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Absence of Smallpox “Take” May Not Indicate Revaccination Failure

By Amesh A. Adalja, MD, May 6, 2011

Successful vaccination against smallpox is generally determined by inspection of the vaccine site approximately one week after vaccination. Vesicles and pustules at the site are considered to be indicative of a successful vaccine take. These lesions are due to a localized dermal infection with the vaccinia virus. 

It has long been observed that people who are revaccinated have lower rates of vaccine takes. This is believed to be due to persistent immunity from prior vaccination that blocks clinical manifestation of localized vaccinia infection. However, it is not clear if the absence of a take represents vaccine failure, ie, a failure to induce immunity, or if it represents just a lack of visible evidence of a successful vaccination. Wiser and colleagues conducted a study of members of the Israeli Defense Forces (IDF) to assess the ability of surrogate immunological markers to assess vaccination results in those revaccinated against smallpox. 

Surrogate Markers of Vaccine Results

This historical prospective study utilized a cohort of 159 adults, aged 24-52 years, who were vaccinated against smallpox in the winter of 2002-2003. Among the 159 subjects, 80 were included in an analysis comparing the immunologic parameters of those with and without a successful vaccination take. Important baseline characteristics are summarized in the table below.

Table: Baseline Characteristics

Characteristic“No-take” group (40)“Take” group (40)Total (159)
Mean age333435
Median # of prior vaccinations333
Mean interval since prior vaccination16 years19 years20 years


Immunologic Evidence of Successful Vaccination 

Several immunologic parameters were assessed at day 0, day 14, and month 24. At baseline, the no-take group demonstrated higher total IgG responses, IgG1 responses, and neutralization antibody titer. This was not unexpected, given that, on average, the no-take group had been vaccinated more recently than the “take group” (the inverse correlation between total IgG level and time since vaccination was statistically significant).

At day 14, levels of IgG—including IgG1-3 subclasses—and neutralization titers were found to be higher in the take group vs. the no-take group. However, most importantly, at month 24, no difference existed in total IgG, IgG subclass, or neutralizing antibody levels between the 2 groups. Moreover, cellular interferon-gamma secretion was higher in the no-take group, and antibody avidity was similar at 23 months. No difference in vaccinia-specific B-cell numbers was found at 24 months. 

Assessing Take in Re-vaccines Unnecessary?

This study demonstrates that, in the setting of re-vaccination, it is not necessary to recall those without a take (for either assessment and/or vaccination again), as a successful immunologic reaction is likely, even in the absence of evidence at the vaccination site. 

This finding has major implications for mass vaccination campaigns that would occur in the event of a credible threat of smallpox release. Mass vaccination campaigns will involve the rapid mobilization of people, vaccinators, and supplies in a chaotic environment. A sizable proportion of the population has been vaccinated against smallpox in the past and may not demonstrate a vaccine take upon revaccination. Eliminating the need to assess this segment of the population for vaccine take will remove an additional task in a time of crisis and alleviate the burden on what will be already severely stressed medical resources.


Wiser I, Orr N, Smetana Z, et al. Alternative immunological markers to document successful multiple smallpox revaccinations. Clin Infect Dis 2011. 52:856-861.