History of Vaccine from Prof. Dr. Oğuz Karabay

What is a vaccine? When and how did vaccines make their way into our lives?

Prof. Dr. Oguz KARABAY

Sakarya University Faculty of Medicine
Department of Infectious Diseases and Clinical Microbiology

Some Definitions about Vaccination

Although we deeply appreciate the great importance of vaccines, the COVID-19 pandemic has served as a key reminder of their significance. It’s 2020 and we are tuning into the news every day, curiously following whether a vaccine has been discovered against the virus. The vaccine is so important, but it is still necessary to answer some questions first.

What is elimination? It is the act of reducing the incidence of new cases within a geographical area down to zero as a result of organized studies and efforts.

What is eradication? It is the complete removal of the cause of the disease from the face of the earth.

What is a pandemic? It is the spread of the epidemic to multiple countries or continents. 1

What is a vaccine? Biological substances which are developed by eliminating the factors (bacteria, virus) causing disease in humans and animals or by removing the effects of poisons (toxins) secreted by some germs are called vaccines. Vaccination ensures both personal and societal immunity. As the number of people vaccinated in a community increases, the probability of those who are not vaccinated to encounter the cause of disease and the risk of the disease occurring in that community decreases. Considering the opposite, however, every individual who is not vaccinated poses a risk for people who have not yet reached the vaccination period in that society.2 The World Health Organization states that global immunization prevents the death of at least 2 to 3 million people every year.3 Millions of people were saved by vaccination. Infectious diseases with the highest mortality (e.g. smallpox, measles, polio, pertussis, and diphtheria) were stopped by vaccination.

Vaccination is one of the most important medical inventions. Three hundred years back, the average life expectancy was 30 years.  We know that the average life expectancy increased to 30 years in the Middle Ages and reached 50 years after the Second World War. So, what happened and the average life expectancy rose to 75 years? How did we gain 45 years? The three most important factors ensuring this are a modern restroom and sewage system, clean drinking water, and vaccination.

Milestones in the History of Vaccination

While the number of child deaths due to the six vaccine-preventable diseases (pertussis, diphtheria, tetanus, measles, polio, tuberculosis) was 5 million in 1989, cases of death from these diseases has considerably decreased today.

Vaccination is crucial for public health. It was observed back in 429 BC that those who suffered from smallpox in Greece did not develop the disease again. Such persons were called immunates. However, the history of vaccination in the world begins with smallpox. The first society to use vaccination is the Chinese. Historical records indicate that the Chinese administered the smallpox vaccine using a technique called variolation back in the 15th century. The way the Chinese used vaccines then was very interesting. Some of these vaccination techniques included touching the lesion or scab on the skin of a person suffering from smallpox with a piece of cotton and then using the very same piece of cotton to touch the nose of a healthy person, thereby vaccinating the latter. Another method was making a healthy person wear the clothes of a person who had recovered from the disease to ensure vaccination.4 A person vaccinated this way would have a fever in about a week, which developed into a mild disease and then immunized the person against smallpox. The Chinese saved thousands of lives through this practice. This method had an approximate frequency of death of 2% due to vaccination while the same rate was 30% in those who had the disease. Therefore, vaccination was well-adopted in China back in those years and the demand for vaccination was very high. This technique spread from China to Central Asia and the Caucasus. One of the most undesirable effects in people who have smallpox was that there would be scars on the skin that would last a lifetime. Therefore, in the Caucasus, it was not desirable specifically for girls to have smallpox. Thus, the Circassians vaccinated their children so that they would not be disfigured. An invisible body part of the child was preferred for vaccination. There were also some changes in the technique in the Caucasus. The pus sample taken from the arm of the person who had an active smallpox lesion would be dried and then transmitted into the skin using a lancet.

Turks also learned and started to successfully apply this method. More importantly, they took this method to the regions where they migrated to. This method finally arrived at Istanbul through the merchants. Back in those years, this technique was applied solely to volunteers in Istanbul. During that period, smallpox caused many outbreaks in Europe. However, the Western states did not know about this practice then. Moreover, smallpox was causing deadly outbreaks in the West, killing thousands of people without discriminating the rich from the poor, the intellectuals from the ignorant, and the urban inhabitants from peasants. One-fifths of those who got the disease died while one third was blinded. Yet, many people were recovering with visible scars on hands and/or face. People who were variolated in Asia, however, were getting mildly sick, with much less dermal scars. Pustules developing due to the disease healed without causing scars and the disease lasted much shorter. Therefore, the interest in and curiosity about variolation began to grow in the West. Emanuel Timoni, who was voluntarily variolated in Istanbul, and Giacomo Pilarino each wrote detailed letters to the Royal Society of London in 1714 and 1716 respectively, and described the variolation technique. However, British royal physicians said the practice was ridiculous and such a method would not be allowed, thereby stopping the application of the method. Variolation could not make it into England for some more time. However, shortly after that, Lady Montague, the wife of the British Ambassador to the Ottoman Empire Edward Wortley Montague, observed all the peculiar features of variolation. Furthermore, Lady Montague was very sensitive about the disease, as she had scars associated with smallpox. She was initially very surprised when she personally witnessed variolation in the Ottoman Empire (Image 1). However, when she found that the children undergoing that procedure did not catch the disease, she immediately got her own children vaccinated. She then found out that her children developed immunity against smallpox and started to write her famous letters (allegedly written in Ali Pasha Madrasa) under a great enthusiasm to report the method to her country. In her letters, she reported the details of the practice to England. Following these letters, the practice of variolation started to spread in England. In the 18th century, this vaccination technique began to spread rapidly to different countries. While it was initially the upper classes of the society that were vaccinated using this technique, the variolation of lower classes also started in time. Then it spread to America.5

Image 1. Lady Mary Wortley Montague

However, an English scientist named Edward Jenner developed a different scientific method in smallpox vaccination. In 1796, he introduced the “Jenner method” named after himself and that method marked an important turning point in the history of vaccination. He showed that cows could transmit smallpox to humans and that smallpox from cows would never enable contracting real smallpox. In 1796, he vaccinated a seven-year-old boy with the materials he obtained from cowpox and proved that the child was not really sick and did not develop the disease except for minor malaise. Shortly after the publication of this experiment, thousands of children in England were vaccinated with Jenner’s vaccine.6 This vaccine has been used successfully over the years, and the WHO created a special task force to eradicate smallpox from the face of the earth. However, despite this decision, it was possible to eradicate smallpox until 1974. In 1975, the WHO published the extended vaccination program. This program rapidly increased vaccination rates in many countries. In 1977, it was finally reported by the WHO that the last smallpox case in Somalia recovered, marking the eradication of smallpox in the entire world.7 This was one of the greatest victories of humanity against infectious disease.

A similar case applies to pertussis vaccination. Many people died of pertussis until the 1900s, but no effective vaccine was developed. In 1906, a researcher named Bordet succeeded in producing this bacterium. He then identified four different antigenic types of bacterium. When new vaccines were administered according to these antigenic types, highly successful results were obtained. In 1936, the whole-cell vaccine was developed and later approved by the American Pediatric Society. The pertussis vaccine was then made publicly available. Following that, the prevalence of pertussis, which had been 2 per thousand, fell to 0.06 per thousand.

One of the major milestones in vaccination is the tuberculosis vaccine, i.e. the BCG vaccine. This vaccine was developed by two French researchers named Albert Calmette and Camille Guérin. They subcultured bovine tuberculosis bacilli (Mycobacterium bovis) 230 times on glycerin-bile-potato mixture over a period of 13 years to isolate the BCG strain from the virulent strain. They later showed that such bacilli did not cause tuberculosis in humans, but developed an immunity to the tuberculosis bacillus. The live bacterium with reduced virulence that did not cause the disease was named BCG (Bacillus-Calmette-Guerin) after the researchers who made the discovery.8

Speaking of the history of vaccination, it is impossible not to mention Jonas Salk, MD. After graduating from medical school, Dr. Salk joined a virology research program. He started working on polio in his virology research lab at the University of Pittsburgh in the USA. During his research, he managed to reproduce polio viruses in monkey kidney for the first time. In 1952, the most frightening polio outbreak in America’s history was sweeping through the country. Almost 50,000 polio cases were recorded back in those years. Two years after the outbreak, Salk obtained the vaccine from the virus inactivated with formaldehyde. This vaccine was called the inactive polio vaccine. Salk had so much confidence in this vaccine that he first administered the vaccine to his wife and three children in front of the press. The vaccine proved effective against polio. In 1957, the number of polio patients in one year decreased to 5,000 under the impact of the general use of the vaccine. An interesting fact was that Dr. Salk never patented the polio vaccine he discovered. If he had done so, he could have made seven billion dollars. Instead, he chose to save people through the widespread use of the free vaccine. This enabled Dr. Salk to be declared a national hero across the country.9

Vaccine Production in Our Country

In 1721, Lady Mary Montague, the wife of the British Ambassador to Turkey, wrote to her country from Edirne, where the local people, as she reported, did something called “ingrafting” against smallpox (variolation method), a method documented to protect from smallpox.10

The Ottoman state attached great importance to vaccination and public health. Vaccine production in line with the “Jenner method” started in Istanbul in 1801. To give a simple example on the subject, a law on vaccination was enacted and this was called the “Smallpox Regulation”. This legislation stipulated that those who were not vaccinated not be admitted to military schools. The regulation of 1915 introduced the obligation for each citizen to be vaccinated three times, at the age of 6 months, 7 and 19 respectively.11

Image 2: Production of smallpox vaccine by Institute Director Mustafa Hilmi (SAĞUN), MD at Sivas Sanitation Institute (From the archive of Chemist Dr. Mustafa Hacömeroğlu)

The Ottoman state also attached great importance to vaccine production. The effort to have the vaccine production technique in Istanbul back in those years was remarkable. The discovery and application of rabies vaccine by Louis Pasteur in France in July 1885 are considered as the second vaccine produced in the history of mankind. Pasteur sought a sponsor to support his efforts to produce vaccines and thus contacted multiple heads of state for financial aid. To that end, he wrote letters to various heads of state in search of a sponsor for his research. One of these letters was sent to Abdulhamit II. The Sultan stated that he would extend financial support to vaccine production studies provided that the work was done in Istanbul. Pasteur refused to leave his country. Thereupon, 10,000 gold coins were sent to Pasteur as well as three people from the Ottoman Empire (Alexander Zoeros Pasha, Dr. Hüseyin Remzi and Veterinary Hüseyin Hüsnü Bey) for training with Pasteur.  Pasteur accepted this proposal. These trained physicians returned to the country in 1887 and established the rabies treatment center. The center became one of the major rabies centers in the world back then. Not only the rabies vaccine but also diphtheria serum was produced at this center (Images 2-7). “Telkihhane”, a vaccine production and research institute, started its studies in July 1892 at a building in the garden of Mekteb-i Tıbbiye-i Askeriye-i Şahane (Military School of Medicine) under the administration of Dr. Hüseyin Remzi Bey.

Sultan Abdulhamit was a leader who closely monitored bacteriology and epidemics, more than his counterparts in his time. He made great efforts to bring all European inventions in microbiology to our country as soon as possible. In 1892, the “diphtheria serum” was discovered by Emil von Behring. For this achievement, Behring was awarded the first-class Order of the Medjidie by Sultan Abdulhamid. Shortly after, the production of the diphtheria serum started in our country in 1896 at the “Bakteriyolojihane” (Bacteriology Center) by Veterinary Mustafa Adil. In 1897, the first cattle plague serum was produced by Mustafa Adil as well. In 1903, red serum was produced.

Typhus has a dramatic importance in the history of our country. Threatened by the typhus outbreak, the 3rd Army joined the Sarıkamış Operation, during which a typhus epidemic broke out, with soldiers, physicians and hospital staff catching the disease. During the outbreak, the Commander as well as the Chief Medic of the 3rd Army contracted the disease and were both martyred. Out of the 2,000 soldiers that contracted typhus back then, 1,100 died. Witnessing the damage done by typhus, Dr. Tevfik Sağlam, asked Dr. Rıza Kor, a most experienced figure in the field of vaccination, to develop a vaccine for typhus. Thereupon, Dr. Rıza Kor developed a vaccine by heating the blood samples he collected from patients with bacteremic typhus during World War I. He administered the vaccine for the first time on March 28, 1915 to nine officers at Hasankale Hospital, which was located within the 3rd Army field and hosted many typhus patients, almost all of them having louse. Five out of the nine vaccinated officers did not develop typhus. The vaccine was then commonly used and only 3 out of the 263 vaccinated individuals were diagnosed with typhus. The same vaccine was administered to many soldiers of the 6th Army in Baghdad including Kazım Karabekir. However, the commander of the 6th Army was the German Field Marshal von der Goltz back then. Although the vaccine was offered to the German Field Marshal and his private physician Oberndorfer, they refused to be vaccinated. None of the vaccinated soldiers of the 6th Army got sick, but Field Marshal Goltz and his physician both caught typhus and died in Baghdad in 1916. This vaccine was registered as the first vaccine developed against typhus. Later on, the vaccine was successfully used on the Caucasian front.12

In February 1917, Dr. Tevfik Sâlim (Sağlam), Medical Commander of the 3rd Army, reported that there had been a “need for an institution” to meet the vaccine requirement. Thereupon, the Sanitation Facility in Sivas started to produce smallpox and rabies vaccines. Dr. Tevfik Sâlim (Sağlam) transferred the vaccine preparation house (“aşı daûlistihzarı”) he established in Erzurum in 1915 to Sivas. Around the same years, Kayseri-Zencidere and Merzifon vaccine preparation houses were preparing vaccines for typhus, cholera, and dysentery. During the armistice years, the smallpox vaccine required by the occupation forces was procured from Telkihhane. In 1928, the “Republic of Turkey Central Sanitation Institute” started its activities in Ankara. From then on, laboratories producing vaccines in Istanbul and Sivas were moved to Ankara.

Vaccines are the most strategic group of products especially when there are epidemics of major depressions. Since the production of the first vaccine in our country, the distribution and administration of vaccines have always been led by the Ministry of Health free of charge. Istanbul was occupied during our War of Independence. Vaccine production had to continue with no interruptions even then. During that period, the vaccine production center was moved first to Eskişehir and then to Kırşehir. The serum laboratory was located in Erzurum during the war but was moved to Aleppo, Niğde, Sivas, and Erzincan during the Russian occupation. Starting from 1933, the Semple rabies vaccine had been produced and administered by Dr. Abdülkadir Çilesiz. In 1934, the Smallpox Vaccine Laboratory in Istanbul was transferred to Ankara. This also marked the end of vaccine production in Istanbul.

One of the important institutions in vaccination in our country is the Sanitation institution. Vaccines for tuberculosis, diphtheria, cholera, pertussis, tetanus, and rabies as well as anthrax and scorpion serums were produced there (Figure 1). For the first time in the world, scorpion serum was produced in our country in 1937. In the Republican era, rabies serum was produced in 1937, followed by cholera in 1940, typhus in 1942, flu in 1950, and dry BCG vaccine in 1976, while full BCG vaccine was produced in 1983.10 In 1950, the BCG laboratory began to serve in a separate building.  In 1953, BCG and Influenza Laboratory was licensed by the WHO. Back then, 18 different vaccines as well as tuberculin were produced in our country. The vaccines produced in our country played an important role in the eradication of smallpox from the face of the earth. The smallpox vaccine produced in our country was given to the World Health Organization and its origin was administered all over the world during the global smallpox eradication campaign.

Figure 1: Vaccines by years

Today, our country has a gradually-increasing success in vaccination programs for children. The WHO recommended the Expanded Program on Immunization (EPI) in 1974, which enabled an increase in the number of antigens administered in childhood vaccination services as well as in vaccination rates. For instance, while vaccines against six diseases (BCG, Diphtheria, Pertussis, Tetanus, Polio, and Measles) were available in our country in 1981, this number has currently increased to 13 (BCG, diphtheria, pertussis, tetanus, polio, Hepatitis B, Hepatitis A, Pneumococcus, Haemophilus influenza type b, measles, rubella, mumps, chickenpox) following the addition of new vaccines to the program. It is reported that the level of success in child vaccination is close to 100% today thanks to the improvement and effective monitoring system in immunization services for children in our country.13

Telikhane Vaccine

Image 3. Telikhane (From the archive of Chemist Dr. Mustafa Hacömeroğlu)


Image 4. Vaccination services in the Republican period (From the archive of Chemist Dr. Mustafa Hacömeroğlu)

After all these advancements, steps were taken to stop our vaccine production in the 1990s. In 1995, modernization efforts were initiated to produce the tetanus vaccine via fermentation technology. Production with the old method was stopped. In 1996, the production of both the tetanus vaccine and the Semple rabies vaccine ended. Although the tetanus vaccine was produced by fermentation in 1999, it was never offered for use.

Image   5.  Vaccine preparation studies from the Republican period (From the archive of Chemist Dr. Mustafa Hacıömeroğlu)                                                               

Is Anti-Vaccination Important?

In recent years, vaccine hesitancy and anti-vaccination have started to become more familiar and more serious problems. Anti-vaxxers are getting organized especially on social media and making efforts to reduce the public desire for vaccines through some controversial and inaccurate information.

The main arguments of anti-vaxxers are based on the claims that some of the ingredients in vaccines are harmful to health as well as religious concerns or the speculations that protection from diseases is possible by consuming certain natural foods. However, if the society truly believes in a vaccine, the hesitancy about getting vaccinated by it is significantly reduced. For instance, although the society does not hesitate about getting vaccinated by rabies vaccine in the case of suspicious bites, it is not possible to say the same for influenza vaccination.

One of the best ways to eliminate any vaccine hesitancy is for healthcare professionals to establish a good dialogue with children to be vaccinated as well as their parents. Furthermore, it will help in the fight against “anti-vaccination” to inform the society about the results of the research on vaccination and its effects and to use communication tools and social media.2

There are people who are against vaccination for religious reasons, claiming that “pig gelatin is used” in vaccines. In fact, there are indeed vaccines produced from pig gelatin abroad. Islamic scholars gathered and issued a fatwa on the subject. Healthcare and religious experts from 129 Islamic countries met in Egypt to examine pig gelatin. They concluded that, while the gelatin was prepared, it was chemically treated in at least 30 stages, and the resulting substance had nothing to do with the pig. Therefore, it was decided that it was religiously permissible. However, despite all these decisions, our Ministry of Health has decided against vaccines involving pig gelatin and exclusively prefers vaccines made of bovine gelatin. We can be perfectly sure that vaccines made of pig gelatin do not enter our country. In brief, the claims that vaccines containing pig gelatin have made it into and are used in our country do not accord with the facts in today’s Turkey.

Another claim commonly suggested by anti-vaxxers is that vaccines cause autism. Discussions around this claim sparkled globally after an article linking a total of 12 autistic children with vaccines had been published. Following this article, thousands of children were not vaccinated. However, it was later found that no control groups had been included in the study that formed the basis of the article and the research had been conducted solely on the 12 children concerned, both proof that the article had been founded on multiple methodological mistakes. The relevant journal withdrew the said article. However, there are still many children who have not been vaccinated based on this invalid and ill-founded study.

If vaccination rates drop in a country or region, outbreaks can result in many deaths. Compromising on vaccination causes consequences that affect the entire society. Field studies involving a large sample size should be planned in order to determine the distribution, level, and rationale of vaccination hesitancy. Furthermore, in-depth qualitative studies should be conducted to identify the psychosocial determinants of vaccine refusal. It is essential for developing appropriate strategies to get and report detailed feedback from the healthcare personnel who experience vaccine hesitancy, vaccine refusal, and anti-vaccination in the field.

Image 6. Adult Vaccination Efforts (From the archive of Chemist Dr. Mustafa Hacömeroğlu)

It may be considered to launch various practices (for example, restriction of state reimbursement for the medical therapy to eliminate the health problems that arise as a result of vaccine refusal, etc.) which could be regarded as an economic sanction against citizens who refuse vaccination, since the increasing vaccine refusal may potentially cause epidemic risks, a sense of inequality and increased health expenses to the detriment of public health.

Vaccination affects not only the individual but also public health. Therefore, vaccination is too important to be left to an individual’s discretion. Legislation on compulsory vaccination should be established in the form of laws. It is necessary to establish a national adult immunization program and gradually incorporate adult vaccines into the national vaccination program.

The system for reporting vaccine-related adverse reactions needs to be developed in a way to allow online reporting. It is important to initiate and expand the practice of issuing halal certificates for vaccines. This will help to significantly eliminate major religious concerns leading to vaccine refusal. Vaccines are strategic products. Domestic vaccine production will be an extremely effective step in eliminating vaccine hesitancy.

It is extremely important to immediately establish the infrastructure required in order to start the production of new generation vaccines in our country. Specialty societies, universities and civil society organizations should cooperate in efforts to eliminate vaccine hesitancy. 14,15

Image 7. The production of a smallpox vaccine by Dr. Hüseyin Remzi at Telkihhane (the institute producing smallpox vaccine) in July 1892.

Efforts to Develop a COVID-19 Vaccine

Although there are various drugs used in the treatment of the COVID-19 infection caused by the SARS-COV2 virus, on which we have been hearing a lot since December 2019, there is not a vaccine approved for human use yet. Given the severity of the pandemic caused by the virus infection, mankind will make great efforts to develop a vaccine against this virus.  However, efforts to develop vaccines against this virus continue in many countries, including our country.  Although some vaccines have reached the level of launching human studies, we are still far from a vaccine that is ready for common use. In our country, there are various ongoing projects for producing a COVID-19 vaccine under the auspices of TÜBİTAK. If a domestic vaccine can be produced in Turkey, it will make a great contribution to our country and humanity alike. Turkey is among the most successful countries in the fight against the COVID-19 pandemic. I hope our country will be able to replicate such success in its efforts to develop a vaccine.

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