A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children
Introduction
In the United States, annual influenza vaccination is now recommended for all children 6 months through 18 years of age [1]. The injectable trivalent inactivated influenza vaccine (TIV) and the intranasal live attenuated influenza vaccine (LAIV) are available for use in young children; LAIV is approved for use in eligible children 2 years and older and some TIV formulations are approved for use in children as young as 6 months. Both vaccines are trivalent, containing recommended influenza A (H1N1 and H3N2) and influenza B strains. Despite widespread use and significant investigation, the protective mechanisms of these vaccines in young children are not completely understood. In 3 randomized studies among children 6 months to 17 years of age, LAIV recipients had 35% to 53% fewer cases of influenza illness compared with TIV recipients, with comparable safety among children 2 years and older [2], [3], [4], [5]. In 1 study among children 6–23 months of age, an increased rate of wheezing through 6 weeks postvaccination was associated with LAIV (LAIV, 5.9%; TIV, 3.8%), and in children 6–11 months of age there was an increased rate of hospitalization through 6 months after vaccination (LAIV, 6.1%; TIV, 2.6%) [3]. Several studies have shown that TIV and LAIV are immunogenic in young children [5], [6], [7], [8], [9], although different immune mechanisms may be involved. TIV can induce a stronger serum antibody response than LAIV, measured by immunoglobulin (Ig) G and IgA antibody levels and hemagglutination inhibition, particularly in older children with previous exposure to influenza [8]. LAIV, on the other hand, has been shown to induce significantly higher levels of mucosal IgA antibody [10]. In addition, studies with LAIV and TIV have shown that both vaccines can induce cellular immune responses [7], [11], [12].
Previous studies have demonstrated that type 1 interferon (IFN)-stimulated genes (ISGs) are significantly overexpressed after RNA viral invasion or vaccination, and that the activation of the type 1 IFN signaling pathway has a critical role in the development of adaptive and innate immune responses against influenza and other viral infections [13], [14], [15], [16]. To better understand the humoral and cellular responses elicited by vaccination, microarrays have been used to survey genome-wide changes in transcriptional profiles after influenza vaccination. Prominent overexpression of type 1 ISGs was displayed in children infected with influenza virus [14], [17]; similar transcriptional profiles were also observed in animals infected with influenza virus [18], [19].
In this study, we compiled a transcriptional profile of the early immune responses induced by TIV and LAIV in young children using whole genome DNA microarrays. A series of coexpressed gene clusters induced by such vaccination were identified. These gene clusters were further characterized by both functional and promoter analyses. In addition to directly comparing the expression profiles between LAIV and TIV, we examined the responses of (1) different age groups and (2) subjects who had/had not previously received the influenza vaccine were compared to understand potential differences in transcriptional regulation. This comprehensive analysis may provide a better understanding of differences in the mechanisms of action between vaccination with TIV and LAIV as well as differences in immune responses between individual subjects.
Section snippets
Patient enrollment
Children 12–35 months of age were enrolled in a prospective, randomized, open-label, multicenter study to evaluate their immune responses to LAIV or TIV. Children with a contraindication or warning against the use of LAIV or TIV were excluded from the study. Eighty-five subjects were randomized at a 1:1 ratio to receive 1 dose of intranasal LAIV (n = 43) or intramuscular TIV (n = 42). The 2006–2007 formulations of TIV and LAIV were used; each contained A/New Caledonia/20/99 (H1N1),
Identification of the genes with significantly differential expression
Of the 85 subjects, 43 subjects were vaccinated with LAIV and 42 subjects were vaccinated with TIV. The subjects were all 12–35 months of age, and only 4 subjects had previously received an influenza vaccine. The demographic data of the 85 subjects in the study are summarized in Table 1. To identify the transcripts that were differentially expressed in subjects vaccinated with LAIV or TIV, the FC values for a subject pre- and postvaccination were calculated. A total of 246 and 39 probe sets
Identification of differentially expressed genes using a nonconventional approach
To identify differentially expressed transcripts between postdose 1 and baseline for each subject, Student's t-test was used. However, only 1 gene (IFI27) was found to be significantly differentially expressed. Because most of the differentially expressed genes identified in this study had a prevalence of <50%, few of them would be selected using a conventional approach, such as a t-test. The low prevalence may be attributed to varying responses in subjects; a subject may have a distinct
Acknowledgments
We thank Joseph Shaw and Gorazd Drozina for the manuscript preparation and Tingting Yi for technical assistance.
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