Abstract
BackgroundFactors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens.Methodology/Principal FindingsDuring the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-γ+ cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-γ+ CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56dim NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56dim NK and DC.SignificanceThese results demonstrate that assessment of baseline biomarkers may predict immunologic outcome of influenza vaccination and may reveal some of the mechanisms responsible for variable immune responses following vaccination and natural infection.
Highlights
Influenza viruses are major respiratory tract pathogens for people of all ages, especially the elderly and very young [1]
Our working hypothesis for this study is that immune responses to vaccine antigens are a function of overall immunity against the antigen at the time of vaccination, as well as a function of the host and vaccine variables that influence activity of immune cells
We searched among a total of seven influenzaspecific baseline immune variables related to either the adaptive or innate immune system, two age-related host variables and one vaccine variable for baseline correlates of T-cell and antibody responses to influenza vaccination
Summary
Influenza viruses are major respiratory tract pathogens for people of all ages, especially the elderly and very young [1]. TIV is approved for use in people ages 6 months or older, LAIV is approved for use in persons 2–49 years of age. Both vaccines are considered safe and effective for the designated age groups, a recent study found that in healthy children aged 6 months–4 years, LAIV had significantly better efficacy than TIV for both antigenically well-matched and drifted strains [4]. Most adults and older children have pre-existing immunity against influenza viruses due to prior infection or vaccination [6,7,8]. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens
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