vivax /em , and a broader range of antigens needs to be examined to identify those responses that best detect changes in transmission at different levels of endemicity

vivax /em , and a broader range of antigens needs to be examined to identify those responses that best detect changes in transmission at different levels of endemicity. the development of sero-surveillance tools for malaria elimination, major gaps in our knowledge need to be addressed through further research. These include greater knowledge of potential antigens, the sensitivity and specificity of antibody responses, and the longevity of these responses and defining antigens and antibodies that differentiate between exposure to and and and may prove helpful for identifying individuals with hypnozoites (which are responsible for relapses) [18], although a suitable serological test is required. Further research is needed to determine whether serology could be a useful tool for monitoring the exposure to or evaluating the burden and distribution of these species PJ 34 hydrochloride in populations [24]. Development of serological tests for malaria surveillance A number of knowledge gaps need to be addressed in order to develop and optimize sero-surveillance tools for use in malaria control programs (Table 2). Ideal tests would provide information about long-term or recent exposure (or both) and be highly sensitive and species-specific. The intended application and target population need to be clearly defined as these will determine the technical performance required from tests, which in turn is achieved largely by appropriate selection of antigens with a strong knowledge of antibody responses to candidate antigens. noninvasive testing would be preferable to optimize the acceptability of a sero-surveillance program, especially if children were to be the major target group and malaria were no longer viewed as a major health threat. Point-of-care testing would facilitate data collection and allow rapid feedback to communities to PJ 34 hydrochloride enhance commitment to control programs. Tests should be standardized so that data could be compared between populations and geographical regions. Standardization should extend to recombinant proteins used (including expression systems), serum dilutions, Immunoglobulin G (IgG) subclass(es) detected, and the definition and calculation of seropositivity [10]. Any test would need to be carefully validated against data from parasitemia and vector surveillance and data on seasonality, spatial distribution of malaria, and other epidemiologic data. Figure 1 provides a general model for the development of sero-surveillance tests. Table 2. Research priorities for developing malaria sero-surveillance tests and sero-surveillance:and antigens.and and sequencesb51% (Ecto-domain)25%45%20% (C-terminus)cPolymorphisms 10% of ecto-domain amino acids in PfAMA1 and PvAMA1 are polymorphic. Antibodies also target cross-reactive epitopesSubstantial polymorphism.3D7 isolate with Sal1 isolate. cC-terminus has the most conservation in sequence between species. AMA1, apical membrane protein 1; CSP, circumsporozoite protein; DBP, Duffy-binding protein; EBA175, erythrocyte binding antigen 175; MSP, merozoite surface protein; PfRH2, reticulocyte-binding homologue; RBP1, reticulocyte-binding protein 1. In the context of elimination programs, sensitivity and specificity of surveillance assays are both important to ensure high-risk subpopulations and geographical hotspots are correctly identified [18]. Many malaria antigens that are targets of naturally acquired antibodies have significant polymorphism that could compromise the sensitivity of a sero-surveillance test. If necessary, strain specificity could be circumvented by including different allelic variants in the assay. Potential cross-reactivity of antibodies to antigens from different malaria species [30-32] could affect test specificity in areas where multiple malaria species are present (particularly both and and include Duffy-binding protein (DBP) and reticulocyte-binding proteins (RBPs) [33,34], and for reticulocyte binding-like homologue protein 2 (PfRh2) are species-specific and show good immunoreactivity [35-37]. Although EBA-175 (PfEBA175) and PvDBP proteins both contain structurally related Duffy-binding-like domains, the sequence identity between these domains is very low. For regions with other malaria species, potential antibody cross-reactivity would need to be investigated when developing sero-surveillance tools. Another important consideration is that antigens that are included in malaria vaccines would not be suitable candidates for sero-surveillance tests because of the difficulty in differentiating between vaccine-induced and naturally acquired antibodies. The RTS,S vaccine is the most advanced malaria vaccine, now in phase three clinical trials, and is based EC-PTP PJ 34 hydrochloride on CSP [38,39]; if the vaccine was to be licensed, CSP would not be an ideal candidate for sero-surveillance tests. Potential antigens for sero-surveillance To date, antibody responses to the merozoite antigens MSP1-19 and AMA1 have been most studied as markers of exposure to antigens have also shown potential for sero-surveillance, including blood-stage proteinsMSP2 [7], glutamate-rich protein (GLURP) [45]and sporozoite (CSP) PJ 34 hydrochloride and liver-stage proteins, such as liver-stage antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) [46-49]. Another approach may be to measure antibodies to specific antigen epitopes or alleles, which can be performed efficiently by using competition ELISAs [50]. Antibody responses to sexual-stage antigens appear considerably less.