A Prospective, Comparative Study of the Immune Response to Inactivated Influenza Vaccine in Pediatric Liver Transplant Recipients and Their Healthy Siblings

Recent outbreaks of severe acute respiratory syndrome and avian influenza demand optimized strategies to protect society from pandemic respiratory illnesses [1, 2]. Of particular concern is the population of solid organ transplant recipients. These individuals are at high risk for morbidity and mortality secondary to influenza, and their immune response to vaccination is poorly understood. Pediatric transplant recipients are, perhaps, the most vulnerable, because even immunocompetent children are susceptible to serious influenza disease [3, 4]. At the time of transplantation, infants and young children often lack prior exposure to influenza and its subsequent protective immunologic priming [5]. Pediatric solid organ transplant recipients are at risk for influenza-related complications, including pneumonia, sepsis, CNS disease, acute graft rejection, and death [6–8]. In a retrospective review involving 42 pediatric solid organ transplant recipients with influenza or parainfluenza, 3 patients with influenza died and 4 developed concurrent infections with cytomegalovirus (CMV) and bacteremia [6]. Liver transplant recipients represent a growing proportion of the population of pediatric transplant recipients. How these children respond to vaccinations, including the inactivated trivalent subvirion influenza vaccine, is poorly understood. Evaluations of the inactivated influenza vaccine in other immunocompromised populations, such as children with HIV infection and cancer, suggest a diminished response to the vaccine that is relative to immunocompetent children [9, 10]. However, the data regarding the immune response in pediatric solid organ transplant recipients are less substantial. Prior studies have yielded conflicting results, with some authors suggesting a diminished antibody response to vaccination [11–13]. The generation of serum antibodies following influenza vaccination is crucial for protection from illness and is an important correlate for vaccine efficacy [5, 14]. However, clearance of influenza and prevention of influenza-associated complications also require a vigorous cell-mediated immune response. Influenza-specific CD8+ T cells mediate the killing of infected host cells and up-regulate proinflammatory cytokines in animal models [15, 16]. Adults with baseline cytotoxic T cell immunity against influenza clear virus more effectively than those with no pre-existing cell-mediated immunity, and cytotoxic T cells may demonstrate cross-reactivity when responding to new influenza A virus subtypes [17]. Influenza in infants stimulates cytotoxic T lymphocyte proliferation, although the degree of this response may not correlate with serum hemagglutination inhibition (HI) antibody levels [18]. Following vaccination, secondary antibody response requires the expansion of memory CD8+ T cells and CD4+ T cell assistance [19–21]. Although small studies involving both pediatric hematopoietic stem cell transplant recipients and adult solid organ transplant recipients suggest a diminished T cell response to inactivated influenza vaccine [22, 23], to our knowledge, no prospective studies have evaluated this response in pediatric solid organ transplant recipients. We present the results of a single center, prospective, comparative evaluation of humoral and cell-mediated immune responses to inactivated influenza vaccine in pediatric liver transplant recipients and their healthy siblings.