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Heritable immunity and smallpox vaccination

Heritable immunity and smallpox vaccination


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As I understand it, lack of heritable immunity caused smallpox to wipe out certain communities of native Americans. If vaccination conveys heritable immunity to a population, shouldn't this make vaccines unnecessary after the first generation?


No.

The heritable immunity you are describing is due to selective pressures on populations where individuals with certain alleles have a survival advantage in the face of particular pathogens. If a population is exposed to deadly diseases like smallpox and there are some individuals in the population who are more resistant, those individuals are more likely to survive to reproduce so future generations will have more resistant individuals. You could think of this as immune system "hardware."

Vaccines trigger the immune system's ability to recognize past infective agents and therefore mount a rapid specific antibody response when exposed to that pathogen again. You could think of this as immune system "software." This software that is aquired during the lifetime is not present in the genome of germ line cells and is not transmitted to offspring.


Epidemics of the Past: Smallpox

Smallpox is one of greatest scourges in human history. This disease, which starts with a distinctive rash that progresses to pus-filled blisters and can result in disfiguration, blindness, and death, first appeared in agricultural settlements in northeastern Africa around 10,000 B.C.E. Egyptian merchants spread it from there to India.

The earliest evidence of smallpox skin lesions has been found on the faces of mummies from the eighteenth and twentieth Egyptian dynasties, and in the well-preserved mummy of Pharaoh Ramses V, who died in 1157 B.C.E. The first recorded smallpox epidemic occurred in 1350 B.C.E., during the Egyptian-Hittite War.

In 430 B.C.E., the second year of the Peloponnesian War, smallpox hit Athens and killed more than 30,000 people, reducing the population by 20 percent. Thucydides, an Athenian aristocrat, provided a terrifying account of the epidemic, describing the dead lying unburied, the temples full of corpses, and the violation of funeral rituals. Thucydides himself had the disease, but he survived and went on to write his historic account of the Peloponnesian War. In this work, he noted that those who survived the disease were later immune to it. He wrote, the sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehensions. For no one was ever attacked a second time, or not with a fatal result. These Athenians had become immune to the plague.

Athens was the only Greek city hit by the epidemic, but Rome and several Egyptian cities were affected. Smallpox then traveled along the trade routes from Carthage.

Potent Fact

Rhazes was a Persian doctor who worked in the main hospital of Baghdad. He ranks with Hippocrates and Galen as one of the founders of clinical medicine and is widely regarded as the greatest physician of Islam and the Medieval Ages. His writings on medicine influenced physicians well through the Renaissance and into the seventeenth century. And his work on smallpox and measles was one of the first scientific treatments of infectious diseases.

In 910, Rhazes (Abu Bakr Muhammad Bin Zakariya Ar-Razi, 864-930 C.E.) provided the first medical description of smallpox, documenting that the illness was transmitted from person to person. His explanation of why survivors of smallpox do not develop the disease a second time is the first theory of acquired immunity.

The patterns of disease transmission often paralleled peoples' travel and migration routes. Disease in Asia and Africa spread to Europe during the Middle Ages. Smallpox was brought to the Americas with the arrival of Spanish colonists in the fifteenth and sixteenth centuries, and it is widely acknowledged that smallpox infection killed more Aztec and Inca people than the Spanish Conquistadors, helping to destroy those empires.

Smallpox continued to ravage Europe, Asia, and Africa for centuries. In Europe, near the end of the eighteenth century, the disease accounted for nearly 400,000 deaths each year, including five kings. Of those surviving, one-third were blinded. The worldwide death toll was staggering and continued well into the twentieth century, where mortality has been estimated at 300 to 500 million. This number vastly exceeds the combined total of deaths in all world wars.

This person, photographed in Bangladesh, has smallpox lesions on skin of his midsection. (Courtesy CDC/James Hicks)

In the United States, more than 100,000 cases of smallpox were recorded in 1921. Strong declines occurred after that because of the widespread use of preventive vaccines. By 1939, fewer than 50 Americans per year died of smallpox.

Variolation: The Earliest Smallpox Vaccines

The idea of intentionally inoculating healthy people to protect them against smallpox dates back to China in the sixth century. Chinese physicians ground dried scabs from smallpox victims along with musk and applied the mixture to the noses of healthy people.

In India, healthy people protected themselves by sleeping next to smallpox victims or wearing infected peoples' shirts. In Africa and the Near East, matter taken from the smallpox pustulesraised lesions on the skin the contain pusof mild cases was inoculated through a scratch in an arm or vein. The goal was to cause a mild infection of smallpox and stimulate an immune response that would give the person immunity from the natural infection. This process was called variolation. Unfortunately, the amount of virus used would vary and some would contract smallpox from the inoculation and die. Nonetheless, this preventive approach became popular in China and South East Asia. Knowledge of the treatment spread to India, where European traders first saw it.

Disease Diction

Variolation is the inoculation of matter taken from the smallpox pustules of mild cases through a scratch in an arm or vein. Used by people in the past, the goal was to cause a mild infection of smallpox and stimulate an immune response that would give the person immunity from the natural infection.

An Englishwoman, Lady Mary Wortly Montagu, was responsible for introducing variolation to England. In 1717, while accompanying her husband, the British ambassador to Turkey, in Constantinople she came across the ancient Turk practice of inoculating children with smallpox matter.

Initially horrified at this seemingly savage practice, she learned that a child was protected from the ravages of smallpox through this process. She then had her six-year-old son inoculated while in Turkey, and in 1721, in the presence of Royal Society Members, she had her daughter inoculated. This led to adoption of variolation, mainly by the aristocracy in England and Central Europe. Before long, variolation to prevent smallpox was widespread. During America's War of Independence, George Washington had his army treated in this way. Napoleon did the same with his army before they invaded Egypt.

Edward Jenner: Vaccine Pioneer

During his training as a physician, Edward Jenner learned from nearby milkmaids that after they contracted cowpox they never got smallpox. Cowpox is a far milder disease than smallpox, yet the diseases are quite similar. In 1796, Jenner decided to test the theory that infectious material from a person with a milder similar disease could protect against a more severe disease.

He put some pus from a cowpox pustule on small cuts made on the arm of James Phipps, an eight-year-old boy. Eight days later, Phipps developed cowpox blisters on the scratches. Eight weeks later, Jenner exposed the child to smallpox. The boy had no reaction at all, not even a mild case of smallpox. The cowpox had made him immune to smallpox. Jenner developed the first vaccine, using cow serum containing the cowpox virus. Jenner tried this new treatment on eight more children, including his own son, with the same positive result.

Potent Fact

The word vaccination is derived from the Latin word for cow, vacca.

After a period of slow acceptance, Jenner's vaccine approach was widely adopted. Vaccination using Jenner's method was key in decreasing the number of smallpox deaths, and it paved the way for global eradication of the disease.

The World Takes Action

In 1959, The World Health Assembly decided to organize mass immunization campaigns against smallpox. The World Health Organization (WHO) announced the global smallpox eradication program in 1967. At that time there were still an estimated 10 to 15 million cases of smallpox a year resulting in two million deaths, millions disfigured, and another 100,000 blinded. Ten years later, after dispersal of 465 million doses of vaccine in 27 countries, the last reported naturally occurring case appeared in Somalia. On October 22, 1977, a 23-year-old male, Ali Maow Maalin, developed smallpox and survived.

Potent Fact

Amazingly, eradication of smallpox, one of the world's most deadly scourges, cost approximately $100 million. Even in today's dollars, this was a bargain.

The global campaign against smallpox ended in 1979 just two years after Maalin's case. Two additional cases of smallpox occurred in Birmingham, England, in 1978, after the virus escaped from a laboratory. There has not been a case reported in more than 25 years.

Variola: The Cause of Smallpox

Smallpox is caused by a virus and can result in one of two forms of the disease, called variola major and variola minor. Variola major kills 20 to 40 percent of unvaccinated people who get it and can lead to blindness. Variola minor, a far less lethal form of the disease, results in death only on rare occasions.

Disease Diction

A sixth-century Swiss bishop named the cause of smallpox variola, from the Latin varius, meaning pimple or spot. In the tenth century, the term poc or pocca was used to describe the scars left behind, which resembled pouches. When syphilis became epidemic in the fifteenth century, the term smallpox was adapted to distinguish between the diseases.

The disease is transmitted primarily by direct contact with droplets from saliva and other body fluids that travel through the air, such as through a sneeze. It may also be spread if an uninfected person handles clothing worn by someone with the disease.

Signs and Symptoms of Smallpox

The incubation period for smallpox is 8 to 17 days, with people usually getting sick 10 to 12 days after infection. Symptoms start with malaise, fever, rigors, vomiting, headache, and backache. The trademark smallpox rash appears after two to four days, first on the face and arms and later on the legs, quickly progressing to red spots, called papules and eventually to large blisters, called pustular vesicles, which are more abundant on the arms and face. Although full-blown smallpox is unique and easy to identify, earlier stages of the rash could be mistaken for chickenpox. When fatal, death occurs within the first or second week of the illness.

There is no effective treatment for smallpox. There are antiviral drugs that might work, but they have not been tested due to restrictions on smallpox research.

Smallpox Vaccine

The smallpox vaccine currently licensed in the United States is made with a virus called vaccinia, which is related to smallpox. It does not contain the actual smallpox (variola) virus. Vaccinia causes the body to produce antibodies that protect against smallpox and several other related viruses.

When a person is vaccinated, the usual response is the development of a red spot atthe vaccination site two to five days after the shot. The red spot becomes pustular, and reaches its maximum size in 8 to 10 days. The pustule dries and forms a scab, which separates 14 to 21 days after vaccination, leaving a scar. Sometimes there is also swelling and tenderness of lymph nodes. A fever is common after vaccine. Fatal complications are rare, with less than one death per million vaccinations.

The CDC is the only source of smallpox vaccine and will provide it to protect laboratory and other health-care personnel at risk for exposure. A reformulated vaccine is now under development.

Smallpox: An Agent of Bioterrorism?

Potent Fact

There were approximately 15 million doses of 20-year-old vaccine available following the September 11, 2001, terror attacks. However, once bioterrorism in the form of anthrax became a real threat, the United States government urgently ordered another 150 million doses of smallpox vaccine to be made available within short order as a precaution.

Several years ago, Ken Alibek, a former deputy director of the Soviet Union's civilian bioweapons program, indicated that the former Soviet government had developed a program to produce smallpox virus in large quantities and adapt it for use in bombs and intercontinental ballistic missiles.

If a smallpox vaccine exists, smallpox bioterrorism shouldn't be a problem, right? Wrong. The vaccine program in the United States was so successful that routine vaccination was discontinued in 1972. Nearly 50 percent of the population has never been vaccinated and, of the vaccinated individuals, the vaccine is of questionable value since it requires boosting every 10 years. For the first time in nearly a century, the United States population is at significant risk for smallpox.

By international agreement, the main stores of smallpox virus from the Cold War superpowers are kept securely at the CDC's headquarters in Atlanta and at a similar institute in Moscow.


Heritable immunity and smallpox vaccination - Biology

Vaccines, from the Latin word vacca which means cow.

While many people know that the first-ever vaccine was for smallpox, a lot of people don’t know about the role cows had in developing that vaccine.

A recent episode of NPR’s Planet Money podcast dug a little deeper into this history.

Some experts say smallpox goes as far back as the 6th century. The devastating smallpox disease was very contagious, had a 30% death rate, and left visible scars on survivors.

The concept of immunity existed but had not been deeply explored.

At some point, in the middle ages, experimenters in China had the idea to “manufacture immunity.” They would scrape off a bit of the unfortunate scabs that smallpox left on its living victims, they would turn it into a powder and then blow it up people’s noses.

It worked—kind of. Severe infections dropped. “I mean, it doesn't work perfectly. But the death rate amongst those who have been treated is much lower,” said Josefa Steinhauer, associate professor of biology at Yeshiva University on the Planet Money episode. We don’t have exact numbers of how effective this new method was. But it was helpful enough to traverse the globe.

As this method of smallpox immunity traveled the world, it was amended and adapted, but it was still very messy and largely unsanitary.

By the late 1700’s some milkmaids in England noticed that their cows had developed something that looked similar to smallpox. But it wasn’t hurting or killing the cows. And the milkmaids themselves were getting similar bumps on their hands and were coincidentally not getting smallpox.

Milkmaids were thought to be immune to smallpox and, before long, it became known that if you too wanted to be immune, all you had to do was get exposed to “cowpox.”

It wasn’t so simple of course. There were some negative side-effects since these humans were the first to experiment with transmitting a disease directly from its animal host to humans.

English physician Edward Jenner decided to formalize the exposure process—and he found the milkmaids to be the perfect intermediary since they worked so closely with cows anyways.

Jenner standardized the practice of spreading cowpox from human to human and the rest is history!

We talk a lot about animals infecting humans, but this is one time in history where an animal spread a cure (technically)!

Once the concept of a vaccine was discovered, it took about 200 years to completely eradicate a devastating disease that had been around for over 1,500 years.

And today, biotech companies like SAB Biotherapeutics are using cows to develop a vaccine for COVID-19 by using the animals to produce human antibodies. This origin story about something we can no longer imagine life without speaks to the power and potential of effective One Health policies.

There is such an interconnectedness between animals and humans that we will really struggle to solve human issues without considering all the ways our relationships with animals affect us.


Innate programming of protective immunity

Most vaccines are believed to confer protection through neutralizing antibodies 48 . Antibodies are thought to be the correlate of protection against blood-borne viruses such as hepatitis 49 and yellow fever 50,51 toxin-secreting bacteria, such as diphtheria 52 and tetanus 53 viruses that infect via mucosal routes, such as influenza 54,55 and rotaviruses 56 rabies virus 57 , which infects neuronal axons and pneumococcal and meningococcal bacteria, which are leading causes of pneumonia and meningitis 58,59 . The antigen-specific antibody responses to such vaccines are measured by assays such as enzyme-linked immunosorbent assays (which measure the titer of binding antibody), as well as assays that measure functional antibody activity, including the inhibition and neutralization of hemagglutination and opsonophagocytosic capacity. Understanding the precise mechanisms by which antibody molecules confer protection against pathogens and learning how to induce such protective responses with adjuvants that target the innate immune system represent key areas of research.

Despite the importance of antibodies, emerging evidence also points to a key role for T cells. For example, persistent varicella-specific T cells induced by vaccination against varicella virus are useful correlates of protection from infection and reactivation (shingles) in children and the elderly 60,61 . Furthermore, antibody titers after vaccination against influenza are unreliable for predicting risk of influenza in the elderly 62 . Instead, an inverse correlation between the magnitude of influenza-specific T cell responses and risk of influenza acquisition has been demonstrated 62 . In addition, patients with high frequencies of cytomegalovirus-specific T cells are less likely to have reactivation of cytomegalovirus when they are given immunosuppressive drugs to prevent rejection after transplantation 63,64 . Finally, humans with particular mutations in the genes encoding IL-17 or its receptor have chronic mucocutaneous immunity to Candida albicans 65 , which suggests a role for TH17 cells in immunity to C. albicans. In fact, many pandemics that need effective vaccines, such as infection with HIV, or tuberculosis and malaria, are believed to require strong T cell responses for protection 66,67,68 .

The goal of any T cell–based vaccine is to induce antigen-specific memory T cells that persist long after the antigen has been eliminated and confer protection against subsequent infection. Vaccine-driven T cell differentiation can result in phenotypically and functionally diverse populations of cells. For example, naive CD4 + T cells can differentiate into any of several subsets of helper T cells (TH1, TH2, TH17, TH21, TFH, TH22 or TH9) with distinct effector functions that mediate protection against different pathogens (Table 1). Thus, intracellular pathogens require TH1-driven CTLs, whereas infections with helminths and fungi are best controlled by TH2 and TH17 responses, respectively. Naive CD8 + T cells can differentiate into effector cells that circulate or reside in tissues and provide immediate protection against infection at the portals of entry, including mucosal tissues. In contrast, central memory T cells reside in the T cell–rich areas of lymphoid organs and provide a pool of precursor cells that undergo rapid clonal expansion in response to antigenic challenge and differentiate into effector cells.


Introduction

Organisms have a wide array of adaptations for preventing attacks of parasites and diseases. The vertebrate defense systems, including those of humans, are complex and multilayered, with defenses unique to vertebrates. These unique vertebrate defenses interact with other defense systems inherited from ancestral lineages, and include complex and specific pathogen recognition and memory mechanisms. Research continues to unravel the complexities and vulnerabilities of the immune system.

Despite a poor understanding of the workings of the body in the early 18th century in Europe, the practice of inoculation as a method to prevent the often-deadly effects of smallpox was introduced from the courts of the Ottoman Empire. The method involved causing limited infection with the smallpox virus by introducing the pus of an affected individual to a scratch in an uninfected person. The resulting infection was milder than if it had been caught naturally and mortality rates were shown to be about two percent rather than 30 percent from natural infections. Moreover, the inoculation gave the individual immunity to the disease. It was from these early experiences with inoculation that the methods of vaccination were developed, in which a weakened or relatively harmless (killed) derivative of a pathogen is introduced into the individual. The vaccination induces immunity to the disease with few of the risks of being infected. A modern understanding of the causes of the infectious disease and the mechanisms of the immune system began in the late 19th century and continues to grow today.

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    How do vaccines work?

    What is a vaccine? A vaccine is a biological preparation that improves immunity to a particular disease. It contains an agent resembling a disease-inducing microorganism– a bacterium, virus or toxin – that activates the body’s immune system. White blood cells – APCs, B cells, and T-cells – recognize, destroy and “remember” this version of the pathogen. That way, the immune system can quickly recognize and destroy this harmful microorganism later on. A vaccine is essentially a pathogen-imposter.

    Today, there are five main types of vaccines. Live, attenuated vaccines fight viruses and contain a weakened version of the living virus (e.g., measles-mumps-rubella and varicella vaccine). Inactivated vaccines also fight viruses and contain the killed virus (e.g., polio vaccines). Toxoid vaccines prevent diseases caused by bacteria that produce toxins in the body and contain weakened toxins (e.g., diphtheria and tetanus vaccine). Subunit vaccines include only the essential antigens of the virus or bacteria (e.g. whooping cough vaccine). Conjugate vaccines fight a different type of bacteria which have antigens with an outer coating of sugar-like substances (polysaccharides) that “hide” the antigen from the child’s immature immune system the vaccine connects (conjugates) the polysaccharides to antigens, so the immune system can react.

    A vaccine is essentially a pathogen-imposter.

    Once the altered pathogen is introduced into the bloodstream, it is captured by antigen-presenting cell (APC), which float around looking for invaders. When an APC detects the vaccine antigen, it ingests it, breaks it apart, and displays a piece of the antigen on its surface. Then, it travels to areas where immune cells cluster (e.g. lymph nodes) and where so-called naïve T cells specific to the antigen recognize it as foreign and become activated. These T helper cells alert other nearby cells. Naïve B cells recognize the antigens carried by the APCs as well and also become activated.

    Some naïve B cells mature into plasma B cells after activation by vaccine antigens and reception of signals from activated helper T cells. They produce antibodies which are “y” shaped proteins that are released at high levels every second. Each antibody tightly attaches to a specific target antigen (like a lock and a key), which can prevent the antigen from entering a cell or mark the antigen for destruction. If the vaccine contains weakened viruses, they enter the cells which are then killed by Killer T cells. What follows is the development of memory (B, T helper and killer T) cells that memorize the vaccine antigen and recognize the real pathogen in the future.

    This means that the body’s response will be stronger and faster than if it had never encountered the pathogen before. This is called a secondary response to the pathogen. Furthermore, secondary responses will result in the production of more antibodies to fight the pathogen and more memory cells to identify it promptly. Thus, vaccinations “program” the immune system to remember a specific disease-inducing microorganism by letting it “practice” with a weakened, killed or inactivated version of the pathogen.

    Vaccines can prevent outbreaks of contagious diseases through herd immunity (or community immunity). This means that a sufficient portion of the population must be immune to an infectious disease (by vaccination and/or prior illness), so that the disease is less likely to spread from one person to another. As the number of vaccinated people increases, the protective effect of herd immunity increases as well. While the herd immunity threshold may start with 40% of the population vaccinated for some diseases, most diseases require vaccination rates as high as 80% – 95% to prevent outbreaks. Moreover, herd immunity protects those who cannot be vaccinated or for whom the vaccination was not successful, such as people with weak immune systems, chronic illnesses or allergies.

    Evidence suggests that the Chinese used smallpox inoculation as early as 1000 BC

    Vaccinations are essentially prophylactic, although there has been an effort in recent years to develop therapeutic vaccinations for infectious diseases like AIDS, tuberculosis, cancer, and various autoimmune diseases. There are also potential vaccinations in development for myasthenia gravis, lupus and diabetes, as well as for cognitive diseases such as Alzheimer’s disease, prion diseases and Huntington’s disease.

    Usually, vaccinations are administered in the form of an injection into the skin or a liquid taken orally. However, some vaccinations may also be processed by inhalation through mouth/nose or application onto the skin. The vaccines risks are very low. Most vaccine reactions are usually minor and temporary (i.e. sore arm, fatigue or an elevated temperature). Very serious side effects like severe allergic reactions are extremely rare and are carefully monitored and investigated. The vaccine benefits definitely outweigh the vaccine dangers. In fact, it is far more likely to be seriously harmed by a vaccine-preventable disease than by the vaccine itself.

    In recent years, the anti-vaccination movement has been claiming that there is a link between vaccinations and autism. The reason for these claims is a 1998 study, which suggested that the measles-mumps-rubella (MMR) vaccine might cause autism. Its publication started a panic among parents that led to dropping vaccination rates, resulting in subsequent outbreaks of vaccine-preventable diseases. However, this study turned out to be seriously flawed, and the paper was even retracted by the journal that published it. There is absolutely no evidence of a link between vaccines and autism or autistic disorders.


    Developing the first smallpox vaccine

    We’re jumping back into the past as we look at the history of vaccines. Smallpox was a disease that killed up to 300 million people in the 20th century. Humans eradicated it, meaning it’s not present on the planet outside specialist labs, in 1977. To find out more about how we got to a smallpox free world, Ruby Osborn took a field trip into a herd of cows with Mary Brazleton from the Department of History and Philosophy of Science in Cambridge, to learn how Edward Jenner came up with the first vaccine.

    Ruby - We're currently stood in a field with some cows and the reason that we've come to visit some cows is because they were very important in the development of one of the first vaccines.

    Mary - That takes us back to the year 1796 and the Gloucestershire physician, Edward Jenner he was actually a country surgeon. People who worked with cows on a regular basis often didn't get smallpox they would often get cowpox, which is a virus that we now know is part of the pox family of viruses, closely related to smallpox, that affects cows and that can be transmitted to people when they handle cows quite closely.

    Jenner conducted a very particular experiment which is to take an eight year old boy by the name of Phipps and introduce cowpox to him through a process that eventually came to be known as vaccination. That is coming from the Latin word for cowlike - vacca. It's a relatively violent process in so far as you're actually taking a lancet and you're making cuts in the arm or in another part of the body and then introducing material from cowpox pustules into the body.

    Ruby - And that's the first introduction of cowpox into the boy was done on 14 May, and that's the same date that we are recording this next to these cows.

    Mary - And then Jenner introduced smallpox to the boy, exposed him to smallpox, and he didn't get sick. Slowly over time, it is recognised that using cowpox virus is something that can produce resistance to smallpox. It is also worth noting that there was this older practice of variolation and was actually quite an old practice that had been traditionally done in places like the Middle East and China. Variolation or inoculation is different from vaccination because when you're protecting somebody against a disease by introducing them to a small amount of the disease itself. Part of the thought was that if you're getting exposed to these things early in life, that's going to give you protection. So the concept of, and some of the practices, of vaccination that Jenner was using weren't necessarily so totally new and strange.

    Ruby - How quickly did the smallpox vaccination catch on? Were people quite accepting of it or was there any resistance?

    Mary - Well, there were reports of resistance really that developed quite quickly. Clerical opposition, religious opposition to the notion that by inducing resistance to a disease you could somehow be subverting divine will. There are concerns about the bastial nature of the process in which you are taking material from an animal originally and introducing it often to the body's of infants. New questions arise of individual rights and the ways in which individual freedoms might be restricted by larger social mandates to vaccinate for the public good. And some concerns are simply that it will hurt, that it will cause some kind of local reaction or inflammation.

    Ruby - The smallpox vaccine came about really just because of an observation, how did we transition from that to actively trying to develop vaccines to specific diseases?

    Mary - That generalisation, a moving from a vaccine for one particular disease - smallpox, to the concept of a vaccine as an intervention that will induce immunity against a particular illness, that is something that we see very much coming out of a much later period particularly the late 19th century development of things like bacteriology and the germ theory, and so for that we have to think about really another generation of researchers. People like Louis Pasteur, Robert Cook, and the ways in which they really do several things in rapid succession. They identify a particular microbiological agents of disease and, moreover, they seek to develop interventions to develop resistance. So when Pasteur develops a means of making livestock resistant to things like anthrax in the 1880s, he calls that intervention of vaccination in honour of Jenner and so that's really when we see vaccination emerge as a general term for a variety of immunological interventions. Even though many of what we think of now as the fundamental parts of immunology, the fundamental theories and understandings, those come even later. The smallpox virus isn't really even isolated and identified clearly as such until the 1930s with the advent of electron microscopy because viruses are so small. So all of the work that's done on smallpox vaccination before that is down to empirical work in many ways, which is fascinating, I think.


    How was global decline & eradication achieved?

    Variolation

    Discovery of variolation

    Variolation (sometimes also inoculation), refers to the deliberate transmission of viral matter.

    Before the year 1000, Indians and the Chinese had already observed that contraction of smallpox protected children against any future outbreaks of the disease. As a consequence they developed a procedure that involved the nasal inhalation of dried smallpox scabs by three-year-olds. 21

    Another commonly practiced technique (whose geographic and temporal origin are unknown) encompassed the injection of the liquid found inside the pustules of a smallpox patient underneath the skin of a healthy person. This would usually result in a milder infection of smallpox after which the person was immune against the disease.਋oth practices became known as variolation (inoculation) techniques.

    The disadvantage of variolation, however, was that during the course of the mild infection the person became a carrier of the disease and could infect other people. Additionally, it was difficult to control the severeness of the infection which sometimes developed into a full-blown smallpox case that could lead to the person’s death. 22

    This meant that the practice usually reduced the severeness of an infection and the likelihood of deaths but that it would never lead to eliminating the virus. If anything, it helped to spread the virus in a population even further and thereby encouraged its survival.

    Institutionalized variolation

    A British ambassador’s wife, Lady Mary Wortley Montague (1689-1762) was the force that pushed for government-mandated variolation in England. She herself had suffered a smallpox infection and lost her younger brother to the disease at the age of 26. She first learned about variolation when she arrived in Istanbul in 1717, where variolation was commonly practiced. She later had the embassy inoculate her two children.

    News spread among the royal family and after following trials Maitland successfully inoculated the two daughters of the Princess of Wales in 1722. Thereafter, variolation became a common practice in Great Britain and became known in other European countries. It became an even more established practice when the French King Louis XV died of smallpox in May of 1776 and his successor and grandson Louis XVI was inoculated with the variola virus one month later.

    Vaccine against smallpox

    At the end of the 18th century British surgeon and physician Edward Jenner (1749-1823) pioneered the first ever vaccination against an infectious disease. He himself had been inoculated with smallpox at the age of 8 and later as a surgeon, variolation was part of his work. 23 He observed that people who had suffered from cowpox would subsequently have a very mild, if at all visible reaction to the smallpox variolation. At the time unknowingly, he had discovered that the cowpox and variola viruses were members of the same orthopoxvirus family.

    He hypothesized that variolation using the cowpox virus would protect children against smallpox as well. Since cowpox infections were much milder and never fatal, this would eliminate the problem of variolated children being carriers of smallpox and sometimes dying of the virus developing into a full-blown infection. On top of protection against the symptoms, it could reduce the stock of humans that the variola virus needed for survival and brought elimination and eventually eradication of smallpox into the realm of possibility.

    In May 1796, Jenner inoculated a boy with cowpox, and then a few months later with the smallpox virus. When the boy did not develop any smallpox symptoms in response to being variolated, his hypothesis of the cowpox offering protection from smallpox was confirmed motivating his further research trials.

    Initially, Jenner faced major barriers to spreading the word about his discovery. When he submitted a paper outlining his findings to the journal Philosophical Transactions edited by the Royal Society, it was rejected. They even advised him not to pursue his ideas any further, pointing to the detrimental impact on his career and reputation. Undeterred, he published his work with an increased number of trials at his own expense two years later (in 1798). He also went on to convince colleagues and supply them with vaccines in other British cities of his new procedure that became known as vaccination (derived from the Latin word for cow, vacca).

    By 1802, the British Parliament did acknowledge his important contribution and awarded him ꌰ,000. Meanwhile, vaccination had spread to most of Europe and New England. 24

    His 1798 publication Inquiry into the Variolae vaccinae known as the Cow Pox had been translated into German, French, Spanish, Dutch, Italian, and Latin within three years. US President Thomas Jefferson figured importantly in the widespread application of vaccination throughout the United States and in 1806, he thanked Edward Jenner in a letter for his discovery and famously predicted 𠇏uture generations will know by history only that the loathsome smallpox existed and by you has been extirpated.” 25

    The dramatic decline in smallpox fatalities in response to Jenner’s vaccine can be traced in the chart, which shows the number of deaths due to smallpox as a share of all deaths in London from 1629 to 1902.򠯯ore the introduction of a smallpox vaccine in 1796, on average 7.6% (1-in-13) of all deaths were caused by smallpox. Following introduction of the vaccine, we see a clear decline in smallpox deaths.

    Click to open interactive version

    Smallpox Eradication Program

    It was only with the establishment of the World Health Organization (WHO) in the aftermath of World War II that international quality standards for the production of smallpox vaccines were introduced. This shifted the fight against smallpox from a national to international agenda. It was also the first time that global data collection on the prevalence of smallpox was undertaken.

    By 1959, the World Health Assembly, the governing body of the World Health Organization (WHO) had passed a resolution to eradicate smallpox globally. It was not until 1966, however, that the WHO provided the ‘Intensified Smallpox Eradication Program’ with funding to increase efforts for smallpox eradication.

    By 1966, the number of infections of smallpox had already substantially been reduced by national governments’ efforts. Nonetheless, skepticism about the feasibility of eradication prevailed and the WHO lacked experience in administering projects that required both technical and material support, as well as coordination across countries. Furthermore, the funding provided to the Intensified Smallpox Eradication Programme was insufficient to meet global needs, resulting mostly in vaccine shortages. 26

    Further still, continued globalization and growth of international air travel resulted in the continual re-introduction of the disease into countries that had previously managed to eliminate smallpox.

    Overcoming the last mile problem: ring vaccination

    Smallpox’s eradication was greatly spurred by making use of the fact that smallpox transmission occurs via air droplets. Initially, the WHO had pursued a strategy of mass vaccination which attempted to vaccinate as many people as possible, hoping that herd immunity (explained in our vaccine entry) would protect the whole population. Soon, however, vaccination efforts were targeted locally around smallpox cases as smallpox was transmitted by sick patients’ air droplets. This is known as the ring vaccination principle.

    People who had been in direct contact with a smallpox patient over the last two weeks were quarantined and vaccinated. The downside of such an approach was that the virus could spread easily if it was re-introduced from overseas. This was the case in Bangladesh, for example, which had previously eliminated smallpox until 1972 when it was brought back from across its border with India. 27

    Despite the risk of re-introductions, ring vaccination greatly reduced the cost of the eradication campaign. The number of administered vaccines dropped and smallpox was increasingly brought under control. Regional elimination came within reach. 28

    One of the last strongholds of the variola virus was India. While 57.7 percent of global reported smallpox cases were reported in India in 1973, this increased to 86.1 percent in 1974. 29 One major push in vaccination campaigns, however, successfully drove down the number of infections to zero in India in 1976.


    The Viruses

    Influenza Biology

    Influenza viruses are spherical orfilamentous, enveloped, negative-sense, single-stranded RNA viruses of family Orthomyxoviridae of approximately 100 nm to 300 nm in diameter that include types A, B, C, and D [1, 2]. Influenza A and B viruses cause mild to severe illness during seasonal epidemics, and influenza A viruses cause intermittent pandemics. Influenza C viruses cause mild infections but not epidemics, and influenza D virus may cause subclinical infection [3, 4]. Influenza A viruses are classified into subtypes based on the combination of the surface glycoproteins hemagglutinin and neuraminidase, with 18 H and 11 N known subtypes [5𠄷]. Specific influenza strains are named according to the World Health Organization (WHO) convention designating influenza virus type, host of origin (if not human), geographic origin, strain number, year of isolation, and subtype (for influenza A viruses) (e.g., Influenza A/California/7/2009[H1N1]) [8].

    Influenza A viruses have eight genome segments that code for structural and nonstructural proteins (Fig. 5.1a ) [9]. Surface glycoproteins include hemagglutinin (HA), required for viral binding and entry, and neuraminidase (NA), required for viral budding. Matrix (M1) protein underlies the host-derived lipid envelope providing structure, and M2 protein is an ion channel integrated into the envelope. Eight single-stranded RNA viral genome segments are coated with nucleoprotein (N) and bound by the polymerase complex, composed of basic polymerase 1 (PB1), PB2, and acidic polymerase (PA). Nuclear export protein (NEP) mediates trafficking of viral RNA segments and nonstructural protein (NS1) inhibits host antiviral responses. The virus can also expressaccessory proteins PB1-F2 and PA-x.

    Schematic of viral structures and key epidemiological features. (a) Influenza virus is spherical or filamentous in shape. Hemagglutinin (HA) and neuraminidase (NA) proteins are integrated into the host-derived lipid envelope and project from the viral surface. Matrix (M1) protein underlies the envelope, and M2 forms an ion channel within the envelope. Eight single-stranded RNA genome segments are coated with nucleoprotein (NP) and bound by the polymerase complex. Nuclear export protein (NEP) mediates export of viral RNA. Influenza has estimated reproductive number (R0) between 1 and 2. Standard, droplet, and contract precautions are recommended to prevent nosocomial transmission. (b) virus is pleomorphic in shape. Hemagglutinin (H) and fusion (F) proteins are integrated into the host-derived lipid envelope, and matrix (M) protein underlies the envelope. The single-stranded RNA genome is coated with nucleoprotein (N) and bound by the polymerase complex. Measles has an estimate R0 between 9 and 18. Standard, airborne, and contact precautions are recommended to prevent nosocomial transmission. (c) are spherical in shape. Spike (S), membrane (M), and envelope (E) proteins are integrated into the host-derived lipid envelope. The single-stranded RNA genome is coated with nucleoprotein (N). SARS and MERS have an estimated R0 of ρ𠄲. Standard, airborne, and contact precautions are recommended to prevent nosocomial transmission. (d) are oval to brick shaped. The biconcave viral core contains double-stranded DNA and several proteins organized as a nucleosome and surrounded by a core membrane. Two proteinaceous lateral bodies flank the core, and a single lipid membrane surrounds the cell-associated form of the mature virion (MV). A second host-derived lipid envelope covers the extracellular virion (EV). Smallpox has an estimated R0 between 4 and 6. Standard, airborne, and contact precautions are recommended to prevent nosocomial transmission of smallpox

    Measles (Rubeola Virus) Biology

    Measles virus is a pleomorphic, enveloped, negative-sense, single-stranded RNA virus of family of approximately 100 nm to 300 nm in diameter [2]. Measles virus causes mild to severe illness during seasonal outbreaks in endemic areas and intermittent outbreaks in nonendemic area [10]. Measles virus codes for six structural and two nonstructural proteins (Fig. 5.1b ) [11]. Hemagglutinin (H) and fusion (F) glycoproteins project from the viral surface and facilitateviral binding to cellular receptors and fusion with the host cell membrane, respectively. Matrix (M) protein underlies the envelope providing structure. The inner nucleocapsid is composed of RNA coated by nucleoprotein (N), bound by the polymerase complex which includes the large (L) polymerase protein, and phosphoprotein (P), a polymerase cofactor. The remaining nonstructuralproteins include C and V.

    Coronavirus Biology

    Coronaviruses are spherical, enveloped, positive-sense, single-stranded RNA viruses of family Coronaviridae of approximately 120 nm in diameter [12]. Coronaviruses are the causative agents of an estimated 30% of upper and lower respiratory tract infections in humans resulting in rhinitis, pharyngitis, sinusitis, bronchiolitis, and pneumonia [13]. While coronaviruses are often associated with mild disease (e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1), severe acute respiratory syndrome coronavirus (SARS-CoV), a lineage B betacoronavirus, and Middle East respiratory syndrome coronavirus (MERS-CoV), a lineage C betacoronavirus, are associated with severe and potentially fatal respiratory infection [14, 15].

    SARS- and MERS-CoV transcribe 12 and 9 subgenomic RNAs, respectively, which encode for the spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins (Fig. 5.1c ) [14]. S, E, and M are all integrated into the host-derived lipid envelope, and S facilitates host cell attachment to angiotensin-converting enzyme (ACE)-2 receptors for SARS-CoV and dipeptidyl peptidase (DPP)-4 receptors for MERS-CoV [16, 17]. The N protein encapsidates the viral genome to form the helical nucleocapsid. The viral replicase-transcriptase complex is made up of 16 nonstructural proteins (nsp1�) including a unique proofreading exoribonuclease that reduces the accumulation of genomemutations [12].

    Smallpox (Variola Virus) Biology

    Poxviruses areoval-to-brick-shaped double-stranded DNA viruses of family Poxviridae that range in size from 200 to 400 nm [2]. Viruses within genus that cause human disease include cowpox virus (CPXV), monkeypox virus (MPXV), vaccinia virus (VACV), and variola virus (VARV), the etiologic agent of smallpox [18].

    Poxviruses contain a biconcave viral core where the DNA genome, DNA-dependent RNA polymerase, and enzymes necessary for particle uncoating reside (Fig. 5.1d ) [19]. This nucleosome is surrounded by a core membrane that is flanked by two proteinaceous lateral bodies. A singlelipid membrane surrounds the cell-associated form of the mature virion (MV). A second host-derived lipid envelope covers the extracellular virion (EV) [2, 19]. Poxvirus genomes are comprised of a large, linear double-stranded viral DNA genome that encodes

    200 genes. Highly conserved structural genes are predominantly found in the middle of the genome, whereas variable virulence factor genes that function in immune evasion, virulence,and viral pathogenesis are found at the termini of the genome [20].


    Smallpox, permafrost, lab accidents and biowarfare - how high is the threat?

    Two great leaders of the battle against smallpox have passed away in the last 6 years - Frank Fenner, the chairman of the Global Commission for the Certification of Smallpox Eradication, in 2010, and in 2016, DA Henderson, who was director of the WHO Smallpox Eradication campaign, among other important leadership roles. They were both recognised as pivotal in the battle against smallpox, and shared the Japan prize for their achievements in smallpox eradication* in 1988. The passing of DA Henderson signals the end of an era, and the loss of a large body of lived experience and knowledge in a world where most doctors have never seen a case of smallpox, and the staff of public health agencies have no experience managing smallpox control. This has renewed discussion about smallpox and whether it still poses a threat to the world. There is speculation about smallpox re-emerging as corpses buried in Siberia thaw due to melting of the permfrost. Analogies have been drawn to an anthrax outbreak thought to have arisen from thawing reindeer corpses, however, the illness caused by anthrax is due to spores rather than to the bacteria itself, and the spores can remain dormant for long periods of time in the environment. Smallpox on the other hand is a virus, and w hilst smallpox has been documented to survive for some time (up to years) in scabs on materials such as blankets if protected from ultraviolet light, it does not otherwise survive for long periods in the environment. The risk of viable smallpox virus emerging from the permafrost is low. Smallpox is a virus, and viruses require living cells in which to survive and replicate, so it is unlikely that living smallpox would re-emerge from dead human cells as corpses from the last century thaw. There is a greater threat of smallpox returning due to two other factors:

    Retained stocks of live smallpox in laboratories after the eradication in 1977. This could be in the two known repositories, in the US or Russia, or in other locations which are unknown. Lab accidents could lead to smallpox. In fact, the last known case of small pox was due to accidental infection in a lab. Insider threat may also enable deliberate release of smallpox, and any clandestine labs harbouring smallpox would be purposely developing it as a weapon.

    Synthetic biology – since 2002, scientists have been able to create viruses in a lab. The genetic sequence for smallpox is known, and quantum advances in science in the last 20 years mean that smallpox could be engineered in a lab. Existing stocks of smallpox in known or unknown locations could also be engineered and modified for increased infectiousness and pathogenicity. This kind of research was allegedly conducted in the Soviet Bioweapons program last century, and is now more accessible with new technology such as CRISPR-cas.

    I have previously shown that when multifactorial risk-analysis is used that smallpox scores highly on the risk scale among category A bioterrorism agents. So, if there is a real threat of smallpox, what can be done about it? This can be separated into response to an epidemic of smallpox, and to mitigation and prevention of such an epidemic occurring. Most countries prepare to respond to a smallpox epidemic by stockpiling vaccines and drugs (such as the antiviral cidofivir) and having a disease control plan for epidemics. The question is about prioritisation of vaccine use in an epidemic, given there will likely not be stocks for the whole population. First responders such as health workers, paramedics, defence forces and emergency services should have the highest priority for vaccination. There are newer smallpox vaccines available, but the evidence around relative safety and efficacy is unclear. The greatest concern In 2016 is that the world's population has much lower immunity to smallpox than in 1977 when the disease was eradicated. At that time, levels of background immunity due to vaccination or natural infection in the population was higher. Anyone born after 1980 or so would have no immunity at all, and vaccine-induced immunity in older people would have waned. In addition, due to advances in medicine, there are many more people living with immunosuppression today than there were in 1977. As such, the impact of a smallpox epidemic today is likely to be very severe, and we may see much higher mortality than was seen in 1977.

    Prevention is much more difficult. Infectious diseases do not recognise geographic boundaries, so experiments on dangerous pathogens done in one country can affect people in other countries. Global governance, legislation and systems to regulate synthetic biology, gain of function research, as well as coordinated approaches to laboratory security, are critical and yet patchy or inadequate. In 2016 the Biological Weapons Convention is being revised, and it is widely regarded as an outdated and unenforceable legislation . It assumes major players in biowarfare will be nation states, when there are clearly other players who could use biological weapons. There is an opportunity to consider the quantum changes in science and technology which have occurred and gaps in the BWC revisions (due in December 2016) related to this. Without such recognition, the BWC risks becoming obsolete.

    Finally, we live in a world where organised crime, cybercrime and terrorism have coalesced, and trade in weapons, including biological weapons, occurs often on the dark web, under the radar of traditional crime surveillance methods. Trade in biological weapons may not be obvious, and may include selling of genetic sequences for viruses or laboratory reagents and materials for the conduct of genetic engineering research. Until the scope of such trade is defined, we cannot quantify the trade in biologicals on the dark web. It is widely recognised in the cybercrime space that technology has far outpaced our systems and legislation, and it is the same for biological weapons. These two areas are related because cybertechnology enables terrorism, including bioterrorism. The problem needs to be addressed from both angles – we need to be able to combat biosecurity risks on the dark web marketplaces where illegal transactions take place, and also in the realm of biological research. Our systems, legislation and capabilities have not kept pace with quantum changes in science, and this leaves us vulnerable in biosecurity.

    In summary, the concerns about the melting permafrost may not be the most pressing concern around smallpox. As long as there are live stocks of smallpox in the world, as well as the ability to engineer smallpox in a lab, there is a real threat of re-emergence, whether by accidental or deliberate release. Crime and terrorism, themselves converging, are greatly enabled by advances in both cyber and biological technologies, and our ability to mitigate threats in biosecurity require quantum changes in our systems, approaches and governance structures.

    Interested in more? Do our course, Bioterrorism and Health Intelligence this summer, November 28th 2016

    ISER produces Epiwatch, a rapid outbreak intelligence service and features the ISER Academy, dedicated to solving wicked problems in biosecurity by bringing together stakeholders from different responder sectors.