Imagine a virus spreading disease in your city. Imagine sending your children and other loved ones to a rural area to be injected with infected material taken from people ill with the virus. Imagine the injections making them sick, but not as sick as they might be from contracting the disease naturally. They will require a month for recovery, but, from that time, they will no longer have to fear the virus. You have now imagined exactly what happened at the start of the age of immunization. The time was the mid to late 1700s, the place was the colonies that would become the United States, and the epidemic was smallpox, a dangerous disfiguring illness. One of the families involved, in 1776, belonged to John Quincy Adams.

At the time, there was no FDA to regulate the treatment, known as variolation (from the Latin word variola meaning spotted).  People risked contracting severe cases of smallpox from the treatment, but they chose to go ahead because smallpox was a fearsome disease which, for centuries,  swept through both the Old and New Worlds in epidemic waves, appearing and disappearing, killing millions, scarring survivors, and changing history as the scourge laid armies low on one side or the other.

An idea with a long history

The idea that suffering a mild case of smallpox prevented a severe case arose independently in several different parts of the world, with the first written reports dating back to the mid-16^thC in China. Cotton Mather, a Boston preacher, learned of the practice of deliberate infection from his African slave Onesimus in 1721 and introduced the practice to the Americas. Infected material or scabs from smallpox pustules were inhaled or scratched into the skin and while the practice killed 2-3% of the patients, that toll was considerably less than the 30% mortality rate of the epidemic disease.

How the variola virus causes smallpox

Pustules are the distinguishing marks of the disease called smallpox. The variola virus, whose only host is the human, enters the body via the mucous membranes of the mouth and nose. The virus multiplies quietly inside cells, producing no symptoms for 10-14 days. Then the body reacts with high fever, headache, and malaise. Patients take to their beds and develop a rash – at first, red spots, but then blisters which fill with pus.  They spread from the mouth and nose, over the face, down the trunk and extremities. Coughing and sneezing spew infected material from pustules into the air, spreading the disease to caretakers. Deep skin lesions leave permanent pocked marks such as those scarring the faces of George Washington and Abraham Lincoln. Unlike many other viruses, variola is fairly hardy outside the body, which enabled its transmission from contaminated blankets given to native Americans by the British during the French and Indian war. The virus also traveled downwind from hospital ships on the Thames River in England in the 1890s.

The role of milkmaids in the history of immunization

The next chapter in the history of immunization occurred in Britain, where the fabled, beautiful skin of milkmaids was attributed to resistance to smallpox, conferred by prior infection with cowpox, a milder disease now known to be caused by the vaccinia (meaning cow) virus. In the late 1700s, Edward Jenner, a Gloucestershire physician, successfully prevented small pox by prior inoculations with the material from cowpox infections. The inoculations were called vaccinations, and Jenner became “the father of vaccination.”

Elimination of smallpox

The cowpox vaccine evolved over time into the standard vaccination procedure which eventually resulted in the elimination of the smallpox virus from the human population in the mid-1900s. The last natural case occurred in Somalia in 1977. Smallpox vaccinations, which had significant adverse effects in 1-2% of the population, were discontinued in the US in 1972 and the WHO declared smallpox eliminated from the world in 1980. Variola is the first and only virus to have been eliminated as a source of human illness, but other infectious diseases have been tamed in similar fashion and the hope is that new ways of creating vaccines will be even more effective.

How vaccines work

Smallpox vaccines were made from whole, live vaccinia viruses. Some vaccines for other diseases come from attenuated viruses (weakened viruses that transmit disease less effectively), or from killed viruses. Some vaccines are directed not at viruses, but at bacteria or at toxins like those produced by the diphtheria bacteria. All of them induce the immune system to create a memory of the specific organism or toxin, which will protect against future infection with the organism or the effects of a toxins like the ones produced by tetanus or diphtheria bacteria.

Because the immune reaction to infection is complicated and involves many types of immune cells as well as production of antibodies to the infecting organism, immunity to future infection is best induced and longest lasting after actual infection. Immunity after smallpox infection is lifelong, but lasts only 5-7 years after smallpox immunization. Other vaccines, especially those made from live organisms, are very effective and, some provide lifelong protection, especially with periodic booster doses. They have made infections like polio, measles, diphtheria, whooping cough and tetanus so rare that many doctors have never seen such illnesses.    

New technology

Like variolation, vaccines that rely on whole organisms can cause serious and unintended consequences. In the last two decades, genetic technology has enabled researchers to create vaccines from small parts of disease-causing organisms like COVID-19 or hepatitis viruses. Since sequencing genomes became automated and less expensive, the world of genetic virology and bacteriology has exploded. It is no longer necessary to rely on tedious and technically difficult culture methods to grow and identify microscopic and submicroscopic organisms. And it is possible to break down genetic information and use it to artificially produce components of these organisms or the proteins they produce, employing stock materials off laboratory shelves.

Using genetic material from viruses, researchers get living cells in laboratories to produce proteins specified by those genes and then create vaccines from the proteins. Or they inject the genetic material directly into people to get their cells to make the proteins. The immune system then recognizes these proteins as foreign and creates antibodies and memory cells against them. Theoretically, the induced immune memory prevents infection should the vaccinated person encounter the virus.  But much work remains. Some of the vaccines tried do not produce robust or long lasting immunity. Some have had paradoxical effects, with the immunized individual responding to actual infection with worse disease, as if a small amount of immunity actually enhanced the ability of the live virus to cause illness. The widespread deployment of the new COVID-19 vaccines – apparently effective in test groups over a relatively short testing period (safety studies in the past have run for years) will provide an enormous amount of information as to long-term safety and efficacy over years to come. This will be the largest and most public trial so far for the vaccine industry’s newest technologies. If the results are as good as the researchers who have developed them expect them to be, you can expect more and more vaccines to appear on the market.

 In the meantime, smallpox virus samples still exist in the US and in Russia. If these stocks had been eliminated, as once was planned, the smallpox virus would truly have disappeared from the world because, unlike most of the viruses that plague us, the small pox virus has no other animal hosts. And while there are long term plans to create new smallpox vaccines, it would be wise, in this uncertain world, to maintain the ability to rapidly understand the genetic makeup of the smallpox virus, as well as to rapidly implement old-fashioned smallpox immunization.