How inactivated vaccines helped humans control the plague in history?

How inactivated vaccines helped humans control the plague in history?  Are inactivated vaccines great? Let’s take a look at how it helped humans control the plague in history. 

Vaccines such as vaccinia and rabies vaccines are all live vaccines. Either it is based on naturally occurring pathogens that are less virulent (such as Jenner’s use of vaccinia), or artificially attenuated vaccines (such as Pasteur’s anthrax and rabies vaccines) through laboratory operations.

In any case, the pathogens used in live vaccines are still alive, although they are almost always attenuated. But what we are going to talk about today is a vaccine developed by a completely different technological route-an inactivated vaccine.

Inactivated vaccines-a different world

Although inactivated vaccines are also vaccines made directly from pathogens, these pathogens need to be physically or chemically grown in culture (the culture can be animals, chicken embryos, cells, or broth, etc.). The method is killed (inactivated) after treatment to destroy the pathogen’s ability to replicate.

It should be emphasized that although the replication activity is destroyed, it must still retain its antigenicity (the ability to cause the body’s immune response after vaccination). This technology is completely different from attenuation, in which inactivated bacterial vaccines were the first to be successfully developed.

In the short decades from the end of the 19th century to the beginning of the 20th century, microbiology and immunology have made amazing progress, targeting infectious diseases caused by three major bacteria that seriously threaten human health, or even threaten the survival of the entire human race. ——Cholera, typhoid fever and plague, scientists took the lead in launching the charge.

Today we will talk about another legend who came out of the Pasteur Institute-Hafkin, and the story of him and the early bacterial inactivated vaccine.

Waldemar Haffkine is a Ukrainian scientist. He left his motherland under the anti-Semitism environment at the time. In 1889, he entered the Pasteur Institute under the recommendation of his mentor and compatriot Ilya Metchnikoff.

Mechniknov will become the founder of immunology in the future. In 1908, he will be awarded the Nobel Prize in Physiology or Medicine together with Paul Ehrlich. .

Attenuated cholera vaccine wins first battle in India

Hafkin first focused on the research of cholera vaccine.

In 1883, German scientist Robert Koch first identified the bacterial etiology of cholera and went to Calcutta, which is considered to be the birthplace of cholera for research. There, he used fresh clinical materials to cultivate the bacterium in a broth medium.

Koch’s discovery promoted the development of vaccines. By the early 1890s, despite the cholera epidemic in Spain, Pasteur still believed that an effective cholera vaccine was possible in his later years, and Hafkin, one of the newest members of the institute, was entrusted with an important task.

Hafkin used two V. cholerae strains for cholera vaccination strategy. The first dose of the vaccine is a vaccine that grows at 39°C and is attenuated. After a period of time after the first dose, the second dose is given. The second dose of vaccine is a bacterial strain whose virulence has been enhanced after multiple intraperitoneal passages in guinea pigs.

Hafkin conducted his first large-scale, uncontrolled study in Kolkata. On this basis, starting in 1894, he rigorously designed vaccine control trials for a clear population to reliably compare the differences between vaccinated and unvaccinated people. Studies have found that the live attenuated cholera vaccine developed by Hafkin can provide effective protection against infection despite serious adverse reactions.

Hafkin’s cholera study in India is recognized as the first human vaccine trial with a control group.

The epidemic of plague at the end of the nineteenth century

While Hafkinsang was conducting research on cholera vaccination in India, another severe infectious disease, plague, also appeared epidemic in India.

Throughout history, the plague, as a cause of an outbreak, occupies a unique and terrifying position, causing a large number of deaths and changing the course of human development. From the Justin Plague in 541 AD, which caused repeated plague epidemics for two centuries, to the Black Death that swept Europe in the 14th century, its population decreased by 40%. The plague has been a continuous threat to the European continent.

By the nineteenth century, the disease began to invade Asia and killed millions of people in India and the Far East.

The pathogen of the plague was independently discovered by Shibasaburo Kitasato and Alexandre Yersin in 1894. At first, it was named Pasteurella pestis, but it was later renamed Yersinia pestis by one of its founders.

Plague inactivated vaccine

In 1896, the Indian plague became popular, and the Indian colonial government invited Hafkin to Mumbai to develop a plague vaccine. Hafkin moved to a temporary laboratory at the Grant School of Medicine in Mumbai to begin his development of a plague vaccine.

Perhaps it is time constraints that do not allow it to be attenuated for repeated generations, or it may be afraid of the strong lethality of the plague. Hafkin did not use Pasteur when developing the plague vaccine. He was the best at cholera vaccine. The development route of using attenuated live vaccines was changed to inactivated vaccines.

After he isolated and cultivated a pure culture of Yersinia pestis, he inactivated it by heating at 70°C for 1 hour to obtain the initial inactivated vaccine. After successfully immunizing the rabbit with the inactivated vaccine, he first vaccinated himself with the vaccine, only noticing fever and pain at the injection site, and no other adverse reactions.

Based on his early controlled cholera vaccine trials in the past 4 years and the experience of plague outbreaks in the city, Hafkin conducted a small controlled trial of his plague vaccine in “volunteers” in the local prison in 1897. Tests have proved that the vaccine is protective.

In the next 4 years, he vaccinated thousands of people and vaccinated 200,000 people in Mumbai alone. The results were very good. Vaccines can not only prevent infection, but also reduce the mortality rate of communities affected by the plague by nearly 50%, and even reduce the mortality rate of people who are already in the latent infection period at the time of vaccination.

As India’s demand for vaccines grows, Hafkin’s business is also growing. By 1901, he served as the general manager of the Plague Research Laboratory in Mumbai, with a total of 53 employees, responsible for the preparation and distribution of plague vaccines and cholera and typhoid vaccines; he was also appointed as a scientific adviser to the Indian government.

Hafkin unswervingly advocates vaccines for the prevention of epidemic bacterial diseases and is an expert in clinical trials of vaccines. His work against the plague in India made him a popular hero.

However, his attitude, style and foreign background may also arouse hostility from the British authorities there.

Little Dreyfus incident

In March 1902, 19 Indian villagers from Mulkowal, Punjab, who were vaccinated with the same vial, died of tetanus. Evidence suggests that a bottle of vaccine labeled 53N was contaminated.

Investigation and research at that time found that there was a problem with the sterilization procedure of the vaccine packaging bottle. The original general bottle sterilization procedure was to use carbolic acid sterilization, but the Hafkin laboratory changed it to heat sterilization. Although this sterilization procedure has been used safely at the Pasteur Institute for 2 years, it has not been approved in the British Empire.

The Indian government’s investigation committee in 1903 concluded that unauthorized use of sterilization procedures was the source of contamination. The Commission of Inquiry sued Hafkin, he was relieved of his duties and returned to England.

This incident was called the “Little Dreyfus Incident” by some people after the French espionage case involving military secrets and anti-Semitism at the time, because its protagonist, Hafkin, was related to the Jewish background.

However, the Lister Institute re-investigated the incident and overturned the verdict: They discovered that an assistant had used a contaminated bottle cap and had not disinfected it. Therefore, the heat sterilization process is not the source of contamination.

Hafkin returned to Kolkata to continue his research, but was banned from testing or producing vaccines until his retirement in 1914. Hafkin returned to France after retirement, and later moved to Lausanne, Switzerland, where he spent the last years of his life.

Hafkin’s great contribution and honor

In the early twentieth century, as the central role of rodents and their fleas in the spread of plague was gradually established, the establishment of public health measures to control disease vectors and improve sanitary conditions greatly reduced the burden of disease. The whole-cell inactivated vaccine developed by Jin obviously also contributed to the control of the epidemic.

Although Hafkin experienced the “Little Dreyfus Incident,” his great contribution to vaccinology is still recognized by the industry and the public. In 1897, Queen Victoria of the United Kingdom awarded the Order of Sir Huffkin in recognition of his outstanding work in the field of microbiology. In 1925, the plague laboratory in Mumbai was renamed the Hafkin Institute, which also marked the restoration of his reputation in India. Later, the laboratory became the largest bacteriology and epidemiology research center in South and Southeast Asia.

Currently, a subunit plague vaccine using recombinant virulence factor protein is being developed clinically to deal with the threat of plague as a potential vector of bioterrorism. Compared with inactivated whole-cell vaccines, these products are fast and highly immunogenic, and have milder local and systemic side effects. The whole-cell inactivated plague vaccine has gradually withdrawn from the stage of history.

With the in-depth understanding of bacterial immunity by humans, the whole-cell inactivated bacterial vaccines that are still widely used have gradually been reduced, and most of them are vaccines with partial bacterial protein components.

However, in the virus world, the situation is not exactly the same as that of bacteria. Next time, we will introduce the most famous polio vaccine. The advantages and disadvantages of and inactivated vaccines are shown to everyone more thoroughly.

(source:internet, reference only)

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