The History of Vaccines: Technologies, Diseases, and Challenges

In Kabul, the capital of Afghanistan, health workers vaccinate local children against polio. Xinhua News Agency

Medical staff mark children who have been vaccinated in Sana'a, Yemen. Xinhua News Agency

Vaccination is considered one of the greatest achievements of medical science and one of the most profitable public health investments. As Anthony Fauci, an American infectious disease expert, wrote in Science magazine, "In the face of a pandemic, developing an effective vaccine is always the most urgent priority," which represents the general consensus of the medical community. Looking back on the history of vaccine invention, we can find that there is scientific rationality, the wisdom, intuition and dedication of scientists, the collaboration and mediation of international organizations, private foundations, national governments, and pharmaceutical companies, as well as the competition of various forces such as politics, business, national security, culture and religion, and even a looming history of anti-vaccine.

1

Practice makes perfect: "Human Smallpox" and "Cow Smallpox"

In 1980, the World Health Organization (WHO) announced that smallpox had been completely eradicated worldwide. It is the only disease that has been eradicated by humans through vaccination to date.

British historian Lord Macaulay once gave this obscure description of smallpox:

"Smallpox lingers all the time, filling the cemetery with corpses. It tortures those who survive with endless fear, and leaves scars on those who survive; disabled and deformed babies, weeping mothers; brides-to-be who have lost their bright eyes and beauty, nightmares for their lovers at midnight!"

In the early 18th century, Lady Mary Montagu, the British ambassador to the Ottoman Empire, learned in Constantinople (today's Istanbul, Turkey) that there was a "smallpox party" held there: a custom in which peasant women inoculated participants with smallpox at the party. So Lady Montagu, who had suffered from the disfigurement of smallpox infection, had her 7-year-old son and 3-year-old daughter inoculated with smallpox. Smallpox inoculation attracted widespread attention in the British upper class, and then spread and became popular on both sides of the Atlantic.

Some historians believe that smallpox vaccination originated in China, then spread to Russia, Arabia and Turkey, and then spread to Europe and the United States. The basis of smallpox vaccination is empirical observation, that is, smallpox survivors will not be infected with smallpox again. Smallpox vaccination is carried out by wearing smallpox clothes, smallpox paste method, dry seedling method or water seedling method, all of which infect healthy people with a mild smallpox, thereby gaining lifelong immunity. However, the safety of smallpox vaccination has also caused controversy, because even if infected with mild smallpox, the risk of death is still as high as 2% to 3%, and the vaccinated person will be somewhat contagious.

The birth of the cowpox vaccination method solved this problem. The invention of cowpox vaccination by British doctor Edward Jenner is regarded as a milestone in the history of vaccines. In order to commemorate Jenner's contribution, the famous French microbiologist Louis Pasteur used "vaccination" (from the Latin Vacca, meaning "cow") to refer to all vaccinations, which has continued to this day.

The story of the discovery of cowpox has been told repeatedly in history textbooks: Jenner, who practiced medicine in Gloucestershire, England, was a smallpox inoculator. He heard that milkmaids would be infected with mild cowpox from the udders of cows with cowpox, and would not get smallpox again. He speculated that perhaps the cowpox of the milkmaids gave them immunity, and cowpox was much milder than smallpox and generally did not cause much harm. In 1796, he chose the gardener's son and a young milkmaid for the experiment. Jenner rubbed a small amount of pus from the cowpox pustules on the hands of the milkmaid and scratched it into the little boy's skin. It is worth noting that six weeks later, in order to verify the effect of "vaccination", Jenner inoculated the boy with the pus of a smallpox patient, but the smallpox was "not inoculated". Then, he inoculated his son and other subjects and found that they would not get smallpox again, thus proving the effectiveness and safety of cowpox.

Not surprisingly, cowpox was initially fiercely opposed by some for religious, cultural and ethical reasons. But by the early 19th century, cowpox vaccination had spread to most parts of the world by applying powdered dried scabs to feathers and lancets, or applying pus to cotton threads. From 1803 to 1806, Spanish botanist Don Francisco Xavier Balmis used a relay vaccination method to bring the cowpox vaccine across the Atlantic from Spain to Latin America, the Philippines and China, and then back to Spain, vaccinating 450,000 people along the way.

After the birth of the cowpox vaccine, people were optimistic that the eradication of smallpox was just around the corner. In 1806, US President Thomas Jefferson wrote in a letter to Jenner, "Thanks to your discovery... people in the future will have to look up books to learn about this hateful disease, smallpox." However, due to technical (such as the difficulty of transportation and preservation caused by the lack of cold chain) and cultural barriers (such as the problem of cowpox being difficult to accept in India), funding (especially prominent in poor countries) and lack of epidemic prevention systems (such as logistics and qualified vaccination personnel), it was not until 1980, nearly 200 years after the invention of the cowpox vaccine, that the goal of eradicating smallpox worldwide was truly achieved. This was due to the improvement of vaccination technologies such as freeze-dried vaccines and trident needles, and the concerted efforts of governments, international organizations and non-governmental organizations.

2

Rabies vaccine intended for treatment

According to WHO estimates, rabies causes 59,000 deaths in more than 150 countries each year, 95% of which occur in Africa and Asia, while it has almost disappeared in Europe and the United States. This is largely related to the long vaccination cycle and relatively high price of rabies vaccination.

On July 6, 1885, a French boy named Joseph Meister from Alsace was brought to Louis Pasteur's laboratory. He was badly bitten by a mad dog. Rabies (also known as hydrophobia) is transmitted through the saliva of sick animals. The rabies virus invades the nervous system and causes terrible symptoms, including fear of water, fear of wind, paroxysmal pharyngeal muscle spasms, and difficulty breathing. The mortality rate is nearly 100%, and there is still no treatment.

Pasteur was a chemist and microbiologist, not a doctor. Previously, he and his research team had prepared a rabies vaccine using the dried spinal cord of rabid rabbits and successfully tested it on dogs. But would it work on people? Pasteur wrote, "Since the death of this child was inevitable, I decided to try it on him, although I felt deeply disturbed, as everyone can imagine." Meister was vaccinated 12 times in 10 days and was lucky to survive.

As the news spread, patients from home and abroad flocked to the hospital. In 1886, 38 Russian farmers were bitten by rabid wolves and traveled thousands of miles to Paris to find a vaccine. 35 of them were saved by Pasteur's vaccine.

Compared with most vaccines, the special thing about rabies vaccine is that it prevents the disease through early vaccination. The vaccine can help the immune system produce a large amount of rabies virus antibodies before the virus invades the nervous system, because the incubation period of rabies is very long.

3

BCG's rough fate

In the 19th century and the first half of the 20th century, millions of people died from tuberculosis, a white plague that killed nine out of ten people. Famous people such as Chekhov, Kafka, Shelley, Keats, Chopin, Lu Xun and Lin Huiyin all suffered from the disease.

In the early 1920s, Bacillus Calmette-Guerin (BCG) was introduced. It is the only vaccine that is not named after the disease, but after the inventors, French scientists Albert Calmette (1863-1933) and Camile Guerin (1872-1961). Although every vaccine has its own bitter story, the fate of BCG after its introduction is particularly bumpy.

Albert Calmet and Camille Guerin began human trials of BCG in 1921. They vaccinated a baby at the Charité Hospital in Paris. The mother died of tuberculosis after giving birth, but the baby did not get sick after taking BCG orally, proving the effectiveness of BCG. Later, as more and more children were vaccinated, a series of experiments provided strong evidence for the effectiveness of BCG, and the acceptance of BCG increased, especially in France and Northern Europe.

In 1928, the World Health Organization of the League of Nations recommended that BCG be universally administered to newborns. However, a tragedy called the Lübeck Vaccine Incident almost ruined the future of BCG. The health department of Lübeck, Germany, began to implement infant vaccination on February 24, 1930. A total of 256 newborns received oral BCG, resulting in 76 infant deaths and 131 illnesses. Subsequent investigations found that the vaccine was accidentally contaminated with toxic strains of tuberculosis bacteria during the production process, rather than a problem with the BCG itself. However, due to concerns about its safety and effectiveness, Germany suspended BCG vaccination, the United Kingdom also postponed the introduction of BCG, and the United States has never listed BCG as a routine vaccine.

During World War II, tuberculosis resurfaced in Europe and Asia, and BCG was used on a large scale. In the 1950s, WHO launched a wide-ranging tuberculosis control campaign to promote BCG around the world. To date, more than 4 billion people have been vaccinated with BCG worldwide.

4

Next disease to be eradicated: polio

The hit movie "Breathe" in 2017 recreates a polio (also known as infantile paralysis) catastrophe in the 1940s and 1950s. During this epidemic, the earliest mechanical respirator, the "iron lung", was widely used. The polio virus invades the nervous system, causing muscle degeneration, paralysis, and sometimes even death from suffocation. President Franklin Roosevelt of the United States was paralyzed in both legs due to polio at the age of 39. In order to help control the deterioration of polio in the United States, he established the National Polio Foundation in 1938.

With the support of this foundation, American physician Jonas Salk (1914-1995) developed an injectable inactivated polio vaccine. In 1954, he successfully conducted the largest double-blind clinical trial in American history, with nearly 1.8 million children participating in the trial. However, soon after, the "Cutter Incident" in 1955 greatly undermined people's confidence in this vaccine. About 200,000 children were vaccinated with two batches of inactivated vaccines prepared by the Cutter Laboratory in California. Due to incomplete production, the vaccine was mixed with incompletely inactivated polio virus, 70,000 people suffered from muscular atrophy, 164 children suffered from hemiplegia, and 10 people died. The huge controversy triggered major reforms in vaccine production and safety.

Also with the support of this foundation, Albert Sabin (1906-1993) developed an oral attenuated live virus vaccine that was "cheap and easy to vaccinate." Sabin conducted experiments on many subjects, including his own family and prison inmates. Later, large-scale vaccinations were carried out in the Soviet Union, with about 10 million children participating. The vaccine was a huge success, and Sabin won the 1965 Nobel Prize in Medicine. However, Salk and Sabin have always been in a tit-for-tat competitive relationship, which has become one of the biggest disputes in medical history. By the early 1960s, Sabin's oral polio vaccine (OPV) had become a standard vaccine in most countries and was included in routine vaccinations.

In 1988, WHO passed a resolution to eradicate polio by 2000. At that time, polio was endemic in 125 countries in five regions. As of 2002, three WHO regions (the Americas, the Western Pacific, and Europe) had confirmed the eradication of polio, and it is expected to become the next disease to be completely eradicated.

On October 24, 2019, on the occasion of World Polio Day (October 24), the World Health Organization officially announced through the Global Polio Eradication Certification Commission that wild poliovirus type 3 has been eradicated worldwide. This is another historic achievement in human public health history after the global eradication of smallpox and wild poliovirus type 2. This means that among the three different types of wild polioviruses in the world, wild poliovirus types 2 and 3 have been completely eliminated, leaving only type 1 with polio cases caused by wild strains. The World Health Organization continues to advocate that the world cannot stop its efforts and urges all stakeholders and partners to adhere to the fundamental policy and strategy of polio eradication until it is finally successful.

5

Fighting a cunning virus: Flu vaccine

According to WHO statistics, seasonal influenza epidemics cause 5% to 10% of adults and 20% to 30% of children worldwide to become ill each year, 3 million to 5 million people to become seriously ill, and 250,000 to 500,000 people to die.

The influenza pandemic that mysteriously broke out and disappeared in 1918-1919 infected 500 million people and killed 50 million people worldwide. This epidemic is also called the "Spanish flu", but not because it first appeared in Spain, but because it was during the First World War. Countries were worried that the epidemic would cause panic and resistance among the people, so they controlled the media to conceal the epidemic. Spain was not a belligerent country, and the government did not censor news reports and publications. It was the first country to face up to and truthfully announce the epidemic. As a result, all the people in other countries who were deceived by the media believed that the plague originated from Spain and called it the "Spanish flu."

In the 1940s, scientists identified the influenza virus and began to mass-produce influenza vaccines, while they also recognized the complexity of the disease. Data show that influenza vaccines have obvious "off-target" phenomena, and their effectiveness is basically between 70% and 90%. In many cases, the effectiveness of influenza vaccines is less than 60%, and even drops to 10% in some years. This is because influenza viruses mutate every few years, produce new strains, and undergo "antigenic drift" or "antigenic conversion". There is no cross-immunity between different strains, and we cannot predict which "new" influenza strains will appear in the future. Only through careful monitoring and the production of new vaccines every year can we provide protection against seasonal epidemic virus strains. To this end, WHO organizes two discussions and analyses every year to collect global influenza epidemic information based on the Global Influenza Surveillance Network (including 13 WHO influenza reference laboratories, including 1 in Beijing and 2 in Hong Kong), predict influenza epidemic trends, and recommend strains suitable for the production of influenza vaccines this year. At present, all sectors are still looking for new technologies to increase the accessibility of influenza vaccines to cope with the next global pandemic.

6

The vaccine paradox: The more we need it, the less we get it

Today, there are 25 high-risk diseases that can be prevented with effective vaccines. In the future, vaccine targets are expected to expand from infectious diseases to autoimmune diseases, allergic reactions, insulin-dependent diabetes, and chronic diseases such as aging, hypertension, and cancer.

However, despite tremendous progress in vaccine development, there are still no effective vaccines that have reached the commercial production stage for the world's major disease killers, such as malaria and AIDS, and the rapid mutation of the HIV virus has caused scientists great headaches.

As the number of vaccine developments increases, a picture of inequality emerges. On the one hand, pharmaceutical companies have begun to shift the direction of vaccine research toward autoimmune diseases, allergic reactions, insulin-dependent diabetes, and chronic diseases such as aging, hypertension, and cancer. On the other hand, there are more than a dozen "neglected tropical diseases" in the world, including onchocerciasis, African trypanosomiasis, and blinding trachoma. These diseases bring a huge disease burden and affect the lives of more than 1 billion people, most of whom are distributed in countries below the poverty line, especially in sub-Saharan Africa. However, most of these diseases do not have vaccines.

Take the children's vaccines against pneumococcus and rotavirus as an example. On the one hand, in low-income countries with poor sanitary conditions, the risk of death from pneumococcal disease and rotavirus infection in children under five is much higher than in high-income countries. However, due to the lack or even absence of health service infrastructure in these countries, vaccines are unaffordable and unattainable. The "African Meningitis Belt" is heartbreaking evidence. Although purified, heat-stable, freeze-dried meningococcal vaccines have long been available, epidemic meningitis still rages periodically in Africa from Senegal in the west to Ethiopia in the east, with a mortality rate of 10% to 50%.

There is still a long way to go to increase vaccination coverage. Taking the pertussis, diphtheria and neonatal tetanus triple vaccine as an example, according to data from UNICEF, in 2018, 14% of children in the world were still not vaccinated or were incompletely vaccinated, 13.5 million were not vaccinated, and 5.9 million were incompletely vaccinated, of which 60% were concentrated in ten low-income countries.

Throughout the history of medicine and disease, the widespread use of vaccines has played an important role in reducing child mortality, which is inseparable from the progress of medical science and the rational allocation of medical resources. People are increasingly aware of the need to solve the problems faced by the world's poorest and most vulnerable people. (Author: Su Jingjing, Associate Professor of the School of Medical Humanities, Peking University)