Our study represents one of the first evaluations of the cell-mediated immune response to inactivated influenza vaccine in pediatric solid organ transplant recipients and suggests a diminished T cell response in a cohort of older, minimally immunosuppressed subjects. An evaluation of the T cell response to influenza vaccination (by ELISPOT assay) that involved 65 adult renal transplant recipients also reported diminished IFN-γ secretion in response to influenza-specific antigen stimulation in the recipients, compared with healthy control subjects [23
]. Similar to our study, in that study [23
], HI antibody titers were not predictive of IFN-γ ELISPOT results.
Although a recent trial involving healthy influenza vaccine-naive children argued the necessity of 2 doses of vaccine to achieve seroprotective antibody titers [30
], our results suggest that a second dose of vaccine has little effect on either humoral or cell-mediated immunity. Our results may be limited by a small sample size, but they are consistent with results of a previous study of the cell-mediated response to inactivated influenza vaccination in healthy infants and children, in whom a second dose of vaccine had little effect on T cell IFN-γ secretion [31
]. IFN-γ secretion following inactivated influenza vaccination in that trial was age dependent and was most prominent in children aged 6 months to 4 years. The relationship between age and immune response to inactivated influenza vaccine is underscored by recent studies suggesting that CD80 and CD86 expression on activated monocytes, which are increased in magnitude in younger persons, are predictive of vaccine immunogenicity [31
]. Additional studies are necessary to clarify the association between age and vaccine immunogenicity, particularly in immunocompromised populations, and to determine whether a second booster dose is beneficial in transplant recipients.
Thirteen transplant recipients in our study did not experience seroconversion to either viral strain, including 8 subjects who demonstrated nonprotective titers at baseline. The statistically significantly increased rate of acute allograft rejection during the study period and the trend towards increased use of non–tacrolimus-based immunosuppressive therapy in this group suggest that the inability to achieve seroconversion may be a result of receipt of more-potent immunosuppressive treatments. The episodes of acute allograft rejection were treated with methylprednisolone (20 mg/kg/day for 1–3 days) and with an increase in the dosage of maintenance immunosuppressive therapy. The increased rates of Epstein-Barr virus and CMV viremia among subjects who did not experience seroconversion did not reach statistical significance, but the trend observed could be related to both virus- and drug-induced immunosuppression. Prospectively identifying cohorts of children who are unlikely to respond to influenza vaccine could also identify the children who may require antiviral prophylaxis in the context of outbreaks of influenza. This vulnerable cohort could also benefit from novel vaccination strategies [33
Four transplant recipients developed mild or moderate biopsy-proven acute allograft rejection during the course of the study. The rate of allograft rejection in this cohort is consistent with national rates of acute allograft rejection during the first 2 years after transplantation [36
]. A small study involving 28 adult heart transplant recipients (14 vaccinated patients and 14 control subjects) suggested an increased risk of reversible, low-level histological allograft rejection following inactivated influenza vaccination [13
], but a larger study involving 51 adult liver transplant recipients identified no association between inactivated influenza vaccination and acute allograft rejection or asymptomatic elevated transaminase levels [37
]. No pediatric studies have thoroughly evaluated the relationship between vaccination and allograft rejection. This is a critical area of investigation, because some transplantation centers delay influenza vaccination following transplantation to avoid vaccine-related graft dysfunction. Evidence suggests that the risk of allograft rejection following acute influenza infection outweighs the theoretical risk of allograft rejection in response to vaccination. The rate of acute allograft rejection approached 62% in a review involving 30 adult solid organ transplant recipients with influenza virus infection [38
], and influenza-mediated allograft rejection was a well-documented cause of mortality in pediatric series [8
]. Influenza virus infection may induce allograft rejection by up-regulating inflammatory cytokines and chemokines, including IL-1, TNF, IL-6, and IL-8, leading to activation of immune mechanisms that result in cellular rejection [38
The small number of subjects in our pilot study, the exclusion of infants, and the lack of age-matched control subjects may have limited the results of our trial. Most of the subjects enrolled in our study had undergone transplantation at least 6 months prior to the study and, thus, were beyond the period of highest risk for allograft rejection. Furthermore, the clinical significance of a diminished ELISPOT response is unclear, because few data exist that document the ELISPOT response to influenza vaccine in a healthy population. In contrast to HI assays in which seroprotective responses are well defined, no established ELISPOT value or fold change from baseline has been demonstrated as predictive of cell-mediated immune response to influenza.
The consistently lower cell-mediated immune responses demonstrated in transplant recipients (compared with their healthy siblings) in this study argue the need for larger and more thorough investigations of the immunogenicity of inactivated influenza vaccine in this population. It is crucial that future studies include the most vulnerable children, including infants and transplant recipients within the first year after transplantation. Ideally, future trials would use more sophisticated immunological studies to elucidate the phenotype of influenzaspecific T cells following vaccination. Larger and more-detailed studies could provide the data necessary to define a truly protective cell-mediated immune response to influenza vaccine in immunocompromised populations and would provide the framework for future studies of live attenuated vaccines. Determining the parameters that predict an effective and safe response to influenza vaccine could lead to more-effective strategies for protecting immunocompromised hosts against influenza pandemics and emerging pathogens.