Smallpox vaccination: A personal perspective on an imperfect essential


A physician who practiced amid an outbreak of smallpox reviews the immunization procedure and complications.


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Smallpox vaccination:
A personal perspective on an imperfect essential

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Choose article section... An effective vaccine Complications of immunization— a pediatric experience Contraindications to immunization The way it was What to expect post-vaccination A legacy of pain Contraindications to smallpox vaccination in the absence of an exposure to smallpox

By David Annunziato, MD

A physician who practiced amid an outbreak of smallpox reviews the immunization procedure and complications, with an eye toward minimizing risks if vaccination of children again becomes a reality.

The threat of bioterrorism and the possible need for a large-scale smallpox vaccination initiative have brought back memories of related events in my life: I have seen smallpox firsthand, vaccinated patients against the disease, and witnessed the complications that can result from immunization. It seems to me (and to some experts) that smallpox is the ideal agent of bioterrorism. One could deposit a load of smallpox virus, perhaps genetically altered to be more devastating, and be thousands of miles away before the disease became manifest and was diagnosed.

The history of variolation goes back to time immemorial. As I reviewed the vaccination procedure and possible complications in both the literature and in my mind, I felt compelled to share this knowledge with others. Indeed, because routine immunization for the disease was discontinued worldwide in 1979, many younger physicians have never performed a smallpox vaccination or seen its complications.

I've seen four cases of smallpox in my 57 years as a physician. And I saw, and attended to, many cases of complications of the smallpox vaccine during my years as an attending physician at a contagious disease hospital. Two of the cases of disease that I observed were during the smallpox outbreak in New York City in 1947, when eight cases occurred. Physicians were called on at the time to carry out a massive vaccination program; most responded. Some 6.3 million people were vaccinated in about three and a half weeks. I'm confident that physicians today would respond the same way to a bioterrorist attack using smallpox.

An effective vaccine

The original immunizing material for variolation came from smallpox matter. Toward the end of the 18th century, Edward Jenner developed a vaccine that used cowpox virus.1,2 Later, in the 19th century, active vaccinia virus was used to inoculate against smallpox. The current vaccine, available only from the Centers for Disease Control and Prevention (CDC), is a live-virus preparation of infectious vaccinia.3,4 It does not contain smallpox (variola) virus. It can be stored in a lyophilized, freeze-dried state for a very long period. When reconstituted, it contains polymyxin B, neomycin, tetracycline, streptomycin, and glycerin.

Recent studies indicate that the vaccine is highly effective in producing immunity even when it is diluted.4–6 Vaccinia vaccine induces development of neutralizing antibodies, which are genus-specific and cross protective for other orthopoxviruses, including smallpox. These antibodies are detectable 10 days after primary vaccination. They protect as many as 97% of vaccinees against smallpox for five years.

Complications of immunization— a pediatric experience

Although we can prevent smallpox, vaccination is not always a benign procedure. As the nation initiates a smallpox vaccination program—even one that currently does not recommend routine vaccination of persons under 18 years of age—we must be acutely aware of the possible complications of vaccination and of their particular expression, incidence, and risks in children. And, we must make every attempt to prevent those risks that are preventable.

Untoward reactions are more common in children younger than 1 year. Before the 1940s, and in other countries after this time as well, many children were vaccinated very early, even in the newborn nursery. Even up until the 1970s in this country, some infants under the age of 1 were vaccinated, such as the children of immigrants arriving from other nations. (There is no age limit to vaccination, however, if a child has been exposed to smallpox.4)

About 70% of children who were vaccinated for the first time (primary vaccinees) experienced a fever,4 which developed most commonly about six to nine days after vaccination. This was expected and considered a normal response.

The following reactions were complications I and other physicians of the time encountered in patients, young and old. Particular reference is made to any pediatric observations.

Erythema (or roseola) vaccinatum is a morbiliform, occasionally urticarial, generalized eruption concentrated more heavily over the upper trunk, legs, and face (Figure 1). The rash appeared one week after vaccination and lasted three to four days. Vaccinees appeared lethargic and irritable and often had fever. In my experience, erythema vaccinatum was by far the most common complication of smallpox vaccination. It was believed to be an allergic reaction and was inevitably benign. Less commonly, erythema multiforme minor developed, and, rarely, the severe form, erythema multiforme major (Stevens-Johnson syndrome), was seen.



Autoinoculation can occur because vaccinia virus actively and freely sheds from the vaccination site from about four to 14 days following immunization (and continues to shed, to a lesser degree, until the scab falls off).4 Accidental inoculation of another part of the anatomy—such as the finger, nose and face, mouth, genitalia, eyelids, and even the eye itself—was common in children (Figure 2). Autoinoculation of the eye jeopardized vision. Autoinoculated sites underwent the same reaction as the primary vaccination site—a papule formed, followed by a vesicle, pustule, scab, and scar formation. Some authors consider autoinoculation the most common complication, although its exact incidence is unknown.



Generalized vaccinia, which occurred in approximately one of every 4,000 primary vaccinees, is a generalized vesicular or pustular eruption at a site other than the vaccination site caused by a vaccinia viremia (Figure 3). It developed six to nine days after inoculation and disappeared in about two weeks. These patients, considered contagious, were only minimally ill as a rule.



Vaccinia necrosum, or progressive vaccinia, is a severe complication. It is believed to have occurred in immunocompromised patients and, until Kempe's vaccinia immune globulin (VIG) became available in the 1960s, was often fatal.7 It began at the vaccination site with necrosis and gangrene (Figure 4); the erythema usually found around the postvaccination pustule did not develop. Frequently, a similar generalized eruption ensued. The lesions did not heal. Even with VIG, about half the patients succumbed.



Eczema vaccinatum is a usually severe complication seen in people with eczema or another open cutaneous disorder (in which the skin barrier is breached) who are vaccinated or come in contact with vaccinia virus from a vaccinee.4,8 In children who experienced this complication, multiple lesions, sometimes as severe as full-blown smallpox, would break out shortly after primary vaccination (Figure 5). Although the incidence of eczema vaccinatum was reportedly only one in 25,000 vaccinees, we had a case admitted to our contagion pavilion about every two months, it seemed. A few patients had only mild illness.



Postvaccinal encephalitis is a severe complication occurring most commonly in infants and adolescents. The usual symptoms of acute inflammation of the central nervous system—headache, vomiting, lethargy, paralysis, convulsions, coma—developed seven to 14 days after vaccination (Figure 6). Almost half of patients died. Of those who survived, some recovered almost completely, but many who recovered had residua, and a few patients remained in a vegetative state. Even among patients who were treated with VIG and the antiviral agent methisazone, only 50% survived. The strain of vaccine used was believed to have contributed to this complication. Incidence declined noticeably once the Lister strain of vaccine was employed, right after the turn of the 20th century.7



Secondary infections. Infection at the vaccination site, such as impetigo, cellulitis, and erysipelas, were seen occasionally (Figure 7). Rarely, sepsis occurred. Most infections were bacterial; rarely, a viral agent (such as herpes) invaded.



Other reported complications included postvaccinal myocarditis (sometimes fatal), pericarditis, toxic epidermal necrolysis (TEN), neurologic problems (polyneuritis), osteomyelitis, fetal vaccinia, Waterhouse-Friderichsen syndrome, and even "chromosomal changes."9

Death. At the time smallpox vaccination was discontinued, it was estimated that the incidence of death from vaccination was one in 1 million. Death was usually caused by one of the complications discussed earlier.

Contraindications to immunization

If a general preventive vaccination program is undertaken, the persons listed in the table at right should not be immunized. Patients with most chronic illnesses, other than those noted in the table, tolerate vaccination well.

If a person, with or without a contraindication to vaccination, is exposed to smallpox, he or she should be vaccinated within three or four days. Smallpox vaccination can be protective if administered less than seven days after exposure to active smallpox, however. Of course, the earlier that person is vaccinated after exposure, the better.

The way it was

When I began seeing patients as a physician in 1946, smallpox vaccination was performed in various ways. Some physicians used the recommended multiple pressure method: The skin was cleansed, usually with acetone or ether, and allowed to dry thoroughly. A drop of vaccine was then placed on the skin and five to 10 punctures were made with a single needle. The residua was wiped with a dry gauze and it, along with the bulk of the vaccine remaining in the vial, was discarded in the general garbage.

Other physicians were still using scratch or incision techniques, some needled multiple sites, and some believed that blood had to be drawn. In 1965, a double pronged or bifurcated needle was introduced and jet injection was occasionally employed when groups were immunized.4

I used only the recommended multiple pressure method. Although a few physicians used alcohol, Merthiolate, or plain tincture of iodine to prepare the skin, I used acetone, which was said to "defat" and cleanse the skin surface, and dry very quickly, thus not inactivating the vaccine. I usually laid only a small drop of the vaccine on the cleansed area. Using the sterile needle supplied in a sealed vial, I made five or six superficial punctures through the drop of vaccine. (A few physicians punctured the skin first, then applied the vaccine at the punctured site and rubbed it in using the back of the needle or a tongue blade.) It was unusual not to get a "positive" reaction or "take" and immunity. We rarely saw a secondary infection.

The site of vaccination that physicians chose also varied. Although the bikini was not yet in vogue, physicians were forever hiding the vaccination scar on little girls. I found scars from smallpox vaccination on the thigh, on the buttock, under the nipple (a bad site), under the arm, over the scapula, and even on the heel and vulva (more bad sites). I vaccinated girls under the upper arm, and boys over the deltoid.

Some physicians covered the site with perforated plastic or glass covers. Others had the patient return when vesiculation began and "painted" the vesicle with collodion. This was an attempt to prevent rupture of the vesicle and viral spread.

In contrast to what was done in the past, no skin preparation is recommended for smallpox vaccination today. Alcohol must not be applied because it has been shown to inactivate the vaccine.10 Using a bifurcated needle dipped once into the vaccine vial, the person administering the vaccine makes a series of perpendicular insertions within an area 5 mm in diameter. The CDC recommends making the insertions in the deltoid area on the upper arm: three insertions for primary vaccination, followed by three more insertions if no trace of blood appears within 15 to 20 seconds; 15 insertions are recommended for revaccination with the Dryvax vaccine.10 Excess vaccine should be absorbed with sterile gauze and discarded appropriately. The site should be covered with sterile gauze, loosely taped.

What to expect post-vaccination

When primary vaccination was performed and was successful (Figure 8), a papule developed after about three to five days, followed quickly by a vesicle one or two days after that. The vesicle became a pustule by seven to eight days after immunization. As the pustule dried, it turned to a scab, which dropped off about 14 to 20 days after vaccination, leaving a classic scar. Most primary vaccinees developed a low-grade fever during the pustule stage, associated frequently with tender swelling of the regional lymph nodes. The latter lasted for three to six weeks or, occasionally, longer. Moderate or severe erythema surrounded the vesicle and pustule (Figure 9).




The recommendation then was to revaccinate children every five years, which we did. In the great majority of these cases, the reaction at the site was only an "immune papule" (Figure 10). This small, hard, red papule developed on the second or third day after the "planting," never vesiculated, and faded away in 10 to 12 days, almost always without a residual scar. This same phenomenon was seen in many people who had not been revaccinated for 15 or even 20 years. In my experience, it was unusual to get a primary reaction when revaccination was conducted five or so years after a primary positive vaccination.3 Occasionally, a so-called accelerated reaction occurred (Figure 10): A papule developed on the third or fourth day, followed quickly by a small vesicle that disappeared in seven to 10 days. This accelerated reaction was believed to reflect fading immunity and was considered to be a booster.



A legacy of pain

Man's dedicated search for a means to prevent the scourge of smallpox was successful, but not without consequences. I have described the vaccination process and its complications as I remember them, with the hope that, if large-scale smallpox vaccination must again be instituted, we can prevent some of those complications.

In my opinion, no other disease, and no war or natural or human disaster, has caused more human suffering or death or had as great an impact on history as smallpox. It ravaged individuals, families, tribes, villages, cities, and nations. It maimed and killed kings as well as paupers.

It is a tribute to man's determination, ingenuity, and wisdom that smallpox was and is the only disease that has been eradicated from the planet. I can only hope that no one will again lay this agent of devastation on mankind.

DR. ANNUNZIATO is director of pediatric education, Nassau University Medical Center, East Meadow, N.Y., and professor of pediatrics at Stony Brook University School of Medicine, Stony Brook, N.Y. Dr. Annunziato has nothing to disclose in regard to affiliation with, or financial interests in, any organization that may have an interest in any part of this article.

Contraindications to smallpox vaccination in the absence of an exposure to smallpox

In either potential vaccinee or a close (e.g., household) contact

Eczema or atopic dermatitis (even if condition is inactive)

Unresolved exfoliative skin disorder (e.g., burns, impetigo, herpes, severe diaper dermatitis that causes the skin not to be intact)

Pregnancy (or plans to become pregnant within 1 month of vaccination)

Breastfeeding a child

Primary or secondary immunodeficiency (including taking immunosuppressive medications)

In potential vaccinee

A previous allergic reaction to smallpox vaccine or vaccine component

Moderate or severe acute illness

Age <1 year

Use of ocular steroid drops

History of heart disease (under investigation as a contraindication; may be a temporary exclusion)

Sources: CDC, American Academy of Pediatrics


1. Jenner, Edward. The Three Original Publications on Vaccination Against Smallpox. The Harvard Classics. N.Y., P. Collier & Son, 1909–14;, 2001

2. Edward Jenner, Origin of the Vaccine Inoculation, Dallas, Major Science Books, 1977

3. Henderson D, Moss B: Smallpox and Vaccinia, in Plotkin SA, Orenstein WA, Zorab R (eds): Vaccines, ed 3, Philadelphia, WB Saunders Co, 1999, pp 74–97

4. Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine Preventable Diseases, ed 7 (updated), Atlanta, Department of Health and Human Services, CDC, 2003

5. Frey SE, Couch RB, Tacket CO, et al: Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002;346:1265

6. Frey SE, Newman FK, Cruz J, et al: Dose-related effects of smallpox vaccine. N Engl J Med 2002;346:1275

7. Kempe CH, Berge TO, England B: Hyperimmune gamma globulin, source, evaluation and use in prophylaxis and therapy. Pediatrics 1956;18:177

8. Moses AE, Cohen-Poradosu R: Eczema vaccinatum— A timely reminder. N Engl J Med 2002;346:1287

9. Hopkins DR: Princes and Peasants: Smallpox in History. Chicago, Ill., University of Chicago Press, 1983.

10. Centers for Disease Control and Prevention: Smallpox vaccination method. . Accessed April 2, 2003


David Annunziato. Smallpox vaccination: A personal perspective on an imperfect essential. Contemporary Pediatrics May 2003;20:62.

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