Kinetics of serum cytokines after primary or repeat vaccination with the smallpox vaccine

Abstract

Background: The smallpox vaccine is associated with more serious adverse events than any other live attenuated vaccine in use today. Although studies have examined serum cytokine levels in primary vaccine recipients at 1 and 3-5 weeks after vaccination with the smallpox vaccine, serial measurements have not been performed, and studies in revaccinated subjects have not been conducted.

Methods: We analyzed cytokine responses in both primary vaccine recipients and revaccinated subjects every other day for 2 weeks after vaccination.

Results: Primary vaccine recipients had maximal levels of granulocyte-colony-stimulating factor on days 6-7 after vaccination; peak levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor 1, interferon (IFN)-gamma, IFN-inducible protein-10 (IP-10), interleukin (IL)-6, and tissue inhibitor of metalloproteinases-1 on days 8-9 after vaccination; peak levels of soluble TNF receptor 2 and monokine induced by IFN-gamma (MIG) on days 10-11 after vaccination; and peak levels of granulocyte-macrophage-colony-stimulating factor on days 12-13 after vaccination. Primary vaccine recipients were significantly more likely to have higher peak levels of IFN-gamma, IP-10, and MIG after vaccination than were revaccinated subjects. Primary vaccine recipients were significantly more likely to have fatigue, lymphadenopathy, and headache, as well as a longer duration of these symptoms and more hours missed from work, compared with revaccinated subjects.

Conclusions: The increased frequency and duration of symptoms observed in primary vaccine recipients, compared with revaccinated subjects, paralleled the increases in serum cytokine levels in these individuals.

Trial registration: Clinicaltrials.gov identifier NCT00325975.

Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1

Symptoms in primary vaccinees and revaccinees receiving the smallpox vaccine. (A) Percent of vaccinees with indicated symptom and (B) Mean number of clinic visits in which symptom was reported.

Figure 2

Percentage of vaccinees with greater than a 1.5-fold increase in cytokine levels from baseline after receiving the smallpox vaccine. Serum levels of IFN-γ, IP-10, MIG, TNF-α, sTNFR1, sTNRF2, IL-6, G-CSF (A), and levels of GM-CSF, TIMP-1, TIMP-2. SCF, eotaxin, and sICAM-1 (B) are shown.

Figure 3

Serum cytokine levels over time in primary vaccinees and revaccinees receiving the smallpox vaccine. Serum levels of IFN-γ (A), IP-10 (B), MIG (C), TNF-α (D), sTNFR1 (E), sTNRF2 (F), IL-6 (G), G-CSF (H), GM-CSF (I) are shown.

Figure 4

Serum cytokines levels and symptoms over time for all vaccinees receiving the smallpox vaccine. Percent of patients with given symptoms (A) and serum levels of IFN-γ (B), IP-10 (C), MIG (D), and G-CSF (D) on different days are shown.