Origins of Immunization, Smallpox, and mRNA Vaccines

    We’ve heard a lot about potential vaccines for COVID-19. Many vaccines have been undergoing large scale trials—specifically mRNA vaccines. mRNA vaccines are completely different type of vaccines than traditional vaccines. This presents a new era in vaccinology. However, getting here was a long and hard process. The origins of immunization dates back thousands of years ago. In order to understand how we got here, we have to look into one of the biggest achievements in global public healththe eradication of smallpox.

    Origins of Smallpox

    Smallpox was a contagious and fatal infectious disease caused by the variola virus. Typical symptoms included high fever, distinct skin rashes, and headaches. There were two strains; the variola major and variola minor. The variola major was the most severe strain while the variola minor caused fewer symptoms, fatalities, rash, and scarring. According to the National Institute of Allergy and Infectious Diseases, about 3 out of 10 people who had the disease died.


    Smallpox was said to have originated 12,000 years ago in agricultural settlements in northeastern Africa. Evidence of similar smallpox skin rashes were found in Egyptian mummies 3000 years ago.1 However, the earliest unmistakable records of smallpox was found in the 4thcentury A.D in China, the 7thcentury in India and Mediterranean, and 10thcentury in southwestern Asia.2 Smallpox spread to Europe around the 5thand 7thcentury. Extinct strains of the variola virus were found in skeletons in Europe during the Middle Ages. Scientists also found evidence in Viking skeletons dating back 1,200 years ago in Oland, Sweden. The Arab expansion spread smallpox into northern Africa, Spain, and Portugal. From the 11thcentury to 15thcentury, the Crusades spread smallpox into Europe, and the Portuguese spread smallpox into part of western Africa. In the 16thcentury, European colonization and the African slave trade contributed to the spread of smallpox into the Caribbean and Central and South America. During the 17thcentury to 18thcentury, the European colonization spread smallpox into North America and exploration by Great Britain spread smallpox into Australia.


    The devastation smallpox brought made it an attractive source of weapon for biological warfare.3 The first evidence of weaponizing smallpox was reported by 19thcentury Francis Parkman. During the French Indian War (1754-1767), British commander Sir Jeffrey Amherst had the idea to use smallpox to reduce the American Indian population. He wrote in a letter, “Could it not be contrived to Send the Small Pox among those Disaffected Tribes of Indians? We must, on this occasion, Use Every Stratagem in our power to Reduce them.4 The British sent two blankets and a handkerchief which came from the smallpox ward.


    Origins of Immunization 

    The idea of immunization dates back 3000 years ago. People knew that those who got the disease became immune. Survivors of smallpox were dependent upon to nurse those who were infected. Many herbal remedies, special cloths, and cold treatments were also used to treat smallpox in the medieval times.5


    Dr. Thomas Sydenham (1624-1689) was an English doctor and author of ‘Observations Medicae’ which became the standard medical textbook for two centuries. Dr. Thomas Dover, who was one of his patients infected with smallpox documented Sydenham’s treatment. He wrote, “Whilst I lived in Dr Sydenham’s house, I had myself the Small Pox. I went abroad, by his Direction, till I was blind, and then took to my Bed. I had no Fire allowed in my Room, my Windows were constantly open, my Bed-Clothes were ordered to be laid no higher than my Waste.He made me take twelve Bottles of Small Beer, acidulated with Spirit of Vitriol, every twenty Four hours.”6 The regime was based on the cooling principle, open windows, no fires, few bedclothes, and “twelve Bottles of Small Beer” every 24 hours.7



    The most efficient way of immunization before vaccination was inoculation. Inoculation was a method where the inoculator would instill the smallpox virus into those who never contracted it. It was done by using a lancet with matter from smallpox pustules and given to those who never had smallpox by scratching it onto their arms, legs, or inhaling it through their nose. This practice was done in countries when they were threatened with a severe epidemic. 


    Inoculation (now referred to as variolation) had possibly originated in China, India, West Asia, and parts of Africa long before it was introduced in Europe.8 The earliest evidence of variolation in China was written in a book from 1549.9 In 1670, Circassian traders introduced inoculation to the Turkish Ottoman Empire.8 Women from the Caucasus who were in demand in the Turkish sultan’s harem in Istanbul because of their beauty were inoculated in parts of their body where scars would not be seen.10 It’s said that these women brought the practice of inoculation to the Ottoman Porte.11 Inoculation was also being used in the 1700s by Arabs in North Africa. Cassem Algaida Aga, the ambassador from Tripoli to the Court of St James, recoded a letter originally written in Arabic about inoculation. His letter was translated and published in a book by John Gasper Scheuchzer, Foreign Secretary of the Royal Society.12


    In 1714, Emmanuel Timonius wrote a letter at Constantinople that went around Europe and read to the Royal Society of London describing the method of variolation. Simultaneously, Giacomo Pylarini (1659-1718) was a known physician in Eastern Europe and Italy. In 1716, he also published a work on variolation.13

                                      Source: Lady Mary Montagu. Melville L. Lady Mary Wortley Montagu; her life and letters (1689–1762). London: Hutchinson and Co. Paternoster Row; 1925. 

    Although it was Lady Mary, an English aristocrat, who was responsible for the introduction of inoculation in England.14 She suffered from smallpox in 1715 and her 20-year old brother died from the illness. In 1717, when she arrived in Turkey as the wife of the British Ambassador, she was convinced of inoculation by old Greek women in Turkey. She wrote a letter to her friend describing variolation and her determination to bring it to England.13 In April 1718, she wrote a letter from Adrianople, “The pus is introduced not under the skin but into the vein; sometimes...into several veins at the same time...Seeing the results, the person to introduce this method into England would be considered a true benefactor of his country. If I live, I shall find myself obliged to do so, even if I am to be at war with the whole medical body of my country.”13


    In March 1718, in Turkey, Lady Mary ordered the embassy surgeon, Charles Maitland, to inoculate her 5-year old son. In April 1721, back in England, Lady Mary had Charles Maitland inoculate her 4-year old daughter with witnesses from the Royal College of Physicians.15 16 In August 1721, Charles Maitland received the Royal Licence to test variolation on six prisoners from Newgate Prison who were granted the King’s favour if they submitted.17 The experiment was done with witnesses from the Royal College of Physicians, the Royal Society, and physicians from court. All prisoners were pardoned that year after they survived and proved to be immune.18 Maitland also treated the two daughters of the Princess of Wales on April 17, 1722.8 In the beginning of the 18thcentury, variolation spread to Europe in light of the publications of Emmanuel Timonius, Giacomo Pylarini, and the advocacy of Lady Mary.18


    In 1721, a severe smallpox epidemic broke out in Boston after a ship arrived from Barbados carrying infected individuals.19 Cotton Mather (1663-1728) of Harvard College sent letters to Boston’s physicians to wage a medical campaign in hopes of inoculating patients to fight smallpox.20 Mather read physician Emmanuel Timmonius’ paper about variolation and was interested in the method to prevent smallpox epidemics.21 However, most physicians were reluctant to use this method in fear of further spreading the disease.22


    Dr. Zabdiel Boylston, a graduate from Harvard University, was the only one who was convinced by Mather’s letter. Mather and Boylston started the first public campaign of inoculation, and were successful in inoculating many volunteers. Mather wrote in a letter about Boylston’s work, “The experiment has now been made on several hundreds of persons, upon both male and female, upon both old and young, upon both strong and weak, upon both white and black.23 However, they faced a lot of criticism in the public and medical community, and their campaign did not last due to increasing controversy surrounding Mather and Boylston. Inoculation also angered many physicians. Dr. William Douglass feared that inoculation was untested and based on folklore.24 Douglass published anti-inoculation pamphlets in The New England Courant in response to Mather’s experiment. This gained support from the public and caused an outrage of violence against Mather and Boylston. A bomb was thrown in Mather’s house at the peak of the epidemic.24 Boylston was criticized in newspapers by Douglass, and he even joked about using inoculation to kill off native communities.25 26 Those who were angered also forced the variolated to isolate themselves.27 Mather and Boylston’s experiment proved to be successful despite the public’s opposition to inoculation. The fatality rate for those who were not inoculated was 14%, while Mather’s and Boylston reported a mortality rate of 2% for those who were inoculated.22


    Inoculation spread to New England during the smallpox epidemic in Boston. By 1766, the British soldiers were all variolated. However, American soldiers under George Washington were not variolated which reduced the number of soldiers due to another smallpox epidemic, making them unable to take Quebec from the British troops.27 Then in 1777, Washington had all soldiers variolated before any military operations.27 Even though many British physicians were still skeptical regarding Mather’s and Boylston’s experiment, variolation spread from England throughout Western Europe.


    Development of Vaccines

    In 1765, Dr. Fewster, a colleague of Jenner, published a paper, “Cowpox and its ability to prevent smallpox” in the London Medical Society. It wasn’t until 1796 when Edward Jenner carried out his theory and used cowpox to inoculate smallpox.

    Edward Jenner (1749-1823) was born in Berkeley, he was known as an English doctor although he had an interest in many topics in science. He went to London as an apprenticeship to John Hunter, a surgeon. In 1773, Jenner went back to Berkeley to practice medicine and became a founding member of a medical group. It is said that he began to investigate the theory of cowpox to inoculate smallpox at that time, but he received a lot of backlash from the medical society.28


    Jenner then published many papers in the natural sciences. He studied geology, conducted experiments on human blood as plant food and developed a method for a medicine known as tartar emetic (potassium antimony tartrate). Jenner also launched his own hydrogen balloon which flew 12 miles. He also conducted a study on cuckoo birds and published it in 1788 which got him elected as a member of the Royal Society.28 His work was criticized by many natural scientists in England. Anti-vaccinationists even used the possible obstructions of the cuckoo study to instill doubt on his other work.8 However, he was reasoned in 1921, when photographers proved his observations.29


    In 1788, Jenner joined another medical group and published medical papers on heart disease and the cause of angina pectoris.29 It was the year 1792 when he became a licensed doctor from St Andrews University in Scotland. In 1794, Jenner published a paper posthumously, “Observations on the Migration of Birds”, and showed original evidence to disprove a widely held belief about bird’s migration. 


    Jenner grew up in a country where he heard the folklore that milkmaids who suffered cowpox were protected from smallpox. At age 13, when he was apprenticed to a surgeon in Sodbury, it was said that he heard a milkmaid say, “I shall never have smallpox for I have had cowpox. I shall never have an ugly pockmarked face.30 On May 14, 1796, he inoculated an 8-year-old boy, James Phipps, with cowpox matter from a milkmaid. He later exposed Phipps to smallpox and proved to be immune.13 Edward Jenner only hoped that his paper including his demonstrations and evidence would be published in the Royal Society but it was rejected.31


    Fast forward to 1798, a cowpox epidemic allowed Jenner to carry out more experiments. He published a paper, “An Inquiry into the Causes and Effects of the Variolae Vaccinae, a Disease Discovered in Some of the Western Counties of England, Particularly Gloucestershire—and Known by the Name of the Cow Pox” which had three important parts to test his hypothesis. His first hypothesis was that cowpox came from a disease transmitted from horses to cows, but the theory was rejected. He then hypothesized that inoculation with cowpox would provide lifelong protection against smallpox. The second part contained observations to test his hypothesis, and the third part was a discussion related to his findings. The publication sparked some controversies in the medical community and public. 


    In 1799, Jenner went to London and found physicians who were supportive of his theory. Dr. William Woodville and Dr George Pearson helped carry out large-scale trials with Jenner. Although they faced some errors and controversies, by 1880, cowpox inoculation rapidly spread in Europe and other parts of the world. The vaccine was spread dried onto lancets, threads, ivory points, and between glass slides sealed in wax. Jenner didn’t hesitate to provide the vaccines to medical physicians who requested it. In 1799, he sent a vaccine and a copy of the “Inquiry” to a former school friend, John Clinch, who performed around 700 inoculations.29 In 1880, Jenner sent a vaccine to Dr. John Haygarth, who sent a strain to Benjamin Waterhouse, a professor of Physics at Harvard University. Waterhouse spread vaccination in New England and convinced Thomas Jefferson to try it in Virginia. Jefferson introduced the practice to Native American tribes and appointed Waterhouse to the National Vaccine Institute, which set up global vaccine programs in the U.S.32 By 1803, translations of the “Inquiry” were published in all European languages. The vaccine spread in all parts of the world, from Vienna to Bombay throughout Constantinople, Damascus, and Baghdad. Inoculation was adopted by the Spanish in November 1803, when an expedition brought vaccine to Canary Islands, Puerto Rico, Spanish colonies in central and south America, the Philippines, Macao, and Canton.33


    Edward Jenner received a lot of recognition and honours as vaccination spread throughout all parts of the world. By 1802, Jenner petitioned for a grant from the British Parliament and was awarded £10,000. In 1807, he received another award of £20,000. In 1808, the British parliament established a National Vaccine program under the Royal Colleges of Physicians and Surgeons. Variolation became prohibited in England in 1840, and vaccination was made compulsory in 1853. 


    Jenner’s family lived in the Chantry House in Berkeley, which became the Jenner museum in 1985. Jenner also built a small hut which he called the “Temple of Vaccinia” to vaccinate the poor for free. 

                            Source: Photo by Robert Hicks from the Jenner Museum, Berkeley, Gloucestershire, England. 

    Jenner slowly withdrew from public as he became overwhelmed with personal life. In 1810, his eldest son at age 21 died of tuberculosis. His sisters Mary and Anne died, and in 1815, his wife Catherine died of tuberculosis. On January 24, 1823, he visited his dying friend. He had a stroke the following morning but regained consciousness. He died on the morning of January 26, 1823. 


    In the late 19thcentury, it was found that vaccination did not implore lifelong immunity and that revaccination was needed. Smallpox still continued to devastate communities, but measures were carried out to eradicate smallpox in 1950. By 1952, smallpox was eradicated in North America, and by 1953, it was eradicated in Europe. The progress to eradicate smallpox globally was carried out in 1958, when a report of the consequences in South America, Africa, and Asia were sent to the World Health Assembly. In 1959, the World Health Organization started a plan to eradicate smallpox but suffered a lack of funds. In 1966, smallpox outbreaks were still frequent in those countries, so in 1967, the WHO intensified the program and brought laboratories in those countries that experienced frequent smallpox outbreaks.34 They also developed a bifurcated needle, established mass vaccination campaigns, and put out surveillance systems to detect and investigate cases. By 1971, smallpox was eradicated from South America, South Asia in 1975, and Africa in 1977. 


    Final Cases of Smallpox

    The last person to have naturally contracted smallpox caused by the variola major was Rahima Banu, a 3-year old girl from Bangladesh. She was isolated at home with guards for 24 hours a day until she recovered. Immediately after, a smallpox vaccination campaign within 1.5-mile radius of her home began. The Smallpox Eradication Program team visited every house, school, and public meeting area to ensure that the illness did not spread.34

          Source: CDC/World Health Organization; Stanley O. Foster M.D., M.P.H.


    The last person to have naturally contracted variola minor was Ali Maow Maalin, in Merca, Somalia. He was a hospital cook and came across two patients with smallpox on October 12, 1977. He developed a fever on October 22 and was mistakenly diagnosed with malaria and chickenpox. On October 30, the smallpox eradication staff correctly diagnosed him and isolated him until he recovered. On July 22, 2013, Ali Maalin died of malaria while working in the polio eradication program.34

                                                                                                                                                                       Source: WHO photo by J Wickett 


    Smallpox was declared eradicated on May 8, 1980 by the World Health Assembly; “The world and all its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake.35 The eradication of smallpox is still considered one of the biggest achievements in global public health. There are only two locations that still store the variola virus for research under WHO supervision, which is the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the State Research Center of Virology and Biotechnology (VECTOR Institute) in Russia. 


    Traditional Vaccine Types

    Vaccines are biological substances that get the body to produce an immune response to a specific antigen from an infectious disease pathogen. There are three categories of vaccines; live attenuated vaccines, inactivated vaccines, and subunit vaccinespolysaccharide, conjugate, toxoid, and recombinant vaccines.


    Live Attenuated Vaccines

    Scientific advances in the 1950s allowed for the development of live attenuated vaccines, which contain a whole virus that has been weakened to create an immune response in healthy people. This type of vaccine can produce long-lasting immunity only after two doses. However, those with weakened immune systems aren’t recommended to take it. Examples of diseases used with this type of vaccine include measles, chickenpox, smallpox, yellow fever, and rotavirus. 


    Inactivated Vaccines

    In the 1900s, scientists also got the idea of using killed or inactivated microbes to induce immunity. Today, inactivated vaccines contain a whole virus or bacteria which have been killed off by chemicals, heat, or radiation so they can’t cause disease. Examples include the hepatitis A, flu, polio, and rabies vaccines. This vaccine can be used for weakened immune systems although it does not provide as long of an immunity as live attenuated vaccines, so revaccination is necessary. 


    Subunit Vaccines

    Subunit vaccines contain specific components of the virus such as polysaccharides, conjugate, toxoid, or recombinant vaccines. These components alone aren’t enough to produce long term immunity, so they require adjuvants to create a stronger immune response. An adjuvant is an ingredient added to the vaccine to enhance the effectiveness and eliminate the need for revaccination. Aluminum is the most common adjuvant that has helped build stronger immunity against the germ in a vaccine. In the 1930s, aluminum salts such as aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate were found to strengthen the immune response and it was used with tetanus and diphtheria vaccines. Aluminum is a common metal found in nature through our air, food, and water. A study published on aluminum adjuvants show that its exposure in vaccines are low risk to infants and its benefits outweigh any concerns.36


    Vaccines used to protect against bacterial infections were usually polysaccharide vaccines. Polysaccharides are sugar molecules taken from the outside layer of the encapsulated bacteria. An example includes the 23-valent polysaccharide vaccine (PPV23) which is active against 23 of the known capsular polysaccharide serotypes.37


    It was found that the polysaccharide vaccine did not elicit a strong immune response in infants, and Haemophilus influenza type B(Hib) was most common in infants. According to WHO, Hib caused more than 8 million illnesses worldwide and 300,000 deaths in children ages 1-59 months.38 This led to the development of conjugate vaccines, where the polysaccharide molecules are taken from the outer layer of the encapsulated bacteria and joined with carrier proteins. This type of vaccine enabled the immune system to recognize the polysaccharide and develop immunity in children. Since 2000, Hib illnesses and deaths in children sharply decreased. 


    Toxoid vaccines use the toxin from the virus or bacteria that causes the disease to produce an immune response against it. The toxins are chemically inactivated so they’re harmless and are known as toxoids. When given a vaccine with a toxoid, the immune system recognizes it and knows how to fight the natural toxin that is produced from the bacteria. Examples include the pertussis, diphtheria, and tetanus vaccines. 


    Recombinant vaccines are produced using recombinant DNA technology. The process is done by using the gene component of a protein from the disease-casing pathogen which is inserted into the gene of another cell such as bacterial, insect, mammalian, or yeast cells.39 The first recombinant vaccine was for hepatitis B using yeast cells. Scientists have also been looking into plant-based technologies to insert the desired gene component of a protein into the genome of a plant cell. Results from human trials using plant-derived vaccines to protect against enterotoxigenic Escherichia coli infection, norovirus,and hepatitis B has been published by Tacket.40 Vaccination against cancer in plant systems have been looked into to produce tumor-associated antigens (TAAs).41 42 According to a study, plant-based vaccines may prevent millions from infectious diseases and help global disease control.42 43


    Nucleic Acid Vaccines

    mRNA Vaccines

    Instead of using the disease-causing antigens to get the body to produce an immune response, RNA (ribonucleic acid) vaccines get our body to produce the antigen. First let’s look at the role of mRNA in protein synthesis. 

    During the transcription process, information stored in the DNA is transferred to the RNA molecule in the cell nucleus. mRNA is a type of RNA that is responsible for carrying information from the DNA out of the nucleus and into the cytoplasm. The next process is called translation because it translates the gene into a protein, which takes place in the cytoplasm. The mRNA seeks out ribosomes (a complex structure in the cytoplasm) that ‘reads’ the sequence of mRNA bases. mRNA bases are categorized into three sets called codons. Each codon codes for one particular amino acid and has a set of bases called an anticodon which are part of the transfer RNA molecules (tRNA). The tRNA assembles the protein one amino acid at a time until the ribosome reads a “stop” codon.44

    RNA vaccines take advantage of this process, which contains an mRNA strand, and the cell will use the genetic information to produce the antigen. RNA vaccines don’t contain the actual disease-causing pathogen, so it is degraded once the protein is made. This type of vaccine is reliable for emerging outbreaks since scientists could code for any type of virus. 


    DNA Plasmid Vaccines

    DNA plasmid vaccines uses the plasmid in the DNA which encodes for specific proteins, taken from the desired antigen to elicit an immune response. A veterinary DNA vaccine against the West Nile Virus for horses has been approved. Although DNA vaccines are currently still in research for human use, as well as possible uses for treatments against cancer, allergies, and autoimmune diseases.45


    Live Recombinant Vector Vaccines

    Recombinant vector vaccines use live viruses or bacteria that are genetically engineered to contain extra genes from the antigen. Many recombinant vector vaccines have been approved for veterinary use to protect animals from infectious diseases such as rabies. Scientists supported by the National Institute of Allergies and Infectious Diseases (NIAD) are developing recombinant vector vaccines for humans against HIV, Ebola virus, and Zika virus.46



    Vaccination was always faced with many controversies and hesitation even in the 18thand 19thcentury. Understanding the origins of immunization and eradication of smallpox is necessary for disease prevention. Scientific advances continue, and the first mRNA vaccine against COVID-19 may be possible, presenting a new era in vaccinology. 



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