Immune Responses to Mumps Vaccine in Adults Who Were Vaccinated in Childhood

Wild-type mumps virus continues to cause outbreaks throughout the world despite widespread immunization programs. An outbreak in the United States in 2006 resulted in 5783 confirmed or probable mumps cases [1]. In this outbreak, high rates of mumps cases were observed among college students 18 –24 years old [2]. The mumps vaccination status was not known in all patients; however, in a subset of these patients (n = 1798), 49% had received at least 2 doses of measles-mumps-rubella (MMR) vaccine, and 14% had received 1 dose [1]. It is unclear whether mumps outbreaks in vaccinated individuals result from failure to respond to vaccination (defined as primary vaccine failure) or waning immunity (defined as secondary vaccine failure) [3–6]. Although studies have reported high rates of serocon-version after mumps vaccination (>90%) [3, 7], efficacy studies have shown rates as low as 64% after 1 vaccine dose, rising to 88% after 2 doses [4– 6]. Immunogencity studies measuring only mumps- specific IgG levels probably overestimate vaccine efficacy. One study evaluated neutralizing antibodies to mumps virus in patients who contracted mumps disease and who had received 1 mumps vaccine dose. These data showed low levels of vaccine-specific neutralizing antibody titers despite high mumps IgG levels [8]. Results of these studies parallel findings with measles vaccine and support the idea that subsets of individuals fail to respond to primary immunization but will respond to a second vaccine dose [9]. Primary vaccine failure clearly contributes to disease susceptibility, but it remains unclear whether mumps vaccination is also associated with waning immunity and subsequent secondary vaccine failure. The possibility of secondary failure is supported by findings of studies using mumps antibody avidity assays in small groups of vaccinated individuals who contracted mumps disease. In these studies, some individuals who had been vaccinated showed high-avidity titers associated with a recall response to antigen and not a primary response [10–12]. These studies were conducted in populations in which the majority of persons had received 1 mumps vaccine dose; therefore, this has not been evaluated extensively in populations in which 2 doses are routine. The immunogenicity of the mumps vaccine depends on the generation of mumps-specific antibodies, particularly neutralizing antibodies, and on the development of cell-mediated immunity [13–15]. Speculation has arisen concerning whether mumps outbreaks may result if there are antigenic differences between circulating wild-type virus and vaccine strains. Mumps vaccine strains vary globally [16], and some data suggest that there are differences between mumps virus strains in the neutralizing ability of serum from vaccinated individuals [3], potentially leaving highly vaccinated populations at risk for infection with a strain not fully neutralized by vaccine immunity. The contribution of cell-mediated immunity to protection against mumps virus infection has not been clearly defined, but evidence supports the importance of T lymphocytes as the main protagonist in the recovery from acute viral infection and in providing long-lasting protection against disease. Although neutralizing antibodies most likely represent the first defense against reinfection with viruses, individuals lacking humoral immunity appear to be protected against infection or severe disease. One study of measles virus showed that, despite the inability to detect antibody responses to measles, positive lymphocyte responses were associated with protection against measles virus infection [17]. Animal studies in macaques demonstrated a limited role of humoral immunity against measles virus replication and control and a more crucial role of cell-mediated immunity [18, 19]. Mumps virus protection would be expected to follow a similar pattern of immunity because it belongs to the same family of viruses as measles virus. The present study investigated mumps-specific cellular and humoral immunity in adults who had received 2 doses of mumps-containing vaccines in childhood in order to evaluate whether immunity persists years after vaccination. In addition, we evaluated mumps-specific immunity in adults who reported a history of mumps virus infection in childhood as a control group. We focused on cell-mediated immunity as an important component of the immune response to mumps. Previous studies had evaluated mumps-specific cell-mediated immunity using skin tests, in vitro lymphocyte proliferation, and cytokine measurement in peripheral blood mononuclear cell (PBMC) cultures in response to stimulation with mumps antigen. We were interested in evaluating the memory CD4+ T cell response on exposure to mumps antigen in vitro. Few published studies have evaluated cell-mediated responses to mumps antigen by cytokine enzyme-linked immunospot assay and/or flow cytometry [20–22]. Using the very sensitive technique of flow cytometry, we were able to evaluate mumps-specific CD4+ T cells and single-cell expression of interferon (IFN)– γ in memory CD4+T cells in response to mumps antigen [22, 23].