Atopy history and the genomics of wheezing after influenza vaccination in children 6–59 months of age

Abstract

Background

A multinational clinical trial compared the safety and efficacy of intranasal trivalent live attenuated influenza vaccine (LAIV) with intramuscular trivalent inactivated vaccine (TIV) in very young children prior to the 2004–5 influenza season [1]. Wheezing was noted more often in recipients of LAIV and laboratory-confirmed influenza infection was noted more often in recipients of TIV. We sought to determine whether epidemiologic or genetic factors were associated with these outcomes.

Methods

Atopy surveys and DNA collections were performed in trial participants at two United States sites, Nashville, TN and Boston, MA. DNA samples were genotyped on Illumina Infinium 610 or 660-Quad. Standard allelic tests of association were performed.

Results

At the Nashville and Boston sites, a total of 99 children completed the trial, 6 (1 TIV, 5 LAIV) developed medically attended wheezing within 42 days following vaccination, and 8 (5 TIV, 3 LAIV) developed laboratory-confirmed influenza during the season. Eighty-one surveys and 70 DNA samples were collected. Family history of asthma (p = 0.001) was associated with wheezing after vaccination. Of 468,458 single nucleotide polymorphisms tested in the genome-wide association study (GWAS), none achieved genome-wide significance for either wheezing after vaccination or laboratory-confirmed influenza infection.

Conclusions

Family history of asthma appears to be a risk factor for wheezing after influenza vaccination. Given the limitations of the sample size, our pilot study demonstrated the feasibility of performing a GWAS but was not able to determine genetic polymorphisms associated with wheezing after influenza immunization.

Introduction

A large multinational clinical trial compared the safety and efficacy of intranasal trivalent live attenuated influenza vaccine (LAIV) with intramuscular trivalent inactivated vaccine (TIV) in children 6–59 months of age prior to the 2004–05 influenza season [1]. In the Nashville and Boston cohorts, 99 children completed the trial, six (1 with TIV, 5 with LAIV) developed medically attended wheezing within 42 days following vaccination, and eight (5 with TIV, 3 with LAIV) developed laboratory-confirmed influenza. The epidemiologic and genetic factors involved with adverse events (AEs) after vaccination and lack of vaccine efficacy are poorly understood.

Earlier studies have demonstrated that epidemiologic factors influenced the occurrence of AEs after vaccination. In one large survey evaluating injection site reactions after multiple different vaccines, significantly higher rates of pain and local reactions were seen in females when compared to males [2]. The pathophysiology of these differential responses was hypothesized to be multifactorial with hypersensitivity reactions, route of administration, and hormonal factors being postulated to be involved [2]. Another study compared the size of Bacillus Calmette-Guérin (BCG) vaccine scar between two groups of young children, one with atopy and one without, and found that children in the atopic group had significantly smaller scars than the control group [3].

Recent publications have evaluated the role of genetic factors in adverse events after vaccination. We and others have shown that the systemic and local reactions after vaccinia are linked to specific genetic polymorphisms [4], [5]. Genetic factors are also associated with variable responses to vaccines. Twin and family studies have shown that responses to Haemophilus influenza type b (Hib) conjugate vaccine [6] as well as live attenuated measles, mumps, and rubella (MMR) [7] and varicella [8] vaccinations have a genetic component. Furthermore, genetic studies of the HLA region suggest associations with variable response to the measles [9] and rubella vaccination [9], [10], [11], [12], [13], and candidate gene studies for the cytokines, toll-like receptors, and innate immunity response genes suggest associations with variable response to rubella vaccination [14], [15], [16].

Specifically for influenza, to our knowledge, no studies have been published on the genetics or genomics of adverse reactions following the seasonal influenza vaccination. But, there is evidence that the variability in acute phase response to influenza vaccination may be in part mediated by genetic variants in HLA class II, which appear to modulate antibody responses to influenza vaccination [17], [18]. Moreover, influenza vaccination results in a mild acute phase response in men with or without severe carotid artery disease, supporting the proposed role of genetic variants in the candidate gene NFKBIA in acute phase response to influenza vaccination [19], [20]. Finally, at least one study suggests that altered responses to inactivated influenza vaccine may be associated with host variants in MBL and IL10 [21].

Given the plausibility that both epidemiologic and genetic factors influence vaccine AEs and immunogenicity, we sought to identify the factors associated with wheezing and the occurrence of natural influenza among children who received intranasal trivalent live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated vaccine (TIV) in the large multinational influenza trial from the Nashville and Boston cohorts.