The induction and persistence of T cell IFN-gamma responses after vaccination or natural exposure is suppressed by Plasmodium falciparum

Abstract

Epidemiological observations suggest that T cell immunity may be suppressed in malaria-endemic areas. In vitro studies, animal models, and limited data in humans link immunosuppression with malaria, malnutrition, and other parasitic infections. However, there are no data to determine whether malaria-induced immunosuppression is significant in the long-term, or relative data comparing it with other factors in malaria-endemic areas, so as to measure the impact of malaria, other parasitic disease, nutritional status, age. and location on the acquisition and longevity of IFN-gamma responses in children in Kenya. We studied these factors in two cohorts of 1- to 6-year-old children in a malaria-endemic area. T cell responses were induced by vaccination in one cohort, and acquired as a result of natural exposure in a second cohort. Serial ELISPOT assays conducted over a 1-year period measured the induction and kinetics of IFN-gamma production in response to the malaria Ag thrombospondin-related adhesion protein. Induced responses in both cohorts and the longevity of response in the vaccinated cohort were fitted to potential explanatory variables. Parasitemia was prospectively associated with reduced IFN-gamma-producing T cells in both cohorts (by 15-25%), and both parasitemia and episodes of febrile malaria were associated with 19 and 31% greater attrition of T cell responses, respectively. Malaria may reduce the efficacy vaccinations such as bacillus Calmette-Guérin and investigational T cell-inducing vaccines, and may delay the acquisition of immunity following natural exposure to malaria and other pathogens.

FIGURE 1

The cross-sectional bleeds used for each data set and their relationships to malaria transmission and vaccination are shown. Each data set uses two cross-sectional bleeds, modeling the impact of T cell responses at the earlier time point, parasitemia at both time points, and malaria episodes during the intervening time on T cell responses seen at the later time point.

FIGURE 2

The study profile for the 405 subjects recruited is shown. ELISPOT data was missing from the four time points because of assay failure in 51, 8, 45, and 7 instances, and because of nonattendance in 0, 33, 57, and 102 instances, respectively. The high number of nonattendances at the last time point appeared to be related to seasonal traveling patterns.

FIGURE 3

T cell responses to vaccination identified by both ex vivo and cultured ELISPOT are displayed over time for each data set analyzed. Median, 25th and 75th quartile, 5th and 95% quartile and outlying results are given by box and whisker plots. Vaccination with FFM ME-TRAP induced ex vivo ELISPOT and cultured responses (p < 0.0005, p < 0.0005, data set 1). There was also a significant rise in T cell responses during the malaria season among control vaccinees (data set 2, p < 0.0005, p = 0.001 for ex vivo and cultured responses, respectively). Vaccine-induced ex vivo response fell over the next 9 mo (data set 3, p < 0.0005), but cultured responses were sustained (p = 0.51). The geometric mean responses are shown below each box and whisker plot.

FIGURE 4

IFN-γ-producing T cells are compared by malaria parasitemia at the cross-sectional bleed before immunological studies (as paired box and whisker plots). The first two box and whisker pairs in each data set show the absolute values seen at the cross-sectional bleed that was analyzed as the outcome data in each data set. The second two box and whisker pairs show the fold change in T cell numbers when the outcome data is divided by T cell numbers seen at a previous cross-sectional bleed. Hence, x1 indicates no change in T cell responses over time. Values of p for each comparison (malaria parasites positive vs malaria parasites negative) are shown under each pair.