The Legacy of Smallpox: Immunization

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-16thC 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.

More On Shingles

Readers wanting to know more about some topics  pose very good questions. My original magazine column about immunization to prevent shingles (September 2011) generated enough reader mail to warrant another column sharing some of the answers.

Recognizing recurrent shingles episodes:

One reader had suffered through an eruption of ophthalmic shingles, which involves the nerve that carries sensation from the eye, including the cornea, from the skin around the eye, and also from the forehead. The reader wanted to know “What are the signs and symptoms for a re-occurrence of the zoster virus in the eye so I would know what to look for if I am getting an attack?”  As in other areas of the body, symptoms that come before the rash erupts  in the eye and the face are sensory  – tingling, burning, itching and pain. Warning sensations in ophthalmic shingles might also include irritating dryness and a sense something lodged in the eye. Our reader understood that taking an antiviral drug early in the course of an eruption might lessen the likelihood of scarring of the cornea, so paying attention to early symptoms has therapeutic consequences.   If an abnormal sensation persists for several hours without explanation or response to simple measures like rinsing the eye out, then the symptom is worth bringing to the attention of the doctor. That said, the use of antiviral drugs early in the course of a shingles outbreak does not prevent the eruption from progressing, but it may shorten the duration and lessen its intensity.  When the surface of the eye is involved, anything that can be done to prevent corneal scarring is of some value.

Drugs that make the virus awaken

The same reader also wanted to know what drugs might predispose her to another eruption, and how to avoid them. The drugs that put people at most risk for a herpes zoster outbreak are the ones that suppress the function of immune cells in the body. The most common offenders belong to the steroid class on anti-inflammatory drugs, and have names like prednisone, dexamethasone, decadron, and prednisolone.  They are used to treat conditions like multiple sclerosis and lupus and rheumatoid arthritis and when used for periods longer than a week, they begin to impair immune response.  Sometimes they are part of a chemotherapy regimen for cancer. Other chemotherapy drugs and radiation also impair immune cell function, so shingles eruptions are not surprising in patients undergoing cancer treatment.  Paradoxically, steroids are part of the treatment for shingles – but they are used for only a short time, to decrease inflammation.

Vaccine questions

Another reader wrote:” My husband never had Chicken Pox and yet he did have a severe case of shingles and he was in his 40’s when they occurred. At that time we were told the opposite of the article…we were told he got shingles because he had never had Chicken Pox.  This was over 20 years ago so perhaps research has changed that.  Does the fact he had shingles mean he cannot get the vaccine?” There are many people whose childhood chicken pox was so mild that they have no memory of the disease. Blood testing will show whether or not there is any trace of immunity to the virus in people who think they did not have the disease. An adult who contracts chicken pox for the first time has a rash that involves much more of his body than the shingles rash does.  He is also extremely sick, much more so than a child with the disease. So if an adult develops what is a typical shingles rash, it is considered proof that he has had chicken pox in the past.

You probably did have chicken pox

Age 40 is on the young side for shingles, but there are many idiosyncrasies in the immune system, with some people have worse immune “memory” for specific viruses than others do. Having had a shingles eruption does not prevent this reader’s husband from getting the vaccine, and given that it is now over 20 years since the last time the virus stimulated his immune system, immunization might be a very good idea.  Guidelines for vaccine administration also do not exclude people who think they did not have chicken pox as a child, even though, in theory, a vaccine made from a live, weakened virus could cause a full blown case of chicken pox in a chicken pox virgin (more on different vaccine constructions below).  It is estimated that 99% of people in the US have had chickenpox, whether or not they are aware of it.

Being refused the vaccine

Getting an immunization proved difficult for another reader. He went to his county health department seeking a shingles immunization, but he was turned down because he has non-Hodgkin’s lymphoma, a form of lymphatic system cancer. While his disease is in remission and his blood work indicates good immune cell function, there is a theoretical risk that the vaccine, which contains a live, weakened version of the virus, will reactivate the line of white cells that caused his lymphoma. Many people face this type of risk-balancing problem in choosing whether or not to get a vaccine, and each individual case requires weighing risks versus benefits. In some cases, for example someone with AIDS who has good white blood cell tests and is not sick, the patient’s doctor may advise getting the vaccine because the risk of the effect of a shingles outbreak is greater than the risk that the virus in the vaccine will cause trouble. In the case of people with history of cancers that arise directly from immune system cells, however, no one wants to take a chance of triggering cells to become cancerous by the introduction of a live virus in the form of a vaccine.  In addition, no one wants to  introduce an infection that the immune system cannot control.  These problems are the reason that researchers have pushed to develop a new vaccine, just becoming widely available in in 2017-18, which does not contain any live virus.

The old and the new vaccines

Lastly, several readers inquired about the frequency of the zoster vaccination.  Immunizing for shingles is relatively new, and recommendations may change, but right now, Zostavax, the old vaccine, is recommended for all people over age 60,  as a one time shot. Zostavax cuts the rate of shingles by 51% and the development of post-herpetic shingles pain by 65%.  The new vaccine, Shingrix, is recommended beginning at age fifty and in tests improves these prevention rates to 98% and 85% respectively. Shingrix requires two separate doses. The effectiveness of the vaccines does wane over time, and there is more experience with the old one. Currently there are not any guidelines about repeat administration, but there are no contraindications to getting the new vaccine for people who have already had the old one.

Where to get immunized

Immunizations are available at pharmacies, grocery stores, county health offices, and walk in clinics and all of these facilities have guidelines which will exclude some people.  Anyone excluded by general criteria should review the reason with a doctor who cares for the problem that caused the exclusion.

No more posts.