Antibodies against a secreted protein from hookworm larvae reduce the intensity of hookworm infection in humans and vaccinated laboratory animals

Abstract

The development of a vaccine would provide an important new tool for the control of human hookworm infection. On the basis of successful vaccination of laboratory animals with living irradiated, third-stage hookworm larvae (L3), we examined the antibody responses of individuals from hookworm endemic areas of Brazil and China against the most abundant L3 secreted antigens, the ancylostoma secreted proteins, ASP-1 and ASP-2. Logistic regression was used to investigate the effects of antibody isotype responses to ASPs on the risk of an individual harboring heavy hookworm infection. A significant protective association was observed between increasing anti-ASP-2 IgE levels and the risk of heavy hookworm infection. To confirm that ASP-2 is a protective antigen, laboratory dogs were immunized with recombinant ASP-2 formulated with the GlaxoSmithKline Adjuvant, AS03. Sera obtained from the immunized dogs exhibited high geometric mean antibody titers, immunoprecipitated native ASP-2 from L3 extracts and localized the site of ASP-2 expression to the glandular esophagus and body channels exiting to the cuticle. The sera also exhibited an increased ability to inhibit migration of L3 through tissue in vitro relative to sera from AS03-injected controls. Upon L3 challenge, the ASP-2 vaccinated dogs exhibited significant reductions in fecal egg counts and intestinal hookworm burden. These findings provide strong support for the development of an effective recombinant vaccine against hookworm infection in humans.

Effects of Treatment on IgE Responses against Parasite Allergen-Like Proteins and Immunity to Reinfection in Childhood Schistosome and Hookworm Coinfections

“…This is not unexpected: responses to larval antigens are likely to reflect exposure to infection as opposed to chronic patent infection. Higher anti-Na-ASP-2 IgE levels have been positively associated and higher anti-Na-ASP-2 IgG4 levels have been negatively associated with heavy hookworm infection in individuals from areas with high rates of transmission in Brazil and China (11). None of the children included in our study produced a detectable anti-Na-ASP-2 IgE response.…”

“…Somatic adult hookworm (AHW) crude antigen extract was derived from Ancylostoma caninum, taken from canines. Na-ASP-2, an excretory-secretory (ES) product released by third-stage Necator americanus larvae, was expressed in Pichia pastoris as previously described (11,42).…”

“…In schistosomiasis, IgE to adult worm antigens has been associated with resistance to reinfection (5)(6)(7)(8); these responses tend to increase with age and after chemotherapeutic treatment in populations in which the disease is endemic (9,10). In hookworm infection, negative relationships between both total and specific IgE and worm weight, fecundity, and heavy hookworm infection have been described (11,12). In contrast to schistosomiasis, there is little evidence for treatment boosting of antibody responses; instead, responses tend to decrease posttreatment (13,14).…”

“…For example, IgE to Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1-IgE) is a marker for human immunity in schistosomiasis mansoni (5,16); SmTAL1 is a member of the TAL family, a group of proteins sharing structural homology with the EF hand allergens, one of the most common groups of clinical allergens (9). In necatoriasis americanus, negative associations between IgE to the recombinant larval protein Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2) and heavy infection intensity have been described (11); Na-ASP-2 shares structural homology with the pathogenesis-related 1 (PR-1) allergens, the majority of which are derived from insect venoms (18).…”

The evolution of the Th2 immune responses and its relationships with parasitic diseases and allergy

“…Aunque en los vertebrados que no producen IgE los mecanismos inmunológicos que controlan la infestación helmíntica son eficientes (al menos, para evitar que alteren la supervivencia de la especie) y en algunos animales se ha observado que la IgE no determina la resistencia, los estudios en humanos y otras especies de mamíferos sugieren que esta inmunoglobulina participa en los mecanismos de protección (22,(54)(55)(56)(57). Sin embargo, es difícil precisar la magnitud en que la IgE habría mejorado la respuesta inmunitaria antihelmíntica, pues aun la inmunidad estéril (eliminación completa de los parásitos en un animal infectado) no es un fenómeno usual; además, no se ha descartado que en los estudios epidemiológicos mencionados, la IgE específica sea sólo una señal asociada a la activación de la inmunidad de tipo 2, la cual, con otros mecanismos efectores, se encargaría realmente de la defensa.…”