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New Study Indicates Long-lived Immunity After Smallpox Vaccination

By Amesh A. Adalja, M.D., December 5, 2008

It has long been held that smallpox vaccination confers 5 to 10 years of protection for recipients, who may then require a booster to maintain immunity. However, researchers from the National Institute of Aging (NIA) have just reported results of a study in which 97% of 209 vaccinated subjects maintained antibody titers for up to 88 years.1

The Study

NIA launched its Baltimore Longitudinal Study of Aging in 1958, with a cohort of 209 men and women who had documented smallpox vaccinations. As part of the study, participants had serum samples banked at each of their visits, which occurred at 1 to 5 year intervals. The serum samples analyzed for this study had been stored for a median of 61 years, with some samples stored for as long as 88 years. Also included in the study were 8 subjects who had a history of natural smallpox infection. Serum was analyzed utilizing both an ELISA assay and a neutralization assay.1

Vaccinia Titers

Prior vaccinees exhibited titers that remained elevated and stable (1:32-1:256) for up to 88 years after vaccination. Among subjects who had been vaccinated multiple times, small but statistically significant increases in titers were observed following each additional inoculation. To demonstrate the ability of these antibodies to neutralize virus, the authors conducted a neutralization assay whereby sera was added to incubating vaccinia-infected cells and fluorescence was measured. Stability of neutralizing titers was found in 98% of subjects (1.4% had no neutralizing activity). Receipt of additional vaccination did not add to neutralization.1

Comparison with Smallpox Survivors

The authors also compared the titers of vaccinees with those of the 8 cohort patients who had sustained natural smallpox infection. They found no difference in antibody titers or neutralization ability, indicating there is no difference between vaccine induced and natural immunity.1


This study’s implication that immunization with vaccinia may confer long-lived immunity, without the need for revaccination, must be interpreted with caution. Evidence from periods in which smallpox circulated in the population indicates that infection could occur despite prior vaccination, likely reflecting a lack of complete correlation between antibody titers and immunologic protection in vivo.2

However, results from a 1972 study by Mack and colleagues indicate that lower neutralizing antibody titers (<1:32) were associated with an increased risk of contracting smallpox after contact with an infected  individual,3 and titers in the current study exceed that threshold. While a substantial number of U.S. residents have already been vaccinated against smallpox, it remains to be determined whether that will provide some barrier to spread of the disease after an accidental or intentional introduction of the virus into the population. Another question this study gives rise to is whether the approximately 10 million Americans unable to receive the currently licensed vaccine due to impaired immune systems may be able to rely on some degree of immunity bestowed from an earlier vaccination.


  1. Taub DB, Ershler WB, Janowski M ,et al. Immunity from Smallpox Vaccine Persists for Decades: A Longitudinal Study. Am J Med 2008. 121: 1058-64. Accessed December 2, 2008.

  2. Kleitmann WF, Ruoff KL. Bioterrorism: Implications for the Clinical Microbiologist. Clin Rev Micro.  2001: 364-381.

  3. Mack TM, Noble J, Thomas DB. A prospective study of serum antibody and protection against smallpox. Am J Trop Med Hyg. 1972: 214-18.