Importantly, there was no difference in LsAg-specific spleen cell proliferation between vaccinated mice that had received RPEs compared to vaccinated mice that had not. lower worm burdens in vaccinated mice given RPEs than in vaccinated controls. These results demonstrate that vaccines which induce type 2 immune responses can maintain their efficacy in the setting of repeated parasite exposures. Keywords:vaccine, helminth, IgE, type NAMI-A 2 immunity, IL-4, basophil, filarial,Litomosoides sigmodontis, immunological tolerance, desensitization, regulatory T-cells == 1. Introduction == Helminths infect more than one billion people, primarily in developing regions in Sub-Saharan Africa, Asia and the Americas [1,2]. Because of increasing appreciation for the substantial morbidity caused by these infections, including growth stunting, anemia, malnutrition, and impaired cognition [1,3,4], in the past several years there has been renewed interest in developing vaccines against human helminth infections. Type 2 immune responses are characterized by the development of antigen-specific NAMI-A IgE, and production of type 2 cytokines such as IL-4 and IL-13. Research efforts have found that induction of type 2 immune NAMI-A responses NAMI-A and antigen-specific IgE may be desirable for the creation of effective helminth vaccines. Protection against helminth challenge CASP3 after vaccination with irradiated parasites is associated with production of type 2 cytokines in animal models of hookworm and filaria infection [5,6]. Similarly, high titers of parasite-specific IgE antibodies in people are associated with partial protection against reinfection withSchistosoma japonicum[7] and hookworm vaccine studies demonstrate that host IgE responses against hookworm antigen correlate with increased protection [8]. Additionally, IgE has been shown to be necessary for vaccine efficacy againstHaemonchus contortus, a blood-feeding nematode of sheep [9], and for vaccine protection in theOnchocercamurine model of filariasis [10]. Because of these findings, consideration has been given towards developing helminth-specific vaccines which induce parasite-specific IgE responses [11]. To date, helminth vaccines that induce type 2 immunity and IgE responses have only been tested against a single challenge infection. A theoretical concern of an IgE-inducing vaccine, however, is that the protective efficacy of an IgE-driven vaccine response could possibly decrease in the setting of repeated parasite exposures in a manner akin to that observed in desensitization protocols of patients with allergen-specific IgE. In allergen-specific immunotherapy (SIT), repeated allergen exposures result in clinical tolerance towards allergen. Immunologic changes associated with SIT include decreases in allergen-specific IgE, increases in allergen-specific IgG4, an allergen-specific T-cell shift from Th2 to Th1, and peripheral T-cell tolerance towards allergen due to increased IL-10 production from antigen-specific and CD4+CD25+regulatory T-cells [12,13]. Thus, as Th2 responses and IgE have been shown to be involved in protection to filarial parasites [10,1419] and as induction of immunotolerance facilitates helminth survival [20,21], we hypothesized that repeated parasite exposures (RPEs) may decrease the efficacy of a type 2 immune-inducing vaccine. Such a phenomenon would have important implications for helminth vaccine design since individuals in endemic areas are repeatedly exposed to parasites. For our studies, we chose to use theLitomosoides sigmodontismurine model of filariasis [22,23] in which a series of three vaccinations with irradiated larvae confers protection against challenge infection with infectious-stage L3 larvae [24]. This vaccination regimen induces a type 2 immune response with increases in type 2 cytokines such as IL-4 [5] and, as we show in this study, elevated levels of parasite-specific IgE. Testing of our hypothesis was done by evaluating whether repeated injections of either irradiated infectious-stage (L3)L. sigmodontislarvae for two or eight weeks or infectious L3 larvae for 3 months substantially alter the immune responses and protective efficacy of the type 2 immune-inducing vaccination regimen againstL. sigmodontis..