T Cell Regulatory and Suppression Mechanisms in Malaria

恶性疟原虫感染和疫苗反应：我们应该假定治疗吗？

Plasmodium falciparum Infection and Vaccine Responses: Should We Treat Presumptively? Individuals with malaria may have blunted immune responses to some vaccines, suggesting that there is an active immune suppression or immunomodulation during infection. How and which vaccines are impacted by clinical malaria or asymptomatic parasitemia is not completely clear, nor is whether the impacts are sufficient to recommend delaying or presumptively treating individuals prior to routine vaccinations or in malaria vaccine trials. In a series of ongoing studies, we are examining the impact of malaria on immune cell function and on vaccine responses in cohorts of adults at various study sites in Mali, West Africa. These studies have examined whether antimalarial treatment, or episodes of parasitemia, alter antibody responses, T cell markers, and/or protective efficacy/activity following vaccination with approved routine vaccines (N=45; Euvax or TWINRIX and Menactra), a whole organism malaria vaccine (N=30, PfSPZ Vaccine) and a transmission blocking vaccine (N=120; Pfs25H-EPA/Alhydrogel). Data from all three studies is currently being analyzed to determine the impact of antimalarial treatment or of incidental malaria episodes on T cell exhaustion and regulation, as well as on vaccine responses. Influence of Seasonal Malaria Chemoprevention on markers of T cell exhaustion and immunoregulation Plasmodium falciparum infections may also compromise immune responses to some vaccines, and thus antimalarial treatments have been considered in conjunction with vaccination. During FY16, in the context of Seasonal Malaria Chemoprevention (SMC), we examined whether malaria prevention decreases the frequency of exhausted T cells and regulatory T cells. The study was conducted in two villages in the district of Ouelessebougou in Mali, an area of intense seasonal transmission. Children either received SMC (Beneko village) or not (Ferekoroba village), and were followed for 6 months with monthly assessment of T cell markers in ex vivo assays. In the group that received SMC, 42% of children (21/50) remained free of P. falciparum (as assessed by blood smears) during the follow-up period compared to only 16% (8/50) in children who did not receive SMC. Despite the impressive effect of SMC treatment on blood stage parasitemia rates, there was no discernible effect on the level of exhausted T cells as measured by the expression of PD-1, LAG3 and CD160. The levels of T regulatory cells (CD4+FOXP3+ T cells) were increased in the non-SMC group and in a subset of the SMC group that were infected. We speculate that under intense malaria transmission, frequent antimalarial treatment (45/50 children in the group that did not receive SMC and 28/50 in the group that received SMC) complicates the ability to observe the effect of SMC on the immune system. We are currently evaluating the effect of malaria prevention during the low transmission season when malaria incidence and treatment is low, and we will analyze these data for comparison in the coming year. Seasonal Malaria Chemoprevention (SMC) is associated with reduced seropositivity to blood-stage antigens Seasonal Malaria Chemoprevention (SMC) entails 3-4 therapeutic doses of antimalarials given to children at monthly intervals. SMC was approved by WHO in March 2012 for malaria control in countries with seasonal malaria transmission, and implementation is being scaled up in Mali. While SMC has substantial benefits against malaria infection and disease, the long-term impact on immunity to malaria is not well understood. During FY16, we assayed and analyzed sera collected during cross sectional surveys at the beginning (N=579) and at the end (N=559) of the 2014 transmission season. Antibody levels to Plasmodium falciparum antigens MSP-142, AMA-1 and CSP were measured by ELISA. Seropositivity was defined as OD above the mean plus three standard deviations of nave donors. P. falciparum infection was diagnosed by blood smear. In August 2014, 53.4% of the children were infected prior to first SMC dose, compared to 22.2% in November one month after last dose. Seropositivity rates prior to and after dosing among uninfected children were 85.9% vs 73.6% to MSP-142, p<0.001; 42.2% vs 30.3% to AMA-1, p=0.001; and 19.4% vs 15.2% to CSP, p=0.2. Among P. falciparum-infected children, the rates prior to and after SMCwere 95.1% vs 91.1% to MSP-142, p=0.1; 54.0% vs 43.3% to AMA-1, p=0.05; and 30.4% vs 25.0% to CSP, p=0.3. The lower seropositivity rates at the end of the malaria season among children who received 3 monthly doses of SMC suggest that the reduced exposure to blood stage parasites is reducing immune recognition of blood stage antigens like AMA-1 and MSP-1. We are currently evaluating the effect of SMC given over 2 or 3 years on seroreactivity rates to blood stage and preerythrocytic malaria antigens. Schistosoma haematobium Prevalence in Target Populations for Malaria Vaccine Trials in Mali. Previous studies have shown that helminth co-infections have an impact on natural immunity against malaria as well as vaccine immunogenicity. In FY16, we evaluated frequency of S. haematobium infection among adult volunteers involved in phase I trials in Bancoumana and Doneguebougou, Mali. Six hundred and sixty-three (663) urine samples were screened for hematuria, using Combur7 test reagent strip, and S. haematobium, using a standard urine filtration technique for the detection of eggs, in Bancoumana (n=358) tested in April-June 2015 and Doneguebougou (n=305) tested in December 2015-April 2016. The prevalence of S. haematobium was 6.7% in Bancoumana and 11.1% in Doneguebougou. Variation between hematuria and Schistosoma infection based on gender was observed in both clinical trial sites, with increased frequency of hematuria seen in females at both locations (Bancoumana: 10.1% in males, 25.5% in females; Doneguebougou: 21.8% in males, 38.4% in females). While no significant differences was seen in schistosomiasis in Bancoumana (males: 6.6%, females: 6.9%), gender differences were seen in Doneguebougou (males: 13.1%, females: 7.1%) but not statistically significant (P=0.125). There was a significant association between Schistosoma infection and hematuria (P<0.001) at both sites. Further studies will explore the relationship of non-malaria parasitic infections including schistosomiasis on T cell markers.