Smallpox from first outbreak to eradication

A paper by Alice van den Broek

2017, Amsterdam - Atlanta

The table of contents page ❖ Introduction --------------------------------------------------------------------------------- 2 ❖ The disease ---------------------------------------------------------------------------------- 4

➢ Symptoms -------------------------------------------------------------------------- 4 ➢ The virus ----------------------------------------------------------------------------- 5 ➢ Subtypes of the disease ------------------------------------------------------- 7 ➢ What happens inside the body -------------------------------------------- 7

❖ The history of smallpox ------------------------------------------------------------------- 9 ➢ An overview of smallpox and its role in our history ------------------- 9 ➢ Vaccine -----------------------------------------------------------------------------11

■ Edward Jenner ----------------------------------------------------------12 ■ Criticism and controversy concerning Edward Jenner----13 ■ Development of the vaccine --------------------------------------14 ■ Research on the vaccine nowadays --------------------------- 16

➢ The eradication of smallpox --------------------------------------------------17 ❖ The future of smallpox -------------------------------------------------------------------- 22

➢ Possible threats nowadays ---------------------------------------------------- 22 ■ Accidental contamination ------------------------------------------ 22 ■ Smallpox as a biological weapon -------------------------------- 23

❖ Acknowledgements ----------------------------------------------------------------------- 25

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Introduction I’m going to try to tell you of one of the greatest success stories in the history medicine, the eradication of smallpox. I first learnt about this disease at a camp I attended this summer. This camp wasn’t just your usual summer camp, it was a ‘Disease Detective Camp’, organized by the CDC. So I found myself flying to Atlanta, all by myself, to spend a week among 30 American peers, all with the same interest in public health. And on top of that, I got to meet thousands of CDC employees, of which we obviously only met a certain number, but who were all extremely kind, helpful and supportive. Let me start by briefly explaining what kind of organization the CDC is. The CDC is short for the Centers for Disease Control and Prevention and is a large federal organization that plays a fundamental role in public health. They bear responsibility for the health of all US-citizens in the case of a multi-state disease-outbreak. As a federal organization they are to refrain from interfering in a single-state outbreak, according to the Tenth Amendment to the United States Constitution. Their staff consists of 15,000 employees and their headquarters are situated in Atlanta. They focus on many public health fields, some of which are infectious disease, foodborne disease and environmental health. They also provide information on non-infectious diseases and undertake action in the case of emergency outbreaks in the US. They serve more or less as a big source of reliable information and as a major research organization regarding health. On top of that, they also play a significant role in Global Health. During my camp I was able to speak with many CDC-employees of whom some worked at the Global

Health-department. They could tell tremendously interesting stories concerning their adventures while travelling to foreign, mostly third-world, countries, in an effort to minimize infections of certain diseases. This is also how the CDC played a major role in the eradication of smallpox. This subject really caught my attention and as the CDC had been so significant in the eradication-process, they had a lot of interesting information available for us. Image 1: WHO magazine World Health declares one of the greatest triumphs of medicine The first cases of smallpox supposedly occurred thousands of years ago, scars were found on Egyptian mummies. The fact that smallpox is now eradicated

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and non-existent is almost inconceivable when thinking of how many people must have suffered with the burden of having, or the fear of obtaining, this disease. According to some estimates smallpox has been responsible for more deaths than all other infectious diseases combined. 1

It made me realize how we should take the eradication of smallpox as an example and try our best to follow the same strategy on other significant infectious diseases. I decided that it would be interesting to dive into the process smallpox underwent, and to investigate this disease, from its first clusters, all the way through understanding the virus, the invention of the vaccine until the very last case.

1 Smallpox virus, Baylor college of Medicine https://www.bcm.edu/departments/molecular-virology-and-microbiology/emerging-infections-and-biodefense/smallpox-virus

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The disease Smallpox is a disease caused by one of two viruses, Variola major or Variola minor , both part of the species Vaccinia . Variola major was a lot more common than Variola minor , it also was a lot more fatal. V. major had a mortality rate between 30-35 per cent. As opposed to V. minor , with death rates historically of 1% or less. Symptoms Once infected with Variola major an incubation period of 7-17 days follows. Most typically the incubation period ranges from 12-14 days. During the incubation period the infected person is not yet contagious, after this period the first symptoms start to show. The first phase is called prodrome and takes 2-4 days, the infected person can be contagious during this period, however not by far as contagious as during the period following the first rash. During the prodrome phase the initial symptoms start to occur, including high fever (38-40 degrees Celsius), head and body aches, overall discomfort, severe back pain and sometimes even vomiting. Following the the prodrome phase an early rash onset occurs, this period takes around 4 days, during which the person is most contagious. Image 2 shows the rash

distribution of smallpox compared to that of chickenpox. First the rash emerges as small red dots on the tongue and in the mouth. After the rash has developed into sores, they burst open resulting in a large spread of the virus in the throat and mouth, at this moment the person is incredibly contagious, as the virus can now be easily spread through face-to-face contact. Around the moment the sores break down in the mouth, a rash emerges over the skin of the body and face, the rash usually spreads over the entire body within 24 hours. After three days this rash turns into little bumps. By the fourth day these abscesses are filled with a thick liquid and pus, they also have a depression in the center,

which makes Image 2: Rash distribution the bump easily identifiable as a smallpox-abscess. After approximately a week since the symptoms first started, the bumps start to turn into pustules, meaning that they become more sharply raised and very firm. The infected person is still very contagious, but not as severe as before.

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After about five days, these pustules start to form a crust, thus turning into a scab. Five days later nearly all of the sores have turned into scabs. During the next six days the scabs begin to fall off the skin. Usually three weeks after the first appearance of the rash, every scab has fallen off. When the scab falls off the skin, the location of the scab is marked by eventually turning into a pitted scar. Thus leaving a person behind with a fully scarred face and body. The infected person remains contagious until every single scab has fallen off, so the period in which a person is contagious is as long as approximately three weeks.

Image 3: clinical presentation of smallpox. Image 4: overview development of 2

bumps Other symptoms could be caused by secondary bacterial infections, however this was rather uncommon, examples are meningitis and encephalitis. In malnourished patients blindness could also occur. Deaths from smallpox were most likely to occur in the second week of the disease. This was usually due to high toxemia levels, hypotension (= low blood pressure) and circulating soluble variola antigens. 3

The virus The virus that causes smallpox is part of the species Vaccinia , two types of this virus were known to cause smallpox, Variola major and Variola minor , the latter only was cause of smallpox in very rare cases. The variola virus belongs to the family of poxviruses, which means it is a member of the orthopoxvirus genus. Before eradication the virus survived by travelling from human to human. There is no record of animals having gotten the disease, which we will later see, turned out to be a crucial factor in the eradication of smallpox. Also, being a carrier of the virus was not possible, animals were simply not susceptible, so they could not be vectors through which the virus was transmitted. Humans couldn’t be carriers either, so being infected by variola always meant getting smallpox. Poxviruses are often even larger than

2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200695/figure/F4/ 3 Riedel, S. (2005), Smallpox and biological warfare: a disease revisited, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200695/

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bacteria, they are the largest animal viruses, and they replicate in a cell’s cytoplasm, so they do not need the nucleus like most viruses do, they also contain double-stranded DNA. Poxviruses are the only viruses (apart from the Herpes virus) 4

that contain a certain defense mechanism. For many poxviruses research has been done (see: Immune Response to Poxviruses Infections in Various Animals, a study by Scott A. Smith and Girish J. Kotwa, 2008 ) relating to interference of poxviruses in the 5

immune system of their host. Because poxviruses contain proteins that can manipulate their host’s immune mechanism, they have a very strong defence. That is the reason for the challenge the body faces when curing itself from poxviruses without help from outside factors, like a vaccine. The study described in footnote 5 couldn’t be done with variola because animal tests aren’t possible with variola, however, the variola genome is fully sequenced, and some proteins were found that would be capable of interference in innate immune systems. In 2004 several scientists conducted a large research with live variola virus, in the laboratories of the Centers 6

for Disease Control and Prevention’s headquarters in Atlanta, they indeed found that smallpox could possibly be capable of interference in their host’s immune systems. The differences of the host’s immune system’s reactions to smallpox (caused by variola, a poxvirus) and ebola (not caused by a poxvirus) are to be seen below in image 5. This image demonstrates the difference in activation of the immune system of smallpox (caused by a poxvirus), compared to a disease not caused by a poxvirus. The amount of activated macrophages can be seen as a measurement for immune response. Therefore these graphs are evidence of how poxviruses somehow manipulate the immune system into becoming less active, once infected.

Image 5: comparison ebola and smallpox immune reactions (measured TNF-alpha, which is usually produced by activated macrophages)

4 http://www.emedicinehealth.com/smallpox/page2_em.htm 5 http://www.tandfonline.com.sci-hub.cc/doi/abs/10.1080/1040-840291046722 6 The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model, by: Kathleen H. Rubins, Lisa E. Hensley, Peter B. Jahrling, Adeline R. Whitney, Thomas W. Geisbert, John W. Huggins, Art Owen, James W. LeDuc, Patrick O. Brown, and David A. Relman in 2004 http://www.pnas.org/content/101/42/15190.full

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The term variola was first used in 570 AD by Bishop Marius of Avenches, the word is derived from the Latin word Varus , which means ‘mark on the skin’, or possibly from Varius , meaning ‘stained’. The term smallpox originates from England in the 15th century, they then used ‘small pockes’ to differentiate between syphilis, which was then known as ‘the great pockes’. 7

Smallpox comes in one of 4 subtypes:

❖ Ordinary smallpox, the ordinary form of smallpox which accounts for 90% of the cases.

❖ Modified smallpox, this is a milder form of smallpox which develops in people who were previously vaccinated.

❖ Malignant (flat) smallpox, this is a type of smallpox in which the lesions did not develop into pustules on the skin, but the lesions remained under the skin. This variety of smallpox was very severe as it was characterized by severe toxemia.

❖ Hemorrhagic (fulminant) smallpox is a very rare but very severe form of smallpox. Many small hemorrhages under the skin cause the skin to turn deep purple. The fatality rate was near 100% because of its high toxemia.

Image 6: Variola major structure What happens inside the body The virus enters the body through inhalation, which makes it a highly contagious disease. So it is either spread through face-to-face contact or through a fomite, which is a nonliving object that is contaminated by the virus. Contamination through a fomite is possible because the virus is capable of staying viable outside the body for up to a week.

7 Edward Jenner and the history of smallpox and vaccination, Stefan Riedel, MD, PhD. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200696/#B3

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When the virus has been inhaled it rapidly advances to the nearest lymph nodes. As the virus enters through the respiratory tract, infected persons often got infections in their upper and lower respiratory tract during the incubation period. During this period the virus also starts circulating through the rest of the body where it rapidly reproduces in the spleen and in bone marrow and also in some other organs like the lungs and liver. This is usually around the 3th-4th day of infection. On top of that the immune system and other circulatory systems are compromised by the virus. It kills large amounts of macrophages and also interferes in the activation of the immune system, this has been elaborated in ‘the virus’. Furthermore, the disease will start attacking the blood vessels in the skin, which causes the rash and later the bumps, pustules and scabs described in ‘symptoms’. 8

Image 7: lymphatic system of the human body, through which the virus spreads.

8 http://www.ehow.com/about_5368472_body-systems-affected-smallpox.html

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The history of smallpox An overview of smallpox and its role in our history When exactly this disease started to occur is, and will, probably always be unclear. It is suspected that the virus originated from a mutation in an even older, less venomous, virus around 10,000 B.C. The first traces of the skin lesions that were typical for smallpox were found on Egyptian mummies. Especially on the mummified faces of the 18th and 20th Egyptian dynasties (1570-1085 B.C). The disease spread to Asia presumably through Egyptian merchants travelling to India. So in China the first cases date back to 1122 BC, and the disease was described on ancient Indian Sanskrit texts. In Europe the disease first occurred many years later. Only between the fifth and seventh century AD was it introduced. In Europe smallpox largely inhibited the growth and development of the Western civilization. Especially during the medieval period and during the expansion of the Roman Empire smallpox epidemics often occurred. The discovery of other continents, just as the crusades, largely contributed to the spread of smallpox. This is obviously also how the disease got introduced in America. Spanish and Portuguese explorers brought this disease, which was then unknown to the New World, to its inhabitants. The large diminution in population, caused by smallpox, was a crucial factor in the fall of the Incas and Aztecs. This serves as an example to the first use of smallpox as a biological weapon during the American-Indian war in 1763. During which the British commander in North America deliberately used the spread of smallpox to reduce the Native American population, so to achieve that the Britons grinded the pus of smallpox pustules into the blankets that were to be distributed among the native Americans. In America slave trade was 9

another significant factor in the spread of smallpox. The slaves came from Africa, where the disease was then endemic. 10

Smallpox made no distinctions between socioeconomic classes, everyone had chances of being infected and the most various possible people could get the disease. Everyone was equally susceptible, two examples: in the eighteenth century in Europe four reigning European monarchs died after being infected by smallpox and in four generations the Habsburg line of succession to the throne changed four times due to smallpox. This describes how the princes and peasants all had equal 11

chances of obtaining the disease. Remarkable is that when the successor to the throne got smallpox and survived it, the church bells would sound as this meant that a

9 Elizabeth A. Fenn, http://www.politicsandthelifesciences.org/Biosecurity_course_folder/readings/fenn.html 10 Edward Jenner and the history of smallpox and vaccination, Stefan Riedel, MD, PhD. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200696/#B3 11 Nicolau Barquet, MD, and Pere Domingo, MD, The Triumph over the Most Terrible of the Ministers of Death. http://annals.org.sci-hub.cc/aim/article/710873/smallpox-triumph-over-most-terrible-ministers-death

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strong king was to come and the nation had a shot at not yet another dynasty dying out entirely because of smallpox, as this was something that happened regularly. This quote clearly shows the large role smallpox played in daily life: “Smallpox was always present, filling the churchyard with corpses, tormenting with constant fear all whom it had not yet stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of the betrothed maiden objects of horror to the lover.” 12

The case-fatality rate differed greatly depending on place, time and severity of the disease, but for a usual Variola major infection, the fatality-rates ranged between 20% and 60%. For infants, the fatality rate was even higher, usually around 80%, with a record of 98% in Berlin during the 18th century. The absolute high point of smallpox was unmistakably during the eighteenth century, where smallpox is suspected to have been accountable for 10% of all deaths in Europe. So the eighteenth century was clearly a fateful century, but around 1790 an English physician named Edward Jenner discovered vaccination, more about the discovery and functioning of the vaccine can be read under the chapter ‘vaccine’. This vaccine was also the basis for the eradication of smallpox, this part of the history of smallpox is elaborated under the chapter ‘The eradication of smallpox’. The interested reader is referred to a timeline of smallpox throughout history: https://www.cdc.gov/smallpox/pdfs/smallpox-timeline.pdf

12 From Centre d'Assistencia Primaria Gratia, Institut Catala de la Salut and Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

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Vaccine The invention of the vaccine against smallpox was, of course, a significant link in the long chain to the eradication of the disease. The period of time between the very first observation which was the foundation for the vaccine (1796), and the invention of the vaccine as it is known today (1960), is almost 200 years. During those years the vaccine has been subject to an incredible development process, this evolvement will be explained in the following chapter. First it is important to distinguish two terms: inoculation (or variolation) and vaccination. Inoculation has presumably been used for many centuries, probably since the 16th century, whereas vaccination was only discovered around 1790. The big difference between variolation and vaccination is that variolation basically means deliberately infecting someone with the disease to insure immunity. It usually included weakening the virus and thus reducing its infectious abilities. Otherwise there would be no difference between naturally obtaining smallpox and inoculation. In China and India the earliest accounts of inoculation of smallpox were written around 1550, in Europe inoculation was first used in the 17th century, after it had been spread to the Ottoman empire. In China inoculation usually included letting smallpox particles go through a process which weakened the virus, and then blowing the smallpox matter up the nose. The process consisted of exposing the virus to certain herbs and temperatures. Inoculation usually had a fatality rate of around 1-3%. Vaccination, however, has a mortality rate that is a lot lower. Usually around 1 to 3 per million. , The reason for the significant differences in mortality rates is that with 13 14

vaccination the virus of a different disease was used. The same antibodies were effective against cowpox as against smallpox, so after having been infected by cowpox, this person would be immune to smallpox. After having discovered this, people deliberately got infected by cowpox to ensure immunity from smallpox. Apparently Edward Jenner, the inventor of the vaccine himself, has undergone the variolation process as a child. This process was one that was imported from Turkey and consisted of starving, bleeding and purging and once the person was weakened he would be infected with the (weakened form of) variola. After that he was locked into a barn for several weeks together with boys who had undergone the same process and only when the disease had subsided they would be let out, and they would be immune. This traumatic experience was never forgotten by Jenner, and this was, perhaps, what gave him the persistence needed to find a vaccine.

13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407399/ 14 Horace G. Ogden, CDC and the smallpox crusade, 1987, page 6 http://globalhealthchronicles.org/archive/files/b6a21a1b33e8cb46ef8d26c5a7c96080.pdf

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Edward Jenner While observing milkmaids, Edward Jenner’s attention was attracted to the fact that those, who had earlier been infected by cowpox, would not fall ill when exposed to smallpox. Using the method seen in image 8 , he started inoculating individuals with cowpox, to ensure immunity against smallpox. Smallpox and cowpox viruses looked a lot like each other as they both belong to the genus of the orthopoxviruses.

Image 8: how Edward Jenner ensured smallpox immunity By 1800, Edward Jenner had published his theories in his book Inquiry throughout many different countries and the vaccine was soon to be used, not only in Europe, but also in the United States. In the US, the doctor responsible for spreading awareness about the low mortality rate (close to zero) and the effectiveness of the vaccine, was Dr. John Clinch. He started a movement in the US to promote vaccination, which has been very important. After having been inoculated, the chances of obtaining smallpox, still weren’t zero. Inoculation, or modified, smallpox, appears in approximately 15% of the infected population. Infection after inoculation usually happened through the cutaneous route (which means the person was infected via the skin). Remarkable about this so-called ‘inoculation smallpox’ was that the incubation period seemed to be 2-3 days shorter than with ‘natural smallpox’. This can be explained by the fact that infection usually happens through the respiratory tract, while inoculation smallpox pertains the skin. Through dermal infection, macrophages can more easily be transported to the lymph nodes than through infection via the respiratory tract (24 hours versus three days). Therefore the inoculation smallpox is often characterized by a shorter than usual incubation period. This variety of smallpox was not often fatal.

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Image 9: Vaccinations done by Jenner in 1796 and 1798 15

Criticism and controversy concerning Edward Jenner Although Edward Jenner is often seen as the inventor of the smallpox vaccine, he wasn’t the first to observe a correlation between cowpox and smallpox. As a matter of fact, cowpox as a precaution to smallpox used to be a countryside fable that had already been tested in 1774 by Benjamin Jesty, a dairy farmer who inoculated his wife and two children with cowpox pus. As an example of someone else observing the 16

correlation: John Fewster, he presumably presented a paper in 1765 in which he expressed his thoughts about the possible protective effect cowpox had over obtaining smallpox. Although there is no doubt Fewster attempted vaccination with cowpox before Jenner, he clearly did not understand the magnitude and importance of his discovery. 17

Also, when his book, Inquiry , was published, there was at first little enthusiasm. Jenner had a hard time finding doctors willing to cooperate and start vaccinating in their hospitals. Meanwhile in London three doctors had started vaccinating, Henry Cline, George Pearson and William Woodville. They listed their findings and the results from their vaccinations clearly in charts and concluded that something was not right with Jenner’s results. On many of Woodville’s patients pustules were found, these characterized smallpox, and not cowpox. Therefore many became sceptical of the vaccine and of the reliability of Jenner’s findings. Jenner, however, was convinced

15 Derrick Baxby, 1981, Jenner’s smallpox vaccine, the riddle of vaccinia virus and its origin. 16 Robert Jesty & Gareth Williams, 2011, Who invented vaccination? http://www.um.edu.mt/umms/mmj/PDF/323.pdf 17 L. Thurston & G. Williams, 2015, An examination of John Fewster’s role in the discovery of smallpox vaccination https://www.rcpe.ac.uk/sites/default/files/thurston.pdf

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that this had to do with the fact that the same lancets were used for vaccination as for variolation. Jenner later turned out to be right but many remained sceptical. , 18 19

Even though there was some criticism on the vagueness of Jenner’s book ‘Inquiry’ and he often turned out to be a careless scientist, sometimes contradicting his own evidence, he was clearly the first to research the influence of cowpox on smallpox on a large scale and the first to publish his findings. He may not necessarily have been 20

the one to come up with the idea, but he did put in motion a large discussion and more research into immunization. Development of the vaccine Initially, in 1796, Edward Jenner scraped puss from the pustules that grew on vaccinated people. With a needle he would push it inside both arms of the person he wanted to immunize. He soon started using another vaccinia virus, this is a virus whose origin is still unclear. It is suspected that it emerged from cowpox or variola through genetic recombination. 21

The method of vaccinating people changed a lot the following years and underwent a development that went on until 1965. Many methods were tested during those years, scratching vaccine with a lancet into the skin, using a painful rotary vaccinator to gouge circular cuts into the skin and firing a spray of vaccine through intact skin with a jet injector (image 10). 22

Image 10: the jet injector that was initially used

18 Nicolau Barquet, MD, and Pere Domingo, MD, The Triumph over the Most Terrible of the Ministers of Death. http://annals.org.sci-hub.cc/aim/article/710873/smallpox-triumph-over-most-terrible-ministers-death 19 Derrick Baxby, 1981, Jenner’s smallpox vaccine, the riddle of vaccinia virus and its origin, chapter seven: The Jenner-Woodville Controversy 20 Gareth Williams, 2010, Angel of Death, the story of smallpox, page 175-204 21 Riedel, S. (2005), Smallpox and biological warfare: a disease revisited, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200695/ 22 Gareth Williams, 2010, Angel of Death, the story of smallpox, page 345-346

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In 1965, however, a groundbreaking method of vaccination was invented by Dr. Benjamin Rubin at Wyeth Laboratories in the US. He found a very simple design, which he called the bifurcated needle (image 11+12 ), it was 5 cm long and had a gap between the prongs. When the needle was dipped into the vaccine, the tension between the prongs held an effective dose of liquid vaccine. Within 15 minutes the vaccination technique could be taught to others, so many people were able to vaccinate. Also the needle was very cheap to produce and easy to sterilize. On top of that the vaccination only took several seconds, was not very uncomfortable and almost always successful. As these facts show, vaccination by the bifurcated needle was highly effective, therefore this is also the method used during the smallpox eradication campaign of 1967. , 23 24

Image 11: bifurcated vaccination needle Image 12: how the bifurcated needle 25

was used in the global eradication campaign 26

In image 13 (on the next page) it becomes clear how the development of the vaccine obviously contributed to the decrease in deaths by smallpox.

23 Derrick Baxby, 2002, Smallpox vaccination techniques; from knives and forks to needles and pins http://www.sciencedirect.com.sci-hub.cc/science/article/pii/S0264410X02000282 24 Gareth Williams, 2010, Angel of Death, the story of smallpox, page 345-346 25 Smallpox, a great and terrible scourge, U.S. National Library of Medicine, https://www.nlm.nih.gov/exhibition/smallpox/sp_eradicate.html 26 Gareth Williams, 2010, Angel of Death, the story of smallpox, page 345

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Image 13: annual death rate per million living from smallpox and other diseases. 27

Research on the vaccine nowadays As can be read in ‘the future of smallpox’, two laboratories are still in the possession of Variola major cultures, these are used for further investigation in the case of another, unlikely but not entirely excludable, smallpox outbreak. Dr. Innocent Mabwuike has been doing research on the response of our immune systems on vaccinia (the poxvirus that is used in the vaccine) and comparing the results of the immune response in elderly people to those of young adults. This study would be important in the case of a new outbreak because the immune response activity to the vaccine declines with age. Also studies have been conducted examining alternatives or surrogate antigens to ensure immunity. This study could potentially lead to a cure for smallpox, or a vaccine that ensures longer immunity and is safer for the older population. Therefore these studies could prove very useful in the case of the use of smallpox for biological warfare. 28

After having discovered the vaccine Jenner was contacted by a Virginia gentleman, Thomas Jefferson’ who wrote him the following: “You have erased from the calendar of human afflictions one of its greatest. . . . Future nations will know by history only that the loathsome smallpox has existed.” Unfortunately nearly two more centuries went 29

by before this became the truth.

27 Gareth Williams, 2010, Angel of Death, the story of smallpox, page 284 28 Smallpox virus, Baylor college of Medicine https://www.bcm.edu/departments/molecular-virology-and-microbiology/emerging-infections-and-biodefense/smallpox-virus 29 Horace G. Ogden, CDC and the smallpox crusade, 1987, page 4 http://globalhealthchronicles.org/archive/files/b6a21a1b33e8cb46ef8d26c5a7c96080.pdf

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The eradication of smallpox The eradication of smallpox has been a fact since 1980, I myself have grown up without the constant fear of obtaining this disease, unlike many others before me. Thousands of years the fear of being infected by variola was a never-ending concern. For me it seems far away, but it fascinates me how big a role this disease used to play in everyday life, that is why I think it is so interesting to observe the road to the eradication of this disease, after thousands of years of trouble. Before I start describing how smallpox was eradicated, we have to understand what the difference between elimination and eradication is. When speaking of elimination, we are looking at a defined geographical area, so for instance a country or state. The number of new cases has to be zero (or another low number) in this defined geographical zone for a certain period of time, usually a year, for a disease to be eliminated. When a disease is established to be eliminated, further measures still have to be taken. The disease has not yet disappeared from the globe, the cases in a certain country or continent are simply very low, but this does not exclude a new outbreak. Eradication, however, is when, for a period of three years, there has not been a single case reported in the entire world. When a disease has been eradicated no further measures have to be taken, because the disease does no longer form a threat to mankind and any form of outbreak can now be excluded. The eradication of smallpox was the result of a vaccination programme which was set up in 1967 as a global campaign to make an international effort to eradicate smallpox. The ‘smallpox eradication programme’ was combined with a campaign to control measles that was already being conducted in Africa. The smallpox eradication programme was a combined effort of three agencies: the World Health Organization (WHO), the Centers for Disease Control (CDC) and the US Agency for International Development (AID). The division of tasks between these three agencies can be described in broad lines. The AID mostly offered financial support, while WHO maintained relations with national governments and therefore provided technical assistance in reaching the goal. The CDC’s task mostly consisted of supplying the campaign with enough personnel to go through all of Africa and vaccinate even the most hidden tribes. As the WHO initiated the plan and gave it technical ground and possibilities, the WHO is often seen as the leading agency, the real action, however, was mostly undertaken by the CDC with funding from AID. Smallpox was declared eradicated in 1980. In this chapter the events leading to this milestone in medical history are described. The campaign and funding were initiated during the Nineteenth World Health Assembly in Geneva in 1966. During the Twentieth Assembly, a year later in 1967, a well-defined plan for the eradication of smallpox was adopted.

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The idea for a smallpox eradication programme came forth from a measles control programme that was already being conducted in Africa. However, this programme proved to be increasingly less promising. The absence of practical vehicles, as the vehicles funded by the AID were too big and poorly designed, and the impractical features of the vaccine for measles slowly shattered hope in success. On top of that, vaccination against measles did not offer lifelong immunity, so this programme would have to be repeated once in the so many years, also, it was unlikely that the donor-countries would maintain their funding for much longer. This programme was officially set up by AID and they didn’t feel like giving up on it, as they considered the programme their baby. They decided to turn to the CDC for help, at first the CDC decided to give their support by offering large amounts of manpower. But, as the programme proved to require an increasing amount of resources, the CDC could no longer agree to support a plan that was in their eyes so hopeless. However, in this same period good news kept coming from the smallpox-experts. In 1965 the vaccine proved to be incredibly effective, especially through the skin, with the newly invented bifurcated needle. On May 1965, the White House issued a press release stating: “President Johnson announced today that he has instructed the U.S. Delegation at the World Health Assembly to pledge American support for an international program to eradicate smallpox completely from the earth within the next decade.” 30

Image 14: WHO promotional poster

Two months later the CDC proposed a new plan to AID, suggesting that they put the measles control programme and the smallpox eradication programme together. The sanctioning of this plan by the White House should not be considered lightly. The programme considered a 5-year plan and numerous CDC-employees busy during this period in other countries. On top of that, all necessary technical commodities were to be provided by the US-government. Months passed before the plan was officially agreed to by all parties involved. All that remained now was to fulfill it. 31

Smallpox has been endemic in the entire world for numerous centuries. The eradication campaign set up in 1967, however, was not active in the whole world. The focus of this programme lay mostly on Western and Central Africa. This is because

30 Horace G. Ogden, CDC and the smallpox crusade, 1987, page 22-24 http://globalhealthchronicles.org/archive/files/b6a21a1b33e8cb46ef8d26c5a7c96080.pdf 31 Horace G. Ogden, CDC and the smallpox crusade, 1987, page 25 http://globalhealthchronicles.org/archive/files/b6a21a1b33e8cb46ef8d26c5a7c96080.pdf

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smallpox had not been endemic in most Western and some Asian countries for several years. Presumably the first country where smallpox was eradicated is Sri Lanka, they claim to have eliminated the illness in the early 1800s. In Sweden the disease got eradicated in 1895, therefore making it the first large country where smallpox was officially eradicated. Austria followed in the 1920s, England, the USSR and the Philippines in the 1930s. In the 1940s numerous others, among which were the US and Canada. As the disease hadn’t disappeared from the globe altogether, because through travelling some clusters re-appeared each year, the disease could not officially be declared eradicated. To ensure long lasting elimination, health agencies realized that the only long-term solution would be full eradication. And they then decided that an effort had to be made. At the beginning of the programme, smallpox was endemic in thirty-three countries, and was reported in forty-four in total. The disease was present in the larger South-American countries, in Africa everywhere under the Sahara and all the way across Southern Asia, from Afghanistan to Malaysia and Indonesia. The reason for the focus of the campaign on Western and Central Africa was mostly because that is where the countries were situated where smallpox was most heavily endemic. Also its geographic and demographic borders offered great challenges, and the idea that if they could do it here, they could do it anywhere, pushed them to persist and achieve eradication in this area. The smashing victory of this achievement in the 1970s, offered renewed faith and stamina in the fact that success of the campaign in the entire world might be possible, although clearly by no means self-evident. Therefore the eradication of smallpox in Western and Central Africa can be seen as the turning point in the struggle. 32

Image 15: WHO poster

DA Henderson once said: “smallpox was the ideal disease to eradicate.” So these were significant factors that made the eradication of smallpox achievable: 33

❖ Animals weren’t susceptible for smallpox. As the variola virus could not be transmitted through animals, only human beings had to be inoculated to ensure immunization. Also people who were infected, either died or recovered and became immune, so it was only relevant to break the links in the chain of the virus.

32 Horace G. Ogden, CDC and the smallpox crusade, 1987, page 10-11 http://globalhealthchronicles.org/archive/files/b6a21a1b33e8cb46ef8d26c5a7c96080.pdf 33 CDC Connects: smallpox eradication: memories and milestones http://globalhealthchronicles.org/archive/files/869774faa96420dc6f1a1628e3fa7127.pdf

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❖ Everyone was very afraid of the disease. Because this disease had such horrifying symptoms and on top of that, an excruciatingly high mortality rate, people lived with a constant fear of obtaining smallpox. Therefore everyone would go through great lengths to help eradicate the disease. In Africa there were even multiple gods and goddesses of smallpox. “No other disease had deities and temples erected to it.” Because of this fear WHO-delegates 34

received a lot of help from locals, as they were trained in identifying and reporting the disease.

Image 16: The WHO smallpox recognition card used Image 17: Shapona, to help locals recognize the disease West African God 35

the Smallpox ❖ Another important factor in the eradication of smallpox was the quality of the

vaccine, as an inoculation usually made one immune for at least ten years. Also scientists found a way to keep the vaccine in a vial in a powdered freeze-dried form, this made it possible to transport the vaccine anywhere, as it could also resist high temperatures.

❖ The persistence of everybody involved in the programme, the organizations participating in the smallpox eradication programme went for it all the way and were clearly not going to stop until full eradication was achieved.

❖ The collaboration between all the different countries, one single country could have never done this alone. Because the disease occurred so often and played such a large role in daily life, nearly every country could benefit from eradication.

34 DA Henderson, MD, http://globalhealthchronicles.org/archive/files/869774faa96420dc6f1a1628e3fa7127.pdf 35 Gareth Williams, 2010, Angel of Death, the story of smallpox

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Nonetheless there were also many obstacles: 36

❖ In some of the countries in which health workers were active, civil wars waged. Even though the WHO had the confidence of the government, workers were often fired upon or kidnapped. The UN would have to persuade the guerillas to let them go.

❖ Not only lack of safety, but also the absence of the quality technology to which we have access today made it an absolute challenge. Especially being able to track the different teams and to communicate with each other and with the outside world would have been a big help.

❖ The worship of the divine gods also had its drawback. Above is explained how smallpox gods showed the fear for smallpox that helped eradicate the disease. But on the reverse side tampering with divine intent was not something Africans took lightly. As they believed that the disease was brought upon a victim through God’s will, fighting smallpox meant messing with the divine, and for many this was unheard of.

❖ Because many populations were nomadic, WHO workers feared that many would go unvaccinated.

Image 18: Parchment signed by the Global Smallpox commission at Geneva on the 9th December 1979 to declare Smallpox eradicated. 37

36 CDC Connects: smallpox eradication: memories and milestones http://globalhealthchronicles.org/archive/files/869774faa96420dc6f1a1628e3fa7127.pdf 37 Archives of the smallpox eradication programme, a guide and inventory, WHO, Geneva, 1982, 2 vol.

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The future of smallpox There are many different opinions considering what to do with the variola virus that is left on earth. Roughly they can be divided into two groups; one of them wants the last cultures of the virus destroyed, which are situated in the government laboratories in the US (at the CDC) and in Russia (at the state research center for virology and biotechnology, VECTOR). The other group however, vows for continuing research to develop better vaccines, this opinion is supported especially by scientists. This ongoing debate goes by the name of the ‘Smallpox virus retention controversy’. The first group is most probably afraid that the vaccine might either escape from a laboratory by accident, or that it might be used as a biological weapon. The second group has stated that “the virus’ genomic information is available online and the technology now exists for someone with the right tools and the wrong intentions to create a new smallpox virus in a laboratory…. Destroying the virus now is merely a symbolic act that would slow our progress and could even stop it completely, leaving the world vulnerable” (Kathleen Sebilius, Why We Still Need Smallpox, New York Times, 2011) 38

Next will be explained why the fear of the first group is not entirely unjustified; Possible threats nowadays Accidental contamination The fear for accidental contamination is quite reasonable, because, as the virus is obviously not visible to the naked eye, it is very well possible that it might accidentally stick to someone’s skin or hair. When I was at the CDC, we were unfortunately not allowed in the BSL-4 labs, as that is where deadly pathogens are being researched. But we were showed pictures of scientists working in them and what the labs looked like from the inside. We were also told that scientists can only enter after an eye-scan, to prevent unwanted people from entering the labs. I was allowed to try on the uniform that is worn by the scientists in the labs. It was very heavy and big, oxygen is supplied through a tube stuck in the back of the suit. This suit is called a ‘positive pressure personnel suit’ (PPPS). Because of the positive pressure, air is always being blown out instead of sucked in, this is another safety feature, in case of, for instance, a puncture in the suit. When scientists leave the labs, they go through an intensive cleaning routine.

38 http://www.nytimes.com/2011/04/26/opinion/26iht-edsebelius26.html?_r=0

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They go through several showers with and without suit, insuring that none of the pathogens is taken outside of the labs. On top of that, before anyone is allowed access into the BSL-4 labs, a six month background check is done by the FBI, to ensure that people with bad intentions do not get a chance. So the necessary safety measures are taken to prevent scientists from accidentally bringing the virus outside the labs, and there are measures in place to prevent them from doing so intentionally.

Image 19: me in a PPPS Image 20: scientists hooked to a PPPS Smallpox as a biological weapon Especially after the events around 9-11, a fear exists that variola might be used as a bioweapon. Biological warfare has been waged before. Because at least a quarter of mankind dies due to infectious diseases, as a bioweapon they could be almost as efficient as a nuclear weapon. Although they do not destroy infrastructure, an infectious disease outbreak could claim an incredibly high number of fatalities. As 39

an example, the death rate of an outbreak of the Spanish Flu in 1918 was even higher than that of the entire World War I. 40

The fact that biological warfare has been conducted before and that terrorist attacks seem to be increasingly common, makes fear for smallpox as bioweapon very justified. In 1992 a Russian defector revealed to have cooperated in a large programme to develop smallpox into a lethal and effective biological weapon.

39 Dr Jean Pascal Zanders, The Threat with Biological and Toxin Weapons, 2003 http://www.law.kuleuven.be/education/iir/nl/activiteiten/documentatie/OldActivities/WMD2002/WMDzanders.pdf 40 World Health Organization, Health Aspects of Biological and Chemical Weapons, Unofficial draft report, Geneva, 17 August 2001, p. 8. (This report was released by the WHO following the terrorist strikes of 11 September 2001 and the fear of follow-on attacks with chemical or biological weapons.)

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However indignant other countries were of these Soviet actions, the Soviets were certainly not the first to come up with the idea to use smallpox for biological warfare. During the French-Indian war (1754-1763) smallpox was used by the British against the Native Americans. Under the leadership of Jeffrey Amherst, they are suspected to 41

have used smallpox-pus covered blankets to decimate the population, in order to increase their chances to siege Fort Pitt. Also, in 1789 in Sydney Cove Britons are suspected to have used smallpox as weapon against the indigenous tribes of New South Wales. This theory was published in JAS (Journal of Australian Studies). 42

A reason that could make smallpox a very capable bioweapon is that the virus is extremely contagious. Variola is airborne, which means that you do not even have to touch an infected person to get infected yourself. This means many people would get contaminated very soon. Also there is no known cure for smallpox and the general population lacks immunity because the routine smallpox vaccinations have ended long ago. On top of that, it is considered very likely that outside the two WHO-laboratories, secret stockpiles exist. As seen in table 1 , smallpox is classified in 43

category A, which signifies fast transmission, contamination and a high mortality rate, thus it is considered a bioterrorism agent of the highest risk. Fortunately, as said before, in order to gain access to the labs, a person is subject to a gigantic background check. But on the other hand creating the virus with help of the chemical structure is not entirely impossible, so preserving the last cultures would help with further research and to possibly even find a cure. Especially considering all the effort that has been put into its eradication and the public disorder it would cause, releasing aerosolized variola deliberately would be an internationally disastrous crime, with unimaginably catastrophic results. Therefore an emergency response programme is necessary in case of a sudden outbreak. A sufficient amount of vaccines needs to be available and the public, as well as healthcare professionals need clear education concerning details of the disease. 44

41 http://www.bbc.co.uk/history/worldwars/coldwar/pox_weapon_01.shtml 42 Christopher Warren, Smallpox at Sydney Cove - who, when why?, 2013 http://www.tandfonline.com.sci-hub.cc/doi/full/10.1080/14443058.2013.849750?needAccess=true 43 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200695/table/T1/ (Table with bioterrorism agents as listed by the CDC) 44 Stefan Riedel, MD, PhD, Smallpox and biological warfare: a disease revisited, 2005, Baylor University Medical Center Proceedings. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200695/#B1

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Acknowledgements First of all I would like to express my gratitude to the ‘Stichting het Zelfstandig Gymnasium’ for coming up with this amazing honours programme, which was a wonderful opportunity for me to start acquiring more knowledge regarding a subject that has interested me for a long time: healthcare. Secondly I would like to thank the Centers for Disease Control and Prevention for welcoming me to their extraordinary camp. They organized a week during which I could further educate myself on everything that has ever interested me and doing so, they opened a whole new world to me. A part of this world consisted of a certain topic: smallpox. This was a disease I knew very little of until last summer, in Atlanta I was introduced to it, and from that point forward my interest for it only kept on increasing. So not only did I get to meet wonderful new people, improve my interview skills, acquire knowledge on every possible subject of public health, and enjoy their incredible sandwiches, they also provided me with the topic I have been delving into for the past months with such delight. Also Tushar van der Wijst, my chemistry teacher, thank you for being there if I had any more complex questions concerning chemicals and pharmaceutics and taking the time to read the entire work and providing it with feedback. Last but not least I would like to acknowledge Peter Lammers who would always respond to my emails within the shortest amount of time that is humanly possible and during the past two years has guided me with a matter of factness and in a straightforward manner that I really appreciated. I’m extremely grateful for now feeling a connoisseur rather than a layman on the field of public health. Alice van den Broek September 2015 - March 2017

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