Smallpox Immunity May Persist From Childhood

Israelis trying to develop skin test to confirm

Health care workers who were vaccinated as children may be protected against fatal smallpox infection even if they declined to participate in recent immunization efforts, according to a recent study.

Researchers report that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral and/or cellular immunity against vaccinia, the virus used to vaccinate against smallpox.1 Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years.

"If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals," the researchers concluded.

However, even if those previously immunized only were infected mildly during a smallpox attack, they still could spread the disease, so health care workers would need to be immunized to protect patients. Still, the historical smallpox literature indicates those who have less severe smallpox infection due to previous vaccination are four times less likely to transmit the disease to their contacts, says lead researcher Mark Slifka, PhD, director of the Oregon Health & Science University Vaccine and Gene Therapy Institute in Beaverton.

"If you’re on a smallpox task force team, you would still want to be vaccinated as an obvious precautionary measure, but for the average person—no," he says.

More importantly, the study by Slifka and colleagues raises the possibility that roughly half of the country—those immunized before the national program was dropped in 1972—have some level of immunity. But the traditional wisdom among smallpox experts has been that immunity fades after 5-10 years post-vaccination.

The Centers for Disease Control and Prevention states on its smallpox web site that, "Smallpox vaccination provides high level immunity for 3-5 years and decreasing immunity thereafter. . . . It is important to note, however, that at the time when the smallpox vaccine was used to eradicate the disease, testing was not as advanced or precise as it is today, so there may still be things to learn about the vaccine and its effectiveness and length of protection."

Since smallpox has been eradicated as a natural-occurring disease, it is difficult to know the nature of persistent immunity in the previously vaccinated. Some in the scientific community remain unconvinced that the issue has any major relevance for smallpox preparedness.

"It’s a nice thought," says Brian L. Strom, MD, MPH, chairman of the Institute of Medicine smallpox panel and director of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine in Philadelphia.

Good News, Bad News

"The good news is there are these serological measures that suggest immunity last longer. The bad news is that we have no idea whether those serologic measures are of any clinical importance whatsoever," he explains.

"Those measures weren’t available when we had disease and now that we have those measures, we don’t have disease. The available data when there was disease would argue that [these findings] are probably not important because they are probably not correct. The people who got vaccinated seemed to get disease after a few years—milder disease—but they seemed to be subject to still getting sick," Strom adds.

But that is precisely the point, Slifka argues—those previously immunized would be considerably less vulnerable to smallpox infection. "It depends on your definition of protection," he says.

"It’s interesting because the same arguments keep coming up over and over again. Even if you got vaccinated six months or six days before you were exposed, there is no guarantee that you won’t contract smallpox.

"But it will be mild. If you knew you were going to have a high probability of exposures, you would probably want to get vaccinated. But for the average person, long-term immunity is probably going to provide that protection," Slifka explains.

Thus it seems the primary implications will arise when and if the public is ever offered smallpox vaccine, which was to occur in the third phase of the national smallpox plan that is now in limbo.

"The historical data on this are really pretty solid," Slifka says. "Obviously, the largest numbers come from back in the days when smallpox was endemic, but a paper published in 1913 shows really quite well that immunity against lethal disease lasts for life."

He also points out that Edward Jenner—who made the connection between cowpox (vaccinia) and smallpox (variola)—was working with farm families that had very good health records kept at churches.

Jenner found that people were protected against smallpox as long as 53 years after cowpox infection, Slifka explains.

"Some 60% to 70% of unvaccinated people, when exposed, get smallpox," he explains. "In contrast, only 4% of vaccinated people get smallpox. Of those [vaccinated people] who get smallpox, mortality is 7% or less. Even if we are conservative and say there is a 10% attack rate instead of the 4% and 10% mortality instead of 7%, 10% of 10% equals 1%. That means that 99% of vaccinated people are protected from lethal infection."

The argument for long-term immunity is borne out by other live virus vaccines, he adds. "This is a live viral vaccine, and it is an acute or short-term infection," Slifka says.

"So this is not unique to vaccinia. If you take a look at measles, mumps, rubella, polio, and yellow fever—those are five other viruses—all of those are short-term infections that induce lifelong immunity. It is not surprising that vaccinia does the same," he adds.

Researchers Seeking Smallpox Skin Test

But even if immunity does persist overall, is there any reliable way to detect it in an individual?

Researchers in Israel are trying to answer that question and develop a simple skin test to determine whether someone has persistent immunity. The skin test is applied to the forearm using the same technique as the tuberculin skin test used for the diagnosis of latent TB infection.

"It is well known that some people who were vaccinated many years ago are well protected against smallpox," says Eli Somekh, MD, head of pediatric infectious diseases and immunology at Wolfson Medical Center in Holon, Israel.

"The problem is how to identify these people. We hope that this skin test will be proved as a simple and reliable method for this purpose," he points out.

In data recently presented recently in Chicago at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Somekh described the quest for a skin test.2

A skin test solution was prepared from vials of smallpox vaccine, which was inactivated by exposure of the vials to temperature of 600°C for one hour.

Inactivation was confirmed by the lack of growth in virus culture. The solution was then diluted in a ratio of 1:20 with normal saline.

The material was injected superficially in the forearm to 77 healthy subjects ages 17 to 55. Twenty patients had been immunized for smallpox within three months before skin testing (group 1).

Thirty-seven patients had their smallpox vaccination in the past, at least 20 years before skin test application (group 2), while 20 patients had never been vaccinated for smallpox (group 3).

Tests were read at 48 hours and were considered as positive when the diameter of swelling was 5 mm or larger. Blood samples were drawn prior to skin testing and kept at –700°C until analyzed for neutralizing antibody assay. Titers of 1:64 or greater were considered as protective.

The skin test reliably differentiated between people who had not been vaccinated for smallpox and those who were vaccinated recently or in past.

In addition, a positive skin test reaction in a person who was vaccinated for smallpox recently or remotely was associated with protective level of antibodies against vaccinia virus.

There was a significant difference in induration (swelling) size of patients from the different groups of patients (mean induration was 7.9 mm, 5.3 mm, and 0 mm for patients from group 1, group 2, and group 3, respectively).

There was a significant correlation of skin test results with serologic results. The specificity and sensitivity of the skin test as compared to the serologic results were 83.3% and 92.3% respectively.

Simple and Cheap Method

Except for the expected local redness and swelling (which was considered as positive reaction to the skin test), there were no other local or generalized manifestations. The results suggest that a vaccinia skin test prepared in a simple and cheap method is a safe and a potentially useful tool by which to assess immunity.

"Skin test reactions represent memory of T Lymphocytes from a previous encounter with a specific antigen/pathogen," Somekh said.

"Positive reaction does not always suggest an existing immunity; however, in our study, skin test reactivity was significantly correlated with protective levels of antibodies to vaccinia. Our results are still preliminary, and we do not suggest avoiding vaccination of people with positive skin test reactions until these results can be further studied and confirmed," he adds. 


1. Hammerlund E, et al. Nat Med. 2003;9(9):1131-1137.

2. Somekh E,et al. Abstract G-1087. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago; September 2003.