Kurzgesagt – In a Nutshell 

Sources – Smallpox

Thanks to our experts: 

Dr. James Gurney

Georgia State University, USA

Dr. Inger Damon

U.S. Department of Health and Human Services | HHS · Centers for Disease Control and Prevention (CDC)

- Evidence for it has been found in Egyptian mummies and in writing from India and China as old as 3000 years.

#Behbehani, A. B. (1983): The Smallpox Story: Life and Death of an Old Disease. Microbiological Reviews, Vol. 47 (4)

https://journals.asm.org/doi/pdf/10.1128/mr.47.4.455-509.1983 

Quote: “Descriptions of smallpox appear in the earliest Egyptian, Indian, and Chinese writings. The mummy of Pharaoh Ramses V (Fig. 1) (discovered in 1898 and currently at the Cairo Museum, Egypt), who reportedly died of an acute illness at the age of 40 years in 1157 B.C., shows a striking rash of yellowish blisters or pustules which closely resembles that of smallpox. 

(...)

However, since obtaining a piece of the mummy's skin containing one or more of the visible lesions was not permitted, the negative results do not preclude death by smallpox (53).

(...)

The disease was present in India for many thousands of years; evidence of the preventive measure of variolation is found in the Sanskrit text "Sacteya," attributed to Dhanwantari. A special god, Kakurani, was recognized for smallpox in the Brahmin mythologies. In China, smallpox was known since 1122 B.C. during the Chou (Tcheou) dynasty (1122 to 255 B.C.), and the nasal route of variolation was practiced during the Sung dynasty (960 to 1280 A.D.) (29).”

#Berche, P. (2022): Life and death of smallpox. La Presse Médicale,

Vol. 51 (3)

https://www.sciencedirect.com/science/article/pii/S0755498222000100 

Quote: “Clinical descriptions of smallpox appear in ancient medical writings from China, India and pharaonic Egypt. The earliest patient to die of smallpox would be Pharaoh Ramesses V, who died at age 40 in 1157 BC (Fig. 2). The mummy shows a rash of yellowish blisters or pustules which closely resembles smallpox.”

Fig. 2. Mummy of Ramesses V dead at 40 in 1157 BC. By G. Elliot Smith - http://www.lib.uchicago.edu/cgi-

#Centers for Disease Control and Prevention (2016): The Spread and Eradication of Smallpox

https://www.cdc.gov/smallpox/history/smallpox-origin.html 

- 1300 years ago smallpox killed up to a third of Japan’s population. 

#Suzuki, A. (2011): Smallpox and the epidemiological heritage of modern Japan: towards a total history. Medical history, Vol. 55 (3)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143877/ 

Quote: “Smallpox was first introduced to the islands of Japan by merchants and Buddhist missionaries from the Korean kingdom of Paekche in the sixth century CE. Once it reached the shores of Japan, smallpox did not disappear but emerged in waves

that were sometimes manageable and were at other times catastrophic. In 735, a second smallpox epidemic afflicted Japan, reducing the population by 30 percent and resulting in labor shortages and declines in agricultural production and tax revenue for the court.”

- By sixteen hundreds, it was one of the major causes of death worldwide.

An exception was Australia, where it was introduced at the end of the 18th century. Similar to the introduction to America before, it caused much suffering among the natives there as well.

#Fenner, F. et al. (1988): Smallpox and its Eradication. History of International Public Health, No. 6

https://apps.who.int/iris/handle/10665/39485 

Quote: “As populations grew in India, China and Europe, smallpox became established in the cities and more populous areas as an endemic disease affecting mainly children, with periodic epidemics that killed up to 30% of those infected. Its impact steadily increased, and by the 16th century it was an important cause of morbidity and mortality in Europe, southwestern Asia, India and China. The occurrence of the disease in Europe was of special importance, for this served as the focus from which smallpox spread to other parts of the world, as an accompaniment of successive waves of European exploration and colonization. In 1507 smallpox was introduced into the Caribbean island of Hispaniola and in 1520 into the mainland of the Americas, in Mexico. It struck the native Amerindians with great severity and was an important factor in the conquest of the Aztecs and the Incas by the Spaniards. Settlement of the east coast of North America occurred about a century later and was also accompanied by devastating outbreaks of smallpox among the Amerindians, and subsequently among the nativeborn colonists. By the mid-18th century smallpox was a major endemic disease everywhere in the world except in Australia and in several small islands. It was introduced into Australia in 1789 and again in 1829 and caused devastation among the aborigines, but quickly died out on both occasions.”

- In late 18th century Europe, it killed 400,000 per year. Every third person who became blind did so because of this virus.

#Fenner, F. et al. (1988): Smallpox and its Eradication. History of International Public Health, No. 6

https://apps.who.int/iris/handle/10665/39485 

Quote: “In 1796, the year of Jenner’s discovery of the protective value of cowpox, smallpox killed over 3500 persons in an epidemic in London. Throughout Great Britain and Ireland, the disease claimed an estimated 35 000 more lives that year. In the German states, over 65 000 deaths were attributed to it. Europe (excluding Russia) was losing over 400 000 citizens each year through deaths from smallpox, which also was responsible for more than a third of all the cases of blindness in Europe.”

- Even in the 20th century, a hot second in history ago, it still killed at least 300 million people. 

#WHO (2019): WHO commemorates the 40th anniversary of smallpox eradication.

https://www.who.int/news/item/13-12-2019-who-commemorates-the-40th-anniversary-of-smallpox-eradication 

Quote: “Until it was wiped out, smallpox had plagued humanity for at least 3000 years, killing 300 million people in the 20th century alone. The last known endemic case of smallpox was reported and the outbreak promptly contained in Somalia in 1977.”

- In 2023, there are only two laboratories left where the living virus is officially stored for research: one in Koltsovo, Russia and one in Atlanta, USA.

Smallpox has been officially eradicated since 1980. To keep it that way, research continues. In addition, research on it also benefits the fight against other pathogens. However, studying small pox is extremely highly regulated and monitored by the WHO. There are only two laboratories that have been authorized by the WHO to conduct research on live virus stocks. 

#Centers for Disease Control and Prevention (2021): Research

https://www.cdc.gov/smallpox/research/index.html 

Quote: "Variola virus (the virus that causes smallpox) causes disease only in people. Other related viruses, such as monkeypox, can infect both animals and people. This unique characteristic of variola virus makes it an important virus to study and help us learn more about infectious diseases.

The goal of smallpox research is to address three areas that are essential for public health:

• Finding better antiviral drugs to treat smallpox disease.

• Making safer vaccines.

• Improving tests to detect variola virus.

All research using variola virus is overseen by the World Health Organization (WHO). The WHO Advisory Committee on Variola Virus Research reviews the research that is proposed each year. There are two WHO-designated sites where stocks of variola virus are stored and used for research: Centers for Disease Control and Prevention, Atlanta, Georgia, United States, and the Russian State Centre for Research on Virology and Biotechnology, Koltsovo, Novosibirsk Region, Russian Federation.”

#Damon, I. K. et al. (2014): Are We There Yet? The Smallpox Research Agenda Using Variola Virus. PLoS Pathogens, Vol. 10 (5)
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004108
Quote: “Smallpox disease was declared eradicated in 1980, and today is the only human disease to be eliminated by WHO. Shortly after WHO officially declared smallpox eradicated, a decision was made to ultimately destroy the remaining stocks of live variola virus, with interim use of the virus permitted only for defined WHO-approved research projects. Variola virus stocks were then voluntarily consolidated in the early 1980s to two WHO Collaborating Center laboratories, one in Russia and the other in the United States, which remain the only two WHO-approved sites for research with live variola virus.”

- Variola is highly infectious and catches a ride in small droplets that you breathed in. Immediately it begins to infect the cells that line your throat and starts killing them to cause chaos. Why? To trick your body into giving it a lift. 

#Byrd, D. et al. (2014): Primary human macrophages serve as vehicles for vaccinia virus replication and dissemination. Journal of virology, Vol. 88 (12)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054380/ 

Quote: “Variola virus is generally transmitted via inhalation, with subsequent infection and replication in epithelial cells of the oral and respiratory mucosa. The next stage of infection involves viral infiltration of lymphoid organs accompanied by strong viremia and skin lesions.”

- As immune cells begin cleaning up dead cells, eating viruses and killing infected cells , variole infects a crucial cell of your immune system: Your Dendritic cells, intelligence cells that gather information and leave the battlefield to get help. They enter your lymphatic system, a highway network that spans your entire body and connects hundreds of immune bases. In these bases your heavy defenses are activated and should be the last place an enemy should invade, but Variola wants to get here.

Research on closely related viruses such as monkeypox virus suggest that the virus infects dendritic cells, allowing it to enter the nodes of the lymphatic system. It may even be that the cells enter the "immune defense base" directly. But macrophages, the immune system's cleanup troops, could also serve as vehicles for the virus. 

#Lum, F.M. et al. (2022): Monkeypox: disease epidemiology, host immunity and clinical interventions. Nature Reviews Immunology, Vol. 22

https://www.nature.com/articles/s41577-022-00775-4#Abs1 

Quote: “a–h | Monkeypox virus (MPXV) might enter the body via the respiratory (panel a) or skin (panel b) route. In the respiratory tract, the virus can infect airway epithelial cells such as ciliated cells. Antigen-presenting cells such as dendritic cells and macrophages (MΦ) are also susceptible to MPXV infection. Upon inoculation in the skin, the virus infects keratinocytes and fibroblasts. Skin-resident immune cells such as Langerhans cells, dendritic cells and macrophages are also targeted. In both scenarios (panels a and b), it is hypothesized that infected antigen-presenting cells travel to nearby draining lymph nodes and facilitate its spread through the lymphatic system (panel c). Direct viral access to the lymphatics has been also speculated. A common feature of human monkeypox is swelling of lymph nodes (lymphadenopathy). The abnormal proliferation and retention of natural killer cells might be one of the causes. Following its spread through lymphoid tissue, MPXV may target other large organs such as the spleen and liver (panel d). Of note, MPXV antigens have been previously been detected in both hepatocytes and Kupffer cells in non-human primate (NHP) models. The viraemia wave could then allow the virus to further spread to distant organs such as the skin and gonads. Recently, MPXV was isolated from semen of infected individuals, highlighting the possibility of sexual transmission (panel e). The infection of skin and mucosae leads to the appearance of infective pustules (panel f) and ulcers (panel g). The latter release high quantities of virus into the saliva, which potentially leads to aerosolized transmission of MPXV (panel h)."

- For about 12 days, the virus quietly infects civilian and immune cells, jumping from cell to cell infecting more and more of them. At some point a critical threshold is reached and variola starts its attack for real. Millions of viruses use the lymphatic highway to spill into your blood and organs, infecting your whole body. Suddenly variola is everywhere. 

Some of the quotes below are based on the basic work "Smallpox and its Eradication" by Fenner, F. et al. (1988). A work that covers all aspects of smallpox in great detail. However, for simplicity, we have chosen to use shorter, more summary quotes. You can also find Fenner's work further below. 

#Bray, M. & Buller, M. (2004): Looking Back at Smallpox. Confronting Biological Weapons, Vol. 38

https://pubmed.ncbi.nlm.nih.gov/14999635/ 

Quote: “Explanations of the sequence of events between the inhalation of virus-containing saliva droplets and the development of a rash have traditionally been based on studies of mousepox [5]. Inhalation of virus presumably initiated foci of mucosal infection in the upper airway but did not cause symptoms or demonstrable lesions. The mousepox model suggests that replication at the point of entry was followed by infection of mononuclear phagocytic cells in regional lymph nodes, possibly with further spread through the bloodstream to similar cells in the liver, spleen, and other tissues. The incubation period ended when the release of inflammatory mediators from infected cells caused fever and other symptoms, and the spread of virus— either within infected monocytes or as free virions—to capillaries in the skin and mucous membranes initiated the rash [5]. 

#Moore, Z. S. et al. (2006): Smallpox. Lancet, Vol. 367 (9508)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68143-9.pdf  

Quote: “Most of the information about smallpox pathogenesis is extrapolated from animal models with non-variola orthopoxviruses.1,35 Epidemiological data and animal studies have shown that the respiratory tract is the usual portal of entry for variola. Skin, conjunctival, and transplacental infection occur in rare instances.1 This initial infection of the respiratory-tract mucosa produces no symptoms or identifiable lesions. After replicating in the respiratory epithelium, the virus is taken up by macrophages, probably after a transient primary viraemia, and enters the reticuloendothelial system.1 Asymptomatic replication continues in the reticuloendothelial system and is followed by a massive secondary viraemia, which causes the onset of symptoms.1

#Fenner, F. et al. (1988): Smallpox and its Eradication. History of International Public Health, No. 6

https://apps.who.int/iris/handle/10665/39485 

- But Variola is able to deactivate interferons, which stuns the anti virus side of your defense system.

#de Marco, F. et al.: (2010): The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, Vol. 24 (5)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857867/

Quote: “The innate immune response is the first line of immune defense. One of its main effectors are interferons (IFNs), a family of multifunctional cytokines that are secreted from cells and inhibit virus replication via their direct antiviral and indirect immunoregulatory activities (8).

(...)

The central role of IFNs in antiviral defense is reinforced by the fact that most viruses interfere with IFN signaling pathways at different levels (8, 13). Poxviruses express intracellular proteins that target this pathway, such as the eIF-2 α homologue K3 (14) and the double-stranded RNA-binding protein E3 (15). An IFN evasion strategy particular to poxviruses is the expression of secreted IFN decoy receptors, including the IFNα/β-binding protein (IFNα/βBP) (16,17,18,19) and IFNγ receptor (20, 21), which bind IFNs with high affinity and prevent their interaction with cellular receptors. The IFNα/βBP, encoded by the VACV strain Western Reserve (WR) B18R gene, is an immunoglobulin (Ig) superfamily glycoprotein of sequence unrelated to type I IFN receptors (22, 23). It is secreted from infected cells and acts both in solution and when associated with the cell surface, preventing the establishment of an antiviral state in surrounding uninfected cells (17).”

- Other systems would usually help - like the complement system, a sort of mobile minefield that can destroy viruses but variola also manages to shut this down too. 

One way the virus turns off the complement system is that it mimics the natural inhibitors in humans that control (or inhibit) the use of complement. 

#Liszewski, M. K. et al. (2008): Smallpox inhibitor of complement enzymes (SPICE): regulation of complement activation on cells and mechanism of its cellular attachment. Journal of immunology, Vol. 181 (6)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774262/  

Quote: “To establish infection, poxviruses must first subvert the innate immune response of the host. The complement system lies at the interface between innate and adaptive immunity, providing a first line of defense against pathogens. It consists of a family of soluble and cell-surface proteins that recognize pathogen-associated molecular patterns, altered-self ligands, and immune complexes (4, 5). One strategy used by poxviruses to control complement activation is the expression of inhibitors of complement enzymes (PICES) that mimic the host’s complement regulators. PICES from variola, monkeypox, and vaccinia are named SPICE, MOPICE and VCP, respectively (6–8).

(...) 

Functionally, the PICES also possess the same two functional activities as those of human regulators: Cofactor activity (CA) refers to the limited proteolytic degradation of C3b and C4b that requires a cofactor protein working in concert with the plasma serine protease factor I while Decay-accelerating activity (DAA) refers to the dissociation or decay of the catalytic serine protease domain from complement-activating enzyme complexes or convertases. Utilizing these inhibitory mechanisms, previous studies have established that SPICE inactivates human complement more efficiently (100–1000-fold) than either VCP or MOPICE (6, 7, 12, 13).”

- All this death activates an immune cell that you really don’t need right now but that is attracted by death: The Neutrophil. Normally a great killer of invaders great and small, it is not very effective against smallpox. And even worse, Neutrophils fight by vomiting deadly chemicals, which kills even more of your cells.

There is evidence that viruses affect the function of neutrophils in different ways. The following review provides an initial overview of this. For example, there are indications that the life span is shortened or that viruses promote the “programmed suicide” of neutrophils (apoptosis). It also seems that the production or transport of neutrophils seems to be disturbed in certain viral diseases. 

#Ma, Y. et al. (2021): Role of neutrophils in acute viral infection. Immunity, inflammation and disease, Vol. 9 (4)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589350/ 

Quote: “In certain viral infections, such as severe fever with thrombocytopenia syndrome virus (SFTSV), the number of neutrophils in circulation is decreased for some reason.77 For example, when neutrophils migrate to the infected tissues and undergo NETosis or apoptosis, the development, differentiation, maturation, and bone marrow mobilization of neutrophils might be affected by viruses, which might negatively affect the neutrophil homeostasis.

(...)
On the contrary, other studies have suggested that viral infection can promote the apoptosis of neutrophils. For example, IAV accelerates the apoptosis of human neutrophils.75 The HIV and Simian immunodeficiency virus (SIV) also induce neutrophil apoptosis, which may increase the sensitivity of the body to bacterial infection due to the viral infection, and the degree of neutrophil apoptosis is positively correlated with the severity of the disease.81, 82

(...)

Studies have confirmed that neutrophils cannot effectively remove bacteria after a viral infection which is mainly because neutrophil chemotaxis, phagocytosis, killing, and release of antimicrobial peptides are inhibited after viral infections; thus, resulting in reduced resistance and increased host susceptibility to fungi and bacteria.84”

#Iba, T. et al. (2014): Neutrophil extracellular traps, damage-associated molecular patterns, and cell death during sepsis. Acute medicine & surgery, Vol. 1(1)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997206/#ams210-bib-0017 

Quote: “In contrast to the well understood cell death types apoptosis and necrosis (oncosis), a unique type of cell death known as “NETosis”, which involves the release of neutrophil extracellular traps (NETs),9 has become well publicized. NETosis plays an important role in the removal of pathogens, but when cellular components that have antimicrobial effects, such as histones, myeloperoxidase, and elastase, are dumped into the circulation, they are also harmful to the host cells. (...)

Neutrophil extracellular traps, released by neutrophils, were first described by Brinkmann et al. in 2004.9 Neutrophils have an important role in the first line of defense against invading microorganisms. Phagocytosis is well known as the process by which neutrophils remove pathogens. Aside from this, a further mechanism named NETosis has become accepted. This is the process whereby NETs are expelled extracellularly and microorganisms are removed through contact with these NETs, which is a network of chromatins (DNA) attached to bactericidal nucleic proteins such as histones, myeloperoxidase, and elastase (Figs. 1, ​,22).10 (...) The process of NETosis is a powerful means of disposing of pathogens; however, the damage to host cells is also significant, in particular on the vascular endothelium and on pneumocytes.17 Granular proteins such as myeloperoxidase and elastase, and nucleic substances such as histones and nucleosomes are thought to be some of the harmful factors in NETs.

There does not appear to be any organ specificity in the pathogenesis of NETs, but there have been many reports focusing on the lungs, where neutrophils are physiologically highly distributed. In an LPS-induced acute lung injury model, it was reported that the formation of NETs within the alveoli and bronchoalveolar lavage fluid correlates with the finding of acute lung injury.18 However, based on the total number of neutrophils, evidence suggests that NETosis occurs in only a low proportion of cells, estimated at 10–30%.19 ”

#Lodge, K. M. et al. (2020): The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host. International Journal of Molecular Sciences, Vol. 21 (4)

https://www.mdpi.com/1422-0067/21/4/1183 

Quote: “In order to affect pathogen killing, these granules can fuse with the pathogen-containing phagosome, releasing their toxic contents into the vacuole to destroy the ingested micro-organisms. Neutrophil granules can also fuse with the plasma membrane, secreting their arsenal of proteins extracellularly (degranulation); this may be in response to pathogens that cannot be internalised, or due to an overwhelming extracellular inflammatory milieu [3,4]. In addition, granule proteins can be released extracellularly in association with neutrophil extracellular traps (NETs) [5]. Although the primary function of granule exocytosis is host defence, the release of cytotoxic granules into the extracellular environment also has the potential to cause damage to nearby host tissue.”

- On top of that, they order inflammation, fluids streaming from your blood vessels into your tissue. All over your body, as first millions, then billions of your cells die, you get a rash that only gets worse and worse. Pus and cellular junk fills it up as your body swells up with hundreds of lesions, all over your skin and inside, even on your organs, all filled with billions of variola viruses.

The rash is the typical symptom of the disease. It occurs a few days after the incubation phase and is initiated by the first feelings of illness. 

#Breman, J. G. & Henderson, D. A. (2002): Diagnosis and Management of Smallpox. The New England Journal of Medicine. Vol. 346 (17)

https://www.nejm.org/doi/pdf/10.1056/NEJMra020025?articleTools=true

Quote: “The incubation period for smallpox is 7 to 17 days (mean, 10 to 12). The prodromal phase, which lasts for two or three days, is characterized by severe headache, backache, and fever, all beginning abruptly.17 The temperature often rises to more than 40°C and then subsides over a period of two to three days. Enanthema over the tongue, mouth, and oropharynx precedes the rash by a day. The rash begins as small, reddish macules, which become papules with a diameter of 2 to 3 mm over a period of one or two days; after an additional one or two days, the papules become vesicles with a diameter of 2 to 5 mm. The lesions occur first on the face and extremities but gradually cover the body. Pustules that are 4 to 6 mm in diameter develop about four to seven days after the onset of the rash and remain for five to eight days, followed by umbilication and crusting. There may be a second, less pronounced temperature spike five to eight days after the onset of the rash, especially if the patient has a secondary bacterial infection. The crusts begin separating by the second week of the eruption. Smallpox lesions have a peripheral or centrifugal distribution and are generally all at the same stage of development.”

Put simply, the thin blood vessels in the skin swell first. Then the cells lining these vessels swell. Later the uppermost living skin cells follow, they literally dissolve, first the cell nucleus, then the membrane and finally they unite to form a vesicle, a small bubble. 

#Institute of Medicine (1999): Assessment of Future Scientific Needs for Live Variola Virus. 3 Clinical Features of Smallpox. 

https://www.ncbi.nlm.nih.gov/books/NBK230904/ 

Quote: “The primary event that triggers the production of focal lesions in orthopoxvirus infections is the localization of virus particles in the small dermal blood vessels. Subsequently, adjacent epidermal cells are infected, and skin lesions develop. The earliest change is dilation of the capillaries in the papillary layer of the dermis, followed by swelling of the endothelial cells in the walls of these vessels and subsequently perivascular cuffing with lymphocytes, plasma cells, and macrophages. Following these early changes, the cells of the Malpighian layer become swollen and vacuolated. The cells continue to increase in size, and the nucleus usually disappears or is lysed. The cell membrane then ruptures, and the vacuoles coalesce to produce the early vesicle. Because this coalescence occurs quickly, a true papule is rarely seen, and the lesions appear vesicular almost from the beginning. Except on the palms and soles, umbilication is a common feature of skin lesions in smallpox. It is due mainly to swelling of the cells around the vesicle and proliferation of the basal cells surrounding the lesion, so that the periphery of the vesicle is raised above its center.”

#Bray, M. & Buller, M. (2004): Looking Back at Smallpox. Confronting Biological Weapons, Vol. 38

https://pubmed.ncbi.nlm.nih.gov/14999635/ 

Quote: “After reaching the skin, the virus spread cell-to-cell through its mid- and basal layers, causing expanding zones of necrosis that formed vesicles (figure 3). In the nonkeratinized squamous epithelium of the oropharynx, the same process produced ulcerated lesions. Recent studies of other orthopoxvirus infections have indicated that the release of proinflammatory mediators from infected cells caused dilatation and increased permeability of local blood vessels and the infiltration of neutrophils, macrophages, and lymphocytes, producing pustules with surrounding erythema and edema, and that cell-mediated immune responses were required for lesion resolution [3, 8–11].”

#Moore, Z. S. et al. (2006): Smallpox. Lancet, Vol. 367 (9508)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68143-9.pdf  

Quote: “The first focal lesions develop in the oropharynx shortly before the onset of the rash, and high concentrations of virus are released in the respiratory secretions (figure 1). Respiratory viral shedding—and therefore infectivity—is highest at the beginning of the rash.1,15 Skin lesions form as macrophages migrate into and infect the epidermis, causing necrosis and oedema. Vesicles form and subsequently become pustular with the influx of polymorphonuclear cells. Virus can be found in these lesions and in the bone marrow, spleen, liver, kidneys, and other organs.1,38”

- Now the critical phase begins. As you fight for survival, you burn up in a high fever, thousands of battlegrounds drain your blood of fluid that streams into your tissue and organs. Blood clotting appears all over your body while floods of toxins from dead cells build up and can cause organs to fail. Your lungs fill up with fluid, making it harder and harder to breathe.

The exact causes of death that result from infection with Smallpox appear to be complex and are not yet fully understood. How severe the disease is and whether, when and from what exactly you die also depends on the form of the disease and the individual immune response. In general, it seems to be a combination, among other reasons, of blood poisoning (toxemia or sepsis), blood clotting disorders (coagulopathy) and multiple organ failure. 

#Bray, M. & Buller, M. (2004): Looking Back at Smallpox. Confronting Biological Weapons, Vol. 38

https://pubmed.ncbi.nlm.nih.gov/14999635/ 

Quote: “The clinical manifestations of most forms of smallpox can be explained by 2 concepts. First, disease severity was determined by the ability of host responses to limit viral replication during the incubation period, as reflected in the level of the secondary viremia; these responses could be strengthened and accelerated by postexposure vaccination. Second, once viral dissemination had occurred, many features of severe illness, including hypotension and coagulopathy, were the result of host inflammatory responses. In severe cases, the release of cytokines, chemokines, and other mediators into the bloodstream caused vascular dysfunction, coagulopathy, and multiorgan failure, resembling septic shock [5, 18, 22–26]. Differences in host responses thus produced a spectrum of disease, ranging from mild illness with few or no lesions in persons with partial immunity, to rapidly fatal hemorrhagic disease when failure to control replication led to high viremia, coagulopathy, and intractable shock.”

#Moore, Z. S. et al. (2006): Smallpox. Lancet, Vol. 367 (9508)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68143-9.pdf  

Quote: “The first focal lesions develop in the oropharynx shortly before the onset of the rash, and high concentrations of virus are released in the respiratory secretions (figure 1). Respiratory viral shedding—and therefore infectivity—is highest at the beginning of the rash.1,15 Skin lesions form as macrophages migrate into and infect the epidermis, causing necrosis and oedema. Vesicles form and subsequently become pustular with the influx of polymorphonuclear cells. Virus can be found in these lesions and in the bone marrow, spleen, liver, kidneys, and other organs.1,38 Smallpox deaths were generally ascribed to toxaemia, characterised by coagulopathy, hypotension, and multiorgan failure.15,38,39 The exact causes of death are not well understood, but inflammatory mediators40 and direct viral cytopathic effects38 could have a role.”

#Martin, D. B. (2002): The cause of death in smallpox: an examination of the pathology record. Military medicine, Vol. 167 (7)

https://pubmed.ncbi.nlm.nih.gov/12125845/

- About a third of people who contract smallpox don’t survive. And if you survive, you are very likely branded by scars and may even lose your eyesight or hearing. 

Here (and in the rest of the script) we mainly address the most common type (Variola major as virus type and “ordinary” smallpox as the clinical type of it), which accounts for the majority of the disease (90%). 

#Moore, Z. S. et al. (2006): Smallpox. Lancet, Vol. 367 (9508)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68143-9.pdf  

Quote: “Variola major had a case-fatality rate of about 30%, and variola minor a case-fatality rate of less than 1%.1 Variola major had clinical types that differed in prognosis, transmissibility, and differential diagnosis.1,15,47 The most common type (nearly 90%) was ordinary smallpox, which was characterised by raised pustular lesions.47 The mortality rate for ordinary smallpox varied from 10% in patients with discrete lesions to about 60% in patients with confluent lesions.47 Flat and haemorrhagic types were rarer and more rapidly lethal and lacked the typical pustular rash. Flat smallpox occurred in 7% of unvaccinated cases47 and had soft, flat, confluent or semiconfluent lesions. Haemorrhagic smallpox occurred in about 2% of unvaccinated cases and had widespread haemorrhages into skin and mucous membranes with a very high case-fatality rate (93–100%).47”

#Fenner, F. et al. (1988): Smallpox and its Eradication. History of International Public Health, No. 6

https://apps.who.int/iris/handle/10665/39485 

- Unfortunately 2-3% of all patients still died because they got the smallpox or suffered other diseases as a result of treatment.

#Riedel, S. (2005): Edward Jenner and the History of Smallpox

and Vaccination. Baylor University Medical Center Proceedings, Vol. 18 (1)

https://www.tandfonline.com/doi/pdf/10.1080/08998280.2005.11928028 

Quote: “In Europe, where the medical profession was relatively organized, the new methods of variolation became known quickly among physicians. Since there was also a demand for protection against smallpox, physicians soon began the variolation procedure on a massive scale. Although 2% to 3% of variolated persons died from the disease, became the source of another epidemic, or suffered from diseases (e.g., tuberculosis and syphilis) transmitted by the procedure itself, variolation rapidly gained popularity among both aristocratic and common people in Europe. The casefatality rate associated with variolation was 10 times lower than that associated with naturally occurring smallpox”

- The innovation was simple – instead of using the real virus to train the immune system, use a related virus, cowpox, that was only mild but also gave you immunity.

#Murphy, K. & Weaver, C. (2017): Janeway's immunobiology. 9th edition

https://inmunologos.files.wordpress.com/2020/08/janeways-immunobiology-9th-ed_booksmedicos.org_.pdf 

Quote: “The beginning of immunology as a science is usually attributed to Edward Jenner for his work in the late 18th century (Fig. 1.1). The notion of immunity— that surviving a disease confers greater protection against it later—was known since ancient Greece. Variolation—the inhalation or transfer into superficial skin wounds of material from smallpox pustules—had been practiced since at least the 1400s in the Middle East and China as a form of protection against that disease and was known to Jenner. Jenner had observed that the relatively mild disease of cowpox, or vaccinia, seemed to confer protection against the often fatal disease of smallpox, and in 1796, he demonstrated that inoculation with cowpox protected the recipient against smallpox. His scientific proof relied on the deliberate exposure of the inoculated individual to infectious smallpox material two months after inoculation. This scientific test was his original contribution. Jenner called the procedure vaccination. This term is still used to describe the inoculation of healthy individuals with weakened or attenuated strains of disease-causing agents in order to provide protection from disease. Although Jenner’s bold experiment was successful, it took almost two centuries for smallpox vaccination to become universal.”

– In 1966 the World Health Organization decided that humanity had to come together in a final, major effort. A global "smallpox news network," based on residents in the hotspots, was spanned – tackling local outbreaks of the virus. Cases were encircled, vaccines given, preventing further spread.

As early as the 1950s, there were global efforts to combat smallpox. However, it was not enough, so in 1966 it was decided to intensify the programs, which began in 1967. 

#Fenner, F. et al. (1988): Smallpox and its Eradication. History of International Public Health, No. 6

https://apps.who.int/iris/handle/10665/39485 

Quote: “Between 1959 and 1966, lack of interest on the part of WHO in smallpox eradication and the perceived lack of progress in the programme must be attributed, in large measure, to WHO's preoccupation, as well as that of many Member States, with malaria eradication. Over this period, the persistent advocacy of smallpox eradication by the USSR in the World Health Assembly served to sustain interest in such a on the part of Member States, even though the Organization assigned few resources to it. Renewed interest the programme was stimulated by the commitment of the USA in 1965 to support regional smallpox eradication programmes in a contiguous group of countries in western and central Africa, a decision which was less a product of rational policy analysis than a reluctantly accepted byproduct of a regional measles vaccination campaign. The decision by the World Health Assembly in 1966 to intensify the effort to eradicate smallpox was made with grave reservations. Eradication, as a concept in disease control, had largely been discredited, and the Director-General himself, believing smallpox eradication to be an unachievable objective, viewed the programme as one which could serve only further to undermine the Organization's credibility.”

- The last naturally occurring infection was in 1977, and in 1980, just shy of 200 years since the first vaccine was used, Smallpox was declared eradicated. 

While the case from Somalia is considered the last natural case (and the patient survived), there was an outbreak from a laboratory in the UK in 1978. A photographer who worked there, became infected and died, is considered the last person to die from smallpox. 

#Deria, A et al. (1980): The world's last endemic case of smallpox: surveillance and containment measures. Bulletin of the World Health Organization, Vol. 58 (2)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395794/pdf/bullwho00425-0112.pdf 

Quote: “On 31 October 1977, the world's last known case of endemic smallpox was discovered in Merca, Somalia. The source of infection was quickly identified; 19 days previously, the male patient had been in contact with two other cases for not more than 15 minutes, but the surveillance activities surrounding these cases did not identify him as a contact. The patient was isolated and containment and surveillance activities and a vaccination campaign were rapidly instituted; 161 contacts were identified, 41 of whom had not been vaccinated within the last three years. The patient recovered and fortunately no other cases occurred.”

#Behbehani, A. B. (1983): The Smallpox Story: Life and Death of an Old Disease. Microbiological Reviews, Vol. 47 (4)

https://journals.asm.org/doi/pdf/10.1128/mr.47.4.455-509.1983 

Quote: “Janet Parker, a 40-year-old medical photographer in the Department of Anatomy worked in a darkroom located on the floor above a research laboratory where a comparative study of smallpox and whitepox viruses was being performed by 48-year-old virologist Dr. Henry S. Bedson (the son of the late Sir Samuel P. Bedson) of the Department of Medical Microbiology. 

(...)

On 27 August, the Abid strain of variola major virus was isolated from Mrs. Parker, and she died of smallpox (renal failure and bacteremia) on 11 September 1978.”

#Centers for Disease Control and Prevention (2021): The Spread and Eradication of Smallpox

https://www.cdc.gov/smallpox/history/history.html 

Quote: “Janet Parker was the last person to die of smallpox. In 1978, Parker was a medical photographer at England’s Birmingham University Medical School. She worked one floor above the Medical Microbiology Department where staff and students conducted smallpox research. She became ill on August 11 and developed a rash on August 15 but was not diagnosed with smallpox until 9 days later. She died on September 11, 1978. Her mother, who was providing care for her, developed smallpox on September 7, despite having been vaccinated two weeks earlier. An investigation suggested that Janet Parker had been infected either via an airborne route through the medical school building’s duct system or by direct contact while visiting the microbiology corridor.”

#WHO (1980): The global eradication of smallpox : final report of the Global Commission for the Certification of Smallpox Eradication, Geneva, December 1979

https://apps.who.int/iris/handle/10665/39253