Immunoglobulin E (IgE) responses to paramyosin predict resistance to reinfection with Schistosoma japonicum and are attenuated by IgG4

Abstract

Schistosomiasis remains a public health concern in developing countries, and rapid reinfection fostered by continued exposure to contaminated water sources necessitates a vaccine to augment current mass treatment-based control strategies. We report isotype-specific (immunoglobulin A [IgA], IgE, IgG1, IgG4, and IgG) antibody responses to soluble worm antigen preparation and the recombinant vaccine candidates rSj97, rSj67, and rSj22 from a Schistosoma japonicum-infected cohort in Leyte, the Philippines, where schistosomiasis is endemic. Sera were collected from infected individuals 1 month posttreatment with praziquantel, and antibody responses were measured using a bead-based multiplex platform. Reinfection was monitored by stool sampling every 3 months, and data up to 1 year were included in the analysis (n = 553). In repeated-measures models, individuals with detectible IgE responses to rSj97 had a 26% lower intensity of reinfection at 12 months posttreatment compared to nonresponders after adjusting for age, gender, village, exposure, pretreatment infection intensity, and clustering by household (P = 0.018). In contrast, IgG4 responses to rSj97 as well as rSj67 and rSj22 were associated with markedly increased reinfection intensity. When stratified by IgG4 and IgE responder status, individuals with IgE but not IgG4 responses to rSj97 (n = 16) had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 responses but not IgE responses (n = 274), even after adjusting for potential confounders (P = 0.016). Together with our previously described protective cytokine responses, these data further support paramyosin as a leading vaccine candidate for human schistosomiasis japonica and underscore the importance of careful adjuvant selection to avoid the generation of blocking IgG4 antibody responses.

FIG. 1.

Intensity of reinfection over time for IgG4 responses to SWAP and the recombinant antigens Sj97, Sj67, and Sj22. LS means represent the mean reinfection egg burden after adjusting for potential confounders and clustering by household in a repeated-measures model. P values are for time by antibody response interaction. Error bars represent standard errors.

FIG. 2.

Intensity of reinfection over time for IgE responses to SWAP, Sj97, Sj67, and Sj22. LS means represent the mean reinfection egg burden after adjusting for potential confounders and clustering by household in a repeated-measures model. P values are for time by antibody response interaction. Error bars represent standard errors.

FIG. 3.

IgE responses to rSj97 (paramyosin) predict resistance to S. japonicum reinfection at 12 months posttreatment and are attenuated by IgG4. LS means represent the mean reinfection egg burden after adjusting for potential confounders and clustering by household in a repeated-measures model using the combined Sj97 IgE and IgG4 response variable (a P value of 0.023 for time by combined IgE-IgG4 variable interaction). Confounders in this model include age, gender, village of residence, exposure, and baseline intensity. P values represent pair-wise comparisons between IgG4 only and the indicated groups. Error bars represent standard errors.