Research priorities for the development and implementation of serological tools for malaria surveillance

Elliott, Salenna R.; Fowkes, Freya J. I.; Richards, Jack S.; Reiling, Linda; Drew, Damien R.; Beeson, James G.

doi:10.12703/p6-100

Cited by 61 publications

(77 citation statements)

References 106 publications

(174 reference statements)

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“…Antibodies may reach a protective threshold level and evolve to become better biomarkers of immunity but poor biomarkers of increased risk of symptomatic malaria. Further studies in different settings and populations are needed to better define optimal antibody biomarkers of malaria (38), and it should be noted that a protective threshold level of antibodies has not yet been defined. However, we believe that this model provides a framework for understanding divergent antibody associations.…”

Section: Discussionmentioning

confidence: 99%

“…However, we believe that this model provides a framework for understanding divergent antibody associations. The utility of antibodies in serosurveillance is also dependent on the longevity of antibody responses in the absence of infection, which is currently poorly understood and appears to be highly variable among individuals (38,60).…”

Section: Discussionmentioning

confidence: 99%

“…IgG levels were significantly associated with age in those that were parasite negative and parasite positive (P Յ 0.02), with the exception of MSP1-19 (P ϭ 0.24 in P. falciparum-positive children) (data not shown). Given the heterogeneity of malaria transmission levels in the study population (39), and the interest in using antibodies as biomarkers of exposure in populations (38), we then examined antibody responses relative to spatial heterogeneity in malaria transmission. Overall, antigen-specific antibody levels differed significantly (P Ͻ 0.001) when individuals were grouped by village of residence (Fig.…”

Section: Figmentioning

confidence: 99%

“…There is increasing interest in using antibodies specific for merozoite antigens as serological biomarkers of Plasmodium exposure or as biomarkers of immunity to help monitor changes in malaria transmission over time, to evaluate the impact of malaria control interventions, and to identify populations at high risk of developing symptomatic malaria to inform malaria control programs (33)(34)(35)(36)(37). However, to achieve this, a greater knowledge of antibody responses to malaria antigens and how they are acquired relative to exposure, age, and immunity is needed (38). Relatively little is known about the early acquisition and role of parasitespecific antibodies in young children, particularly in populations outside Africa, how such responses compare to responses in older children with higher levels of immunity, or the extent to which immunity may depend on the magnitude of antibody responses or the quality or nature of these responses (including antibody isotypes and IgG subclasses).…”

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confidence: 99%

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Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

et al. 2015

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i Individuals in areas of Plasmodium falciparum endemicity develop immunity to malaria after repeated exposure. Knowledge of the acquisition and nature of protective immune responses to P. falciparum is presently limited, particularly for young children. We examined antibodies (IgM, IgG, and IgG subclasses) to merozoite antigens and their relationship to the prospective risk of malaria in children 1 to 4 years of age in a region of malaria endemicity in Papua New Guinea. IgG, IgG1, and IgG3 responses generally increased with age, were higher in children with active infection, and reflected geographic heterogeneity in malaria transmission. Antigenic properties, rather than host factors, appeared to be the main determinant of the type of IgG subclass produced. High antibody levels were not associated with protection from malaria; in contrast, they were typically associated with an increased risk of malaria. Adjustment for malaria exposure, using a novel molecular measure of the force of infection by P. falciparum, accounted for much of the increased risk, suggesting that the antibodies were markers of higher exposure to P. falciparum. Comparisons between antibodies in this cohort of young children and in a longitudinal cohort of older children suggested that the lack of protective association was explained by lower antibody levels among young children and that there is a threshold level of antibodies required for protection from malaria. Our results suggest that in populations with low immunity, such as young children, antibodies to merozoite antigens may act as biomarkers of malaria exposure and that, with increasing exposure and responses of higher magnitude, antibodies may act as biomarkers of protective immunity. In areas of malaria endemicity, immunity that protects from high (H)-density parasitemia and symptomatic disease develops over a number of years (1). Knowledge of the precise nature of the protective immune responses to Plasmodium falciparum, in terms of the immune mechanisms, the specific target antigens, the nature of responses, and the rate of acquisition of immunity, has been sought, and while advances have been made, our current understanding is still limited (2, 3). Past experiments involving the passive transfer of immunoglobulin from immune adults into P. falciparum-infected individuals provided strong evidence that antibodies (Abs) play an important role in mediating immunity and target the blood stages of infection (4-6). Targets of antibodies include antigens expressed by the merozoite stage of the parasite, and these antibodies function by inhibiting merozoite invasion of red blood cells and by opsonizing merozoites for uptake by phagocytes and antibody-dependent cellular inhibition (7)(8)(9)(10)(11)(12)(13)(14).An important approach for identifying antigens as targets of protective immunity in humans is to assess the acquisition of antibodies and the association between antigen-specific responses and protection from symptomatic malaria in malariaexposed populations (3), particularly in lo...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

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Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

et al. 2015

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“…Serologic assays offer the potential to provide incidence estimates for symptomatic and asymptomatic Pf infection, which are currently obtained from cohort studies, at the cost of cross-sectional studies (36)(37)(38). Although Pf infections are transient, a record of infection remains detectable in an individual's antibody profile.…”

Section: Significancementioning

confidence: 99%

Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities

Helb

Tetteh

Felgner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Tools to reliably measure Plasmodium falciparum (Pf) exposure in individuals and communities are needed to guide and evaluate malaria control interventions. Serologic assays can potentially produce precise exposure estimates at low cost; however, current approaches based on responses to a few characterized antigens are not designed to estimate exposure in individuals. Pf-specific antibody responses differ by antigen, suggesting that selection of antigens with defined kinetic profiles will improve estimates of Pf exposure. To identify novel serologic biomarkers of malaria exposure, we evaluated responses to 856 Pf antigens by protein microarray in 186 Ugandan children, for whom detailed Pf exposure data were available. Using data-adaptive statistical methods, we identified combinations of antibody responses that maximized information on an individual's recent exposure. Responses to three novel Pf antigens accurately classified whether an individual had been infected within the last 30, 90, or 365 d (cross-validated area under the curve = 0.86-0.93), whereas responses to six antigens accurately estimated an individual's malaria incidence in the prior year. Crossvalidated incidence predictions for individuals in different communities provided accurate stratification of exposure between populations and suggest that precise estimates of community exposure can be obtained from sampling a small subset of that community. In addition, serologic incidence predictions from cross-sectional samples characterized heterogeneity within a community similarly to 1 y of continuous passive surveillance. Development of simple ELISAbased assays derived from the successful selection strategy outlined here offers the potential to generate rich epidemiologic surveillance data that will be widely accessible to malaria control programs.any countries have extensive programs to reduce the burden of Plasmodium falciparum (Pf), the parasite responsible for most malaria morbidity and mortality (1). Effectively using limited resources for malaria control or elimination and evaluating interventions require accurate measurements of the risk of being infected with Pf (2-15). To reflect the rate at which individuals are infected with Pf in a useful way, metrics used to estimate exposure in a community need to account for dynamic changes over space and time, especially in response to control interventions (16)(17)(18).A variety of metrics can be used to estimate Pf exposure, but tools that are more precise and low cost are needed for population surveillance. Existing metrics have varying intrinsic levels of precision and accuracy and are subject to a variety of extrinsic factors, such as cost, time, and availability of trained personnel (19). For example, entomological measurements provide information on mosquito to human transmission for a community but are expensive, require specially trained staff, and lack standardized procedures, all of which reduce precision and/or make interpretation difficult (19)(20)(21)(22). Parasite prevalence can be meas...

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Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

et al. 2017

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Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity.

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Research priorities for the development and implementation of serological tools for malaria surveillance

Cited by 61 publications

References 106 publications

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities

Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

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