Our longitudinal study of the durability of immune responses to vaccinia immunization suggests that nearly all individuals who have been vaccinated maintain both specific and neutralizing antivaccinia antibodies at levels that suggest protection against smallpox. Multiple vaccinations produced slightly higher levels of antibody, but levels of antibody do not decrease significantly over time after vaccination.
The dogma on smallpox vaccinations has been that individuals with repeated exposure to smallpox (eg, travelers to endemic countries) should be revaccinated every 5 years.10-12
However, several cross-sectional epidemiological studies have suggested that smallpox vaccination provided recipients with protection against lethal smallpox for longer periods of time and that multiple inoculations might not be necessary.11,13-21
Our longitudinal data support this argument; a single vaccination elicits functional antibody that remains stable over the lifetime.
While the specific roles of humoral and cellular immunity in the long-term protection against smallpox are not completely defined, 2 prospective studies indicate that high levels of neutralizing antibodies may be associated with protective immunity against smallpox.22,23
demonstrated that subjects who were in contact with smallpox victims possessing vaccinia virus neutralizing titers <1:32 were more susceptible to smallpox infection (3 of 15, or 20% of contacts infected) compared with subjects with antibody titers of ≥1:32 (0 of 127 or <1% of contacts infected. In a smaller study,23
6 of 43 (14%) contacts with neutralizing titers <1:20 contracted smallpox. whereas 0 of 13 contats with titers of 1:20 or higher contracted the disease. Thus, these serum-neutralizing antibody levels might be useful at least as biomarkers of protective immunity, regardless of whether the protection is mediated by humoral or cellular immunity or both.
In a study by Hammarlund et al,24
>90% of volunteers vaccinated between the ages of 25 and 75 years retained substantial humoral or T-cell immunity against vaccinia virus. Antiviral antibody responses were present 1 to 75 years after vaccination, while antivaccinia T-cell responses decreased 8 to 15 years after the last vaccination.
Another study found that virus-specific T-cell memory can persist for up to 50 years in the presumed absence of antigen.25
We similarly observed the maintenance of high levels of circulating antivaccinia antibody at many different time points in an individuals’s life span over a 13- to 88-year period. In contrast, studies by Hsieh and coworkers26
revealed that the longevity of vaccinia-specific T-cell-specific immune memory in a cohort of 220 Taiwanese individuals (aged 18-70 years) was easily detectable in subjects previously vaccinated 23-30 years earlier but more difficult to detect in subjects vaccinated 31-40 years earlier. These findings differ somewhat from the reports where vaccinia-reactive T cells could be detected as long as 50-75 years after vaccination.24
The reasons for such differences remain unclear.
In a more recent study,27
159 healthy, previously vaccinated adults between the ages of 24 and 52 years were revaccinated; of these, 88% with clinical “take” (skin reactivity to vaccine) were found to seroconvert, while subjects with no clinical take demonstrated little to no antibody response. Moreover, the level of preexisting antibodies inversely correlated with the rates of clinical take and sero-conversion with the group of vaccinees with the lowest preexisting levels of antibodies (86%) developing antibody responsese to vaccine challenge. This study also demonstrated that the time since the last vaccination was significantly associated with the rates of clinical take and antibody seroconversion. The longer the interval since the last vaccination, the greater the rate of clinical take and seroconversion. Unfortunately, in our longitudinal study, precise information on clinical take was not retained over the ex-tanded time periods. However, a small cohort of subjects did have such documentation and demonstrated similar antibody maintenance patterns as subjects without such documentation (dada not shown).
Individuals who have survived a smallpox infection are thought to maintain lifelong protection; by contrast, vaccination generally induces a response that diminishes over time. Thus, we expected that individuals with a history of infection would have higher levels of immunity than those who were vaccinated. However, we found that vaccinia-specific antibody titers were comparable in these 2 groups (). The mechanism of the lifelong persistence of vaccinia-elicited smallpox immunity is undefined.
The morbidity associated with vaccine administration and the risk of mortality among elderly and immune-compromised populations also are critical factors that will influence a vaccination policy. Little information is available about the safety and efficacy of smallpox vaccines in elderly populations. Furthermore, the aging process is associated with immune response abnormalities.28-30
Development of immunization guidelines for the population will need to consider these factors.
Protecting the population against smallpox in the face of limited supplies of vaccine may be a challenge. Frey et al31
have shown that 1:10 dilutions of the vaccine also are highly efficient at eliciting clinical takes in previously unvaccinated individuals. Our revealed that nearly all the individuals who have been vaccinated one or more times maintained antivaccinia IgG and neutralizing antibody titers above 3 natural logs indefinitely. Titers were stable for up to 88 years. Moreover, those who survived active smallpox infections in their youth retained vaccinia-specific immunity throughout their lives and their antivaccinia antibody titers were similar to the levels of vaccinated subjects. Thus, vaccinated subjects remain immune to vaccinia indefinitely and do not require booster vaccinations even if they are many decades removed from primary vaccination. These data imply that limited supplies of vaccine can be more usefully applied (perhaps in diluted form) to individuals who have never been vaccinated, primarily individuals born after 1972.
- Vaccinia elicits antiviral antibody levels and virus neutralizing activity that remain elevated for the life of the patient.
- Multiple vaccinations achieve only marginally higher levels of antibody and virus neutralizing activity than single vaccination.
- Levels of antibodies and virus neutralizing activity are comparable in vaccinated individuals and those who developed smallpox and recovered.
- Vaccinia should be used first on individuals who have never been vaccinated before.