Our data suggest a high force of S. mansoni
transmission in this area along Lake Victoria in western Kenya. After two years of diagnosing and treating infected children every four months, the prevalence of S. mansoni
in Arm A of our cohort was still approximately 30%. This is close to the overall prevalence of 37% found in our initial survey of 8-10 year old children in the study area. More than half (56%) of the children in Arm A had 2 or more positive S. mansoni
diagnoses during the course of two years after treatment of the initial infection. Since we did not assess cure after each treatment, we cannot be certain that each positive diagnosis was a reinfection rather than a cure failure. Since the cure rate of PZQ is >70% after one dose [25
], the majority of these positive diagnoses likely represented true cures and reinfections.
The original design of the study was to examine differences in immune parameters between children kept as free from S. mansoni infection as possible for 2 years (Arm A) and children treated only once 2 years prior (Arm B). However, when Arm A was analyzed as a group, we did not find a difference in levels of schistosome-specific IgE between arms A and B at the end of the study. What we did not anticipate was that some children in this area had developed an apparent level of resistance to reinfection prior to age 8-10 when they were enrolled in this study, as they did not become reinfected for two years following one PZQ treatment. When Arm A was stratified according to the number of S. mansoni diagnoses each child had during follow-up, which is a close approximation to how many times the child was reinfected, those children that did not get reinfected for at least 2 years after treatment of their baseline infection had significantly higher levels of anti-SWAP IgE and borderline significantly higher levels of CD23+ B cells than the more susceptible children with at least 2 repeat S. mansoni diagnoses (and likely ≥2 reinfections) within 2 years. After 3 or more PZQ treatments, both anti-SWAP IgE and the percentage of CD23+ B cells had significantly increased in the more susceptible children, indicating that frequent treatment of infected children can drive immune responses to more closely resemble those of the children who remained uninfected over the course of follow-up.
Numerous studies have reported an association between higher levels of schistosome-specific IgE and resistance to reinfection with S. mansoni
]. We recently reported increases in anti-SWAP IgE that paralleled the change from a state of susceptibility to S. mansoni
infection to a state of increased resistance to reinfection in our cohort of adult males undergoing repeated cycles of treatment and reinfection [20
]. We also recently reported a correlation between the percentage of CD23+ B cells and the level of resistance to S. mansoni
reinfection in our cohort of adult males, suggesting that B cells expressing CD23 may play a role in the development of protective immunity [12
]. CD23 is the low affinity receptor for IgE and has shown to be essential for IgE-mediated enhancement of specific immune responses in murine models [28
We did not see an increase in anti-SWAP IgE in children who received 2 PZQ treatments during the course of follow-up. However, this group was likely a combination of children who failed to cure after the initial PZQ treatment, children who had already developed an intermediate level of resistance, and children who had more than one reinfection but were not diagnosed as repeat positives due to the insensitivity of the Kato-Katz test on a single stool. While there was an overall increase in CD23+ B cells over the two-year period in both study arms, this was not unexpected as studies have shown that the proportion of B lymphocytes expressing CD23 slowly increase until age 12 in normal pediatric populations [29
]. However, within Arm A, the increase was more dramatic in the more susceptible children who received 3 or more PZQ treatments than in the more resistant children who only required 1 initial PZQ treatment.
A high level of co-infection between S. mansoni and malaria and STHs was present in this population. We found no association between levels of schistosome-specific IgE and co-infection with either malaria or STHs. Children co-infected with STHs and S. mansoni at baseline had a statistically significantly higher percentage of CD23+ B cells than children without STH infection. A higher percentage of CD23+ B cells in co-infected children was only seen at baseline when they likely had long term S. mansoni and STH infections. The difference did not persist after baseline treatment of their infections.
In conclusion, we found that some children in this highly endemic area exhibited a phenotype indicative of resistance to S. mansoni
reinfection by 8-10 years of age. Infections in lakeside communities have been shown to begin very early in life [31
], and some of our 8-10 year old subjects could have been infected for 7-9 years at the time of their enrollment, providing an opportunity for them to have already experienced dying worms. The resistant phenotype was characterized by high schistosome-specific IgE and elevated levels of CD23+ B cells. Frequent PZQ treatment of more susceptible children increased these immune responses towards protective levels. The effect of PZQ treatment on the production of anti-SWAP IgE and CD23+ B cells was obscured when data were analyzed without accounting for differences in prior development of apparent resistance to S. mansoni