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 to 59 months of age prior to the 2004–05 influenza season1. 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 males2. The pathophysiology of these differential responses was hypothesized to be multifactorial with hypersensitivity reactions, route of administration, and hormonal factors being postulated to be involved2. 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 group3.
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 polymorphisms4, 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 vaccine6 as well as live attenuated measles, mumps, and rubella (MMR)7 and varicella8 vaccinations have a genetic component. Furthermore, genetic studies of the HLA region suggest associations with variable response to the measles9 and rubella vaccination9–13, and candidate gene studies for the cytokines, toll-like receptors, and innate immunity response genes suggest associations with variable response to rubella vaccination14–16.
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 vaccination17,18. 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 vaccination19,20. 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.