Annual Vaccination Against Influenza Virus Hampers Development of Virus-Specific CD8⁺ T Cell Immunity in Children

Abstract

Infection with seasonal influenza A viruses induces immunity to potentially pandemic influenza A viruses of other subtypes (heterosubtypic immunity). We recently demonstrated that vaccination against seasonal influenza prevented the induction of heterosubtypic immunity against influenza A/H5N1 virus induced by infection with seasonal influenza in animal models, which correlated with the absence of virus-specific CD8(+) T cell responses. Annual vaccination of all healthy children against influenza has been recommended, but the impact of vaccination on the development of the virus-specific CD8(+) T cell immunity in children is currently unknown. Here we compared the virus-specific CD8(+) T cell immunity in children vaccinated annually with that in unvaccinated children. In the present study, we compared influenza A virus-specific cellular and humoral responses of unvaccinated healthy control children with those of children with cystic fibrosis (CF) who were vaccinated annually. Similar virus-specific CD4(+) T cell and antibody responses were observed, while an age-dependent increase of the virus-specific CD8(+) T cell response that was absent in vaccinated CF children was observed in unvaccinated healthy control children. Our results indicate that annual influenza vaccination is effective against seasonal influenza but hampers the development of virus-specific CD8(+) T cell responses. The consequences of these findings are discussed in the light of the development of protective immunity to seasonal and future pandemic influenza viruses.

Fig. 1.

Influenza A virus-specific humoral immunity. The proportion of children of the healthy unvaccinated control group (gray bars) and the vaccinated group of children with CF (white bars) with antibodies against at least one of the influenza viruses was calculated for all influenza viruses of each subtype (A) or for all indicated viruses individually (B). Bars represent percentages with 95% confidence intervals. (C) GMTs were calculated for all samples in which antibodies against the indicated viruses were detected. Bars represent GMTs with standard deviations, and the horizontal gray bar indicates the detection limit of the assay. The asterisks indicate significant differences between the two groups (P < 0.05).

Fig. 2.

IgG antibody responses to various viral and bacterial vaccine antigens. Mean IgG antibody response (±SDs) to various viral and bacterial antigens included in the Dutch national vaccination program of the healthy unvaccinated control group (gray bars) and the vaccinated group of children with CF (white bars) for measles (A), mumps (B), rubella (C), varicella-zoster (D), diphtheria toxin (E), and tetanus toxin (F).

Fig. 3.

Correlation between age and influenza virus-specific T cell responses. The percentage of virus-specific CD8⁺ IFN-γ⁺ T cells (A and B) and CD4⁺ IFN-γ⁺ T cells (C and D) was determined and plotted as a function of the age of the individual subjects. Each dot represents the result for an individual subject, and the correlation between all subjects of one group was calculated and is indicated by the black line. Data for both unvaccinated control children (A and C) and vaccinated children with CF (B and D) are shown. The correlation between age and the percentage of CD8⁺ IFN-γ⁺ T cells was significantly different (P < 0.05) between the two study groups.

Fig. 4.

T cell responses to stimulation with SEB. The percentage of CD4⁺ IFN-γ⁺ T cells (A and C) and CD8⁺ IFN-γ⁺ T cells (B and D) responding to SEB was determined for each subject of the group of unvaccinated control children (A and C) and the vaccinated children with CF (B and D). The percentage of SEB-specific CD8⁺ IFN-γ⁺ T cells was also plotted against the percentage of influenza virus-specific CD8⁺ IFN-γ⁺ T cells for both the control children (E) and the vaccinated children with CF (F).