Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis

Abstract

Background: Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination.

Objective: We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD.

Methods: In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination.

Results: YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4(+) T-cell responses was observed.

Conclusions: YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.

Trial registration: ClinicalTrials.gov NCT00723489.

Keywords: AD; AE; Adverse event; Atopic dermatitis; IgE; LNI; Log neutralizing index; NT(50); Neutralizing titer 50; T-cell memory; YFV; Yellow fever virus; antibody; atopic dermatitis.

Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Figures

Figure 1

Flow diagram of study subjects participating in the trial

Figure 2. Duration of YFV RNAemia after subcutaneous or transcutaneous vaccination

Kaplan-Meier curves show the proportion of YFV-seroconverted subjects who score positive for YFV RNA by RT-PCR during the first two weeks after vaccination. The limit of detection was n = 18; TC-NA, n = 14; SC-AD, n = 17; SC-NA, n = 20.

Figure 3. Induction of neutralizing YFV-specific antibody responses following subcutaneous or transcutaneous vaccination

(A) At 30 days after YFV vaccination, seroconversion rates were determined for the different vaccine groups and was defined as a YFV-specific neutralizing titer of 10 or more. (B) Levels of YFV neutralizing antibody among seropositive subjects were measured by the log neutralizing index (LNI) in which serum is held constant and different amounts of virus are neutralized. (C) Levels of YFV neutralizing antibody among seropositive subjects were measured by determining the serum dilution required to neutralize 50% of virus plaques (held constant at 50-100 YFV plaques). Error bars represent 95% confidence intervals.

Figure 4. Kinetics and magnitude of vaccine-induced YFV-specific CD4+ and CD8+ T cell responses

The frequency of virus-specific T cells was measured by stimulating PBMC with purified YFV and measuring the frequency of IFNγ+TNFα+ T cells at each time point by intracellular cytokine staining analysis. Representative flow cytometry dot plot showing the virus-specific CD4+ and CD8+ T cell response after YFV vaccination (A). The dot plots were pre-gated on CD4+CD8− and CD4−CD8+ T cells and show the number of events per 106 CD4+ or CD8+ T cells after background subtraction (medium alone). The kinetics and magnitude of YFV-specific CD4+ T cells (B and C) or CD8+ T cells (D and E) were measured in subjects vaccinated by the subcutaneous route (B and D) or the transcutaneous route (C and E). The numbers indicate measured P values at each time point and error bars represent 95% confidence intervals.

Figure 5. Comparison between baseline total IgE levels and YFV vaccine-induced immune responses

Total serum IgE levels obtained at baseline were compared to subsequent YFV vaccine-induced immune responses at 30 days post-vaccination and included YFV-specific neutralizing titers (NT50) (A and B), YFV-specific CD4+ T cell responses (C and D) and YFV-specific CD8+ T cell responses (E and F) in subjects vaccinated by the subcutaneous route (A, C, and E) or the transcutaneous route (B, D, and F). The red symbols represent AD patients and the blue symbols represent non-atopic (NA) subjects and the red or blue ellipses represent 95% confidence interval ellipses.