D. A. Henderson critiques report on duration of smallpox immunity

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Aug 21, 2003 (CIDRAP News) – Dr. D. A. Henderson, who led the global smallpox eradication campaign in the 1960s and 1970s, says researchers who recently reported on the duration of immunity conferred by smallpox vaccination were wrong in suggesting that immunity can last for decades or even for life.

Henderson said researchers from Oregon Health and Science Unviersity who published an online report in Nature Medicine this week drew unwarranted conclusions from their data on the persistence of humoral and cellular immunity in smallpox vaccinees and from existing epidemiologic studies.

The Oregon researchers reported that they found "remarkably stable" levels of vaccinia-specific antibodies in their subjects as long as 75 years after vaccination and that T-cell memory of vaccinia, though it declined after vaccination, could still be detected after 75 years (see Aug 19 CIDRAP News story). The authors said they found "substantial humoral or cellular immunity (or both)" in more than 90% of the 300-plus volunteers in their study. They suggested that this could mean that many people who were vaccinated in childhood would be protected in the event of an outbreak.

But in an interview, Henderson told CIDRAP News that the findings don't change the clear evidence from many epidemiologic studies and general observation that immunity after a single smallpox shot begins to fade after 5 to 10 years. Because most Americans either were never vaccinated or had one shot more than 30 years ago, most would be susceptible if smallpox reappeared today, he said. Henderson is now a special advisor to Health and Human Services Secretary Tommy Thompson.

"It's been known since the time of Jenner that a single vaccination did not protect for life or even for a long time," Henderson said, referring to the 18th century English physician who developed the smallpox vaccine. "My own concerns and recommendations would be to say that the threat or risk of smallpox is no different from that which we've assessed all along, The population is highly susceptible—probably somewhere between 70 and 75% are susceptible to the disease and a potentially fatal outcome."

Henderson said the new data on antibody levels and T-cell memory in vaccinees mean little because no one knows what levels of these variables actually indicate immunity. "We have no idea what the correlates of immunity are," he said.

The Oregon researchers cite two studies from the 1970s that suggested a specific level of neutralizing antibodies that confers protection against smallpox. But Henderson said those studies were too small to be definitive. Moreover, meaningful comparisons of the antibody titers reported in the 1970s studies and those seen in the new study are not possible because findings vary so much among different laboratories, he said.

"If you give out blood specimens to a variety of labs [for antibody testing], they'll get a wide range of results, because so much depends on the techniques employed," he said. "So even the information they have from these two [1970s] studies doesn't mean anything because there's no way to compare the titers that they have with the very few that were done in studies in the past. So from the standpoint of knowing what the antibodies mean, we really don't know."

Henderson also took issue with the Oregon researchers' use of previous epidemiologic studies. They cited a 1972 British report that they said showed mortality rates of 6% and 7% in people who had been vaccinated 11 to 20 years and more than 20 years, respectively, before exposure to smallpox. But Henderson said the mortality rate for those groups was actually 11%. In addition, he said, the researchers didn't mention that among 561 smallpox patients included in the study, 473 had been vaccinated.

The Nature Medicine report also cites two English reports from around the end of the 19th century that suggested that smallpox vaccination protected more than 90% of vaccinees for many years and possibly for life. But Henderson said that because smallpox was endemic in Britain in the 19th century, the people described in those studies probably were exposed to smallpox repeatedly and may have had subclinical infections that boosted their immunity. A similar phenomenon occurs with measles, he said.

The boosting effect of repeated exposure "would make the shot look awfully good," he said. "But we don't have smallpox circulating in this country and we haven't had it since the 1940s. So we can assume we have virtually nobody with that type of protection."

Henderson said one thing that does appear to provide fairly long-term protection against smallpox is a second vaccination. "If you've been vaccinated a couple of times, your protection against acquiring the disease is probably much longer, but we don't know how much longer. And protection against death could be lifetime."

However, few Americans have been vaccinated more than once, he noted. He said 45% of American are younger than 32 and therefore have never had a smallpox shot. Of the 55% of Americans older than 32, a generous estimate would be that about half may still have some protection because of their childhood vaccination, and the rest would not, he said. Thus, about 72% of the population have no immunity, "and that's probably understating it," he said.

In Henderson's view, the bottom line is that the new study has "no implications whatsoever" for current vaccination programs or for outbreak response planning.

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