included sewage and slaughterhouse waste. Pasteur was so disbelieved that one day during his lecture on the causes and prevention of chicken cholera at the French Academy of Medicine, he was challenged to a duel by a famous orthopedic doctor and the oldest member of the Academy, 80-year-old Jules Guerin. The duel was avoided only after the intervention of the president of the academy.
To prove his theory, Pasteur began studying anthrax. In 1876, the German physician Robert Koch isolated the causative agent of anthrax and described the life cycle of the bacterium. Koch has learned to keep it in a dried state so that the bacterium remains pathogenic. Pasteur immediately picked up the technique and began experiments to create a vaccine against chicken cholera and anthrax. He managed to chemically weaken the isolated pathogens of both diseases in such a way that the result was vaccines in almost the form in which we use them now.
Types of vaccines
Today, five generations of vaccines are known. The first is whole–virion drugs: live and inactivated vaccines that contain a full-fledged virion. These are vaccines for the prevention of plague and anthrax, influenza, smallpox, yellow fever and measles. Despite their high efficiency, they are difficult to deliver to remote regions if there is no refrigerator at hand. Inactivated vaccines are made from pathogens killed by high temperature or poison and do not cause infection, and therefore their effectiveness is lower than that of live vaccines. In order for the body to develop immunity, such vaccines are administered several times, which is not required with live analogues.
The second generation is split vaccines, or split vaccines. They are a mixture of components of a virus or a bacterium – their proteins or antigens. These components can be taken from a pathogen fragmented in the laboratory.
The third generation of vaccines includes subunit vaccines, for the production of which pathogen particles are also used. For example, in the case of the influenza virus, the surface proteins hemagglutinin and neuraminidase are taken. For the vaccine against the SARS-CoV-2 coronavirus, a surface S-protein is used, in bacterial vaccines, protective antigens are used, to which the immune system reacts.
The fourth generation is adjuvant vaccines. They contain a small component of the pathogen, but an adjuvant is added to it – a substance that increases the immune response to the antigen. Adjuvants based on aluminum salts are most often used. Adjuvants can also be other substances, including viruses of other carriers, for example plants.
Today, several more types of vaccines are being actively tested, which are considered the fifth generation – based on DNA (gene vaccines), RNA and viral vectors. In this case, platform viruses are also used, where the necessary virus fragments are included. So after the introduction of a vaccine based on the DNA of the virus, the genetic material of the virus enters the cell, and it begins to reproduce viral antigens. This activates the immune system and causes it to destroy infected cells. RNA vaccines operate on the same principle, but reproduce the virus directly in the plasma of the cell, bypassing the cell nucleus. Viral vectors are weakened viruses that have had the regions of the genome responsible for replication removed.
Why do we need vaccines?
Thanks to vaccines, a person develops adaptive (acquired) immunity. To produce it, only a small particle of the pathogen is required – an antigen, for example, a viral protein that binds to the cell.
The main tool of adaptive immunity is lymphocytes. T-lymphocytes are responsible for cellular immunity, and B-lymphocytes are responsible for humoral: they produce antibodies to antigens. When a vaccine is injected into the body, the immune system begins to produce antibodies.
Antibodies are large molecules with "sticky areas" at one end that recognize the antigen, and at the other – a "contact" area that provides binding to receptors and proteins of the body itself. The "sticky" area approaches the antigen according to the "key – lock" principle. But B-lymphocytes very rarely can immediately pick up an antibody that is ideally suited to the pathogen. They change the structure of the "sticky end" randomly, trying to find the right "key". When this happens, the other "contact" end is recognized by phagocytes and eats the antibody along with the antigen attached to it. Often, many antibodies are produced to the same virus because they react to different antigens.
Is it possible to create a universal vaccine that will respond to the antigens of several strains of the same virus? For example, against the most common virus – influenza – vaccination is considered an effective means of prevention. But not everything is so simple.
The influenza virus has two main antigens – the proteins neuraminidase and hemagglutinin. They quickly change their antigenic properties, so a new vaccine is needed every year. If vaccinated regularly, cross-immunity to the next strain may occur.
A completely different scenario with the human immunodeficiency virus (HIV). It mutates several times faster than the flu virus, so scientists cannot yet create an effective vaccine using known approaches. Thus, for each pathogen, the task of developing a vaccine should be set separately.
In total, there are now about 100 registered vaccines for 30 diseases in the world. The first half – vaccines against viral infections, the second – from bacterial.
Vaccines of the future
One of the most promising areas in virology is the creation of adjuvant vaccines based on plant viruses. Plant viruses are absolutely safe for humans, and therefore they are trying to use them one way or another to create vaccine preparations.
Plant viruses are combined with full-fledged viral particles or parts thereof. To do this, the desired antigen is "attached" to the surface of a plant virus that is safe for humans by chemical or genetic engineering methods, that is, a particle of the virus against which the vaccine will work. The plant virus serves not only as a platform for the desired antigen, but also as an adjuvant that dramatically increases the body's immune response.
Tobacco mosaic virus is often used as such adjuvant, but almost any plant viruses can be taken. Preclinical studies of a vaccine against rubella virus based on a structurally modified tobacco mosaic virus have already been conducted. The same studies are being conducted with respect to rotavirus infection, anthrax and SARS-CoV-2 – the causative agent of COVID-19. In addition, on the basis of plant viruses, various antitumor drugs can be produced that specifically destroy tumor cells.
There are also vaccines based on animal viruses. Such viruses are used as a carrier to deliver the necessary antigens to cells due to their ability to penetrate human cells. We include a vaccine against smallpox, which is produced on the basis of the cowpox virus (now it is a separate vaccine strain of the smallpox vaccine virus). In addition, vaccines based on the monkey adenovirus are being actively developed in the world, from which pieces of the genome responsible for the virulence of the virus itself are being cut out. Such vaccines are currently being developed against the coronavirus that causes the disease COVID-19.
Vaccine testing and side effects
Developing a vaccine is a long and expensive process. In a standard situation, the development of a vaccine begins with a basic study of the pathogen and the development of the primary structure of the drug. When the prototype of the drug is ready, the researchers proceed to preclinical trials: the vaccine is tested on live cells, and then on laboratory animals. According to the results, the effectiveness, safety and dosage of the vaccine are evaluated. After that, with the permission of the supervisory authorities, clinical trials on humans begin. They include three phases, in each of which the effectiveness of the drug, side effects and the immune response of patients are studied. Even after the registration and release of the vaccine to the market, it continues to be investigated and evaluated for safety.
On average, 10-15 years pass from the moment the vaccine is created in the laboratory to its release to the market. Sometimes the vaccine can be made faster, as happened with the Ebola virus vaccine.
In 2014, there was a strong outbreak of fever in Central Africa. The number of infected did not decrease, so this vaccine was released earlier, without waiting for the completion of all stages of clinical trials. However, the drug itself appeared on the market only in 2020.
A similar situation was repeated with vaccines against the new coronavirus SARS-CoV-2. As of August 2020 in China and Two coronavirus vaccines have been registered in Russia, despite the short duration of clinical trials. Although less than a year has passed since scientists discovered the first infected.
Preclinical studies include tests in which the drug is tested on animals. According to the protocol, it is necessary to use several classes of animals: mice, rats, hamsters and rabbits. Monkeys become the most suitable objects for such tests, but rarely use more than a few individuals for one stage for ethical and financial reasons (keeping animals costs researchers very much).
If the vaccine is released too early, people may have adverse reactions that were not noticed during the shortened clinical trials. In 1955, the American pharmaceutical company Cutter Laboratory launched an inactivated polio vaccine on the market. It did not pass clinical trials properly, so 120 thousand doses of vaccines with a pathogenic strain were on sale. After that, tens of thousands of cases of polio were reported within a week. In several dozen children, the infection caused paralysis up to respiratory arrest. This story was the impetus for the creation of protocols for clinical trials of vaccines.
About the author: Nikolay Nikitin – Doctor of Biological Sciences, Head of the Department of Virology, Faculty of Biology, Lomonosov Moscow State University.
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