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1 Supplemental Materials for Diagnostics to Support Malaria Elimination: Choosing an Appropriate Biomarker to Target the Subclinical Plasmodium Falciparum Transmission Reservoir July 18, 2014 MAILING ADDRESS PO Box Seattle, WA USA ADDRESS 2201 Westlake Avenue Suite 200 Seattle, WA USA TEL: FAX:

2 Appendix A: Pf Parasite Attributes and Analysis Stage 1,2 Description Appearance Density Clearance time Invasion Liver Blood A female Anopheles mosquito carrying malaria-causing parasites feeds on a human and injects malaria parasites in the form of sporozoites (5-20) into the bloodstream. The motile sporozoites travel to the liver and asymptomatically invade liver cells. Asexual schizogeny occurs over 5-16 days,* as the sporozoites asymptomatically grow, divide, and produce tens of thousands of haploid merozoites per liver cell. Asexual replication: Aggregates of merozoites exit the liver cells as merosomes and re-enter the bloodstream, beginning a cycle of invasion of erythrocytes, asexual replication, and release of newly formed merozoites from the red blood cells repeatedly over 1-3 days.* Asexual replication advances from small rings to large ring stage trophozoites then to schizonts that subsequently burst, releasing 8-32 merozoites, each of which invades new erythrocytes. Multiple cycles can release millions of parasite-infected cells in the host bloodstream, leading to illness and complications of malaria that can last for months if not treated. Cyto-adherence in between cycles can lead to sequestration in adipose tissue, lungs, and liver. Sporozoites are in peripheral blood immediately after an infected bite. Merozoites develop over 5-16 days after an infective bite. Merozoites first appear in blood 1-2 weeks after an infective bite. Rings form within 24 hours after merozoites are released. Trophozoites form hours after merozoites are released. Schizonts can form within 18 days of bite per infective bite. 5*10^4 develop in the liver. 5*10^4 from the liver and 8-32 from each schizont. Total asexualstage parasite density can reach up to 10^11. Within minutes. Depends on species: Plamodium falciparum clears merozoites within 3 weeks while Plasmodium vivax and Plasmodium ovale harbor longlived merozoites for months. Within 24 hours. Rings, trophozoites, and schizonts clear to the next stage within days, but new asexual parasites are generated with each cycle during active infection. sensitivity VERY VERY specificity Biomarker utility Duration in the body is too short. VERY Sampling liver is too invasive. Duration in the body is too short and density is low. Despite very high peak densities, sequestration of Plasmodium falciparum asexual stages in adipose, lungs, and liver can vary density from levels greater than 1000/µL to sub-patent levels over short durations of less than 48 hours. A-1

3 Stage 1,2 Description Appearance Density Clearance time Mosquito Sexual stage production: Some of the merozoite-infected red blood cells leave the cycle of asexual multiplication. Instead of replicating, the merozoites in these cells develop into non-pathogenic sexual forms of the parasite: gametocytes. The formation and maturation of gametocytes take place in five morphologically distinct stages. The male and female gametocytes that circulate in the bloodstream can linger for months. 3 When a mosquito bites an infected human, it ingests the gametocytes which mature, combine sexually, and ultimately produce sporozoites. The cycle of human infection restarts when the mosquito takes a blood meal, injecting the sporozoites from its salivary glands into the human bloodstream. Gametocytes can form within 3 weeks of an infective bite. Variable, visible gametocyte density is a fraction (1%-5%) of visible asexual stage density. Mean clearance is 3-7 days; however, some remain for weeks. sensitivity specificity Not applicable to infection detection in humans. Biomarker utility despite long clearance times, densities are often lower than asexual stage densities *Time-frame depends on the malaria parasite species. A-2

4 References 1. Page on Life Cycle of the Malaria Parasite Stage. National Institute of Allergy and Infectious Diseases website. Available at: Accessed July 18, Page on Malaria Diagnostic Findings. Centers for Disease Control and Prevention website. Available at: R/Malaria/body_Malariadiagfind2.htm. Accessed June 17, Bousema T, Drakeley C. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clinical Microbiology Review. 2011;24(2): A-3

5 Appendix B: Pf Molecular Attributes and Analysis Description Density Conserved sensitivity specificity Biomarker potential for identifying transmission risk 18S ribosomal RNA gene (18S rrna) copies/parasite genus specific high high Well-established standard, conserved, allows speciation, limit of detection limited by number of copies. Cytochrome b gene 2,4, copies/parasite genus specific high moderate High copies/parasite but useful specificity has not been demonstrated. Pfmt869 6,7 20 copies/parasite Pf high high Pgmt19 6,7 20 copies/parasite genus specific high high Pfr364 probe 8,9 41 copies/parasite (Pf) 6 copies/parasite (Pv) Pf and Pv high high Wide limit of detection range from limited data. MAL5_18S and MAL7_18Sa 10 10^4 copies/parasite asexual stages high high Very high copy. B-1

6 Description Density Conserved sensitivity specificity Biomarker potential for identifying transmission risk Pgmet gene 5,11 1 copy/parasite Pan-genus unclear unclear Low copies/p, single species, lack of data. β-tubulin gene 11,12 1 copy/parasite Pf and Pk unclear unclear Low copies/parasite and lack of data. Pfs16 mrna gene copies/gametocye all sexual forms unclear unclear Asexual stages constitute a risk. Pfs25 mrna gene copies/gametocye stage V gametocytes unclear unclear Asexual stages constitute a risk. Pf = Plasmodium falciparum Pv = Plasmodium vivax Pk = Plasmodium knowlsi Po = Plasmodium ovale B-2

7 References 1. Snounou G. Detection and identification of the four malaria parasite species infecting humans by PCR amplification 404. Methods in Molecular Biology. 1996;50: Steenkeste N, Incardona S, Chy S, et al. Towards high-throughput molecular detection of Plasmodium: new approaches and molecular markers. Malaria Journal. 2009;8: Snounou G, Viriyakosol S, Zhu XP, et al. High sensitivity of detection of human malaria parasites by the use of nested polymerase chain reaction. Molecular and Biochemical Parasitology. 1993;61(2): Farrugia C, Cabaret O, Botterel F, et al. Cytochrome b gene quantitative PCR for diagnosing Plasmodium falciparum infection in travelers. Journal of Clinical Microbiology. 2011;49(6): Baltzell KA, Shakely D, Hsiang M, et al. Prevalence of PCR detectable malaria infection among febrile patients with a negative Plasmodium falciparum specific rapid diagnostic test in Zanzibar. The American Journal of Tropical Medicine and Hygiene. 2013;88(2): Polley SD, Mori Y, Watson J, et al. Mitochondrial DNA targets increase sensitivity of malaria detection using loop-mediated isothermal amplification. Journal of Clinical Microbiology. 2010;48(8): Polley SD, Gonzalez IJ, Mohamed D, et al. Clinical evaluation of a LAMP test kit for diagnosis of imported malaria. The Journal of Infectious Diseases Demas A, Oberstaller J, DeBarry J, et al. Applied genomics: data mining reveals species-specific malaria diagnostic targets more sensitive than 18S rrna. Journal of Clinical Microbiology. 2011;49(7): Patel JC, Oberstaller J, Xayavong M, et al. Real-time loop-mediated isothermal amplification (RealAmp) for the species-specific identification of Plasmodium vivax. PLoS One. 2013;8(1):e Murphy SC, Prentice JL, Williamson K, et al. Real-time quantitative reverse transcription PCR for monitoring of blood-stage Plasmodium falciparum infections in malaria human challenge trials. The American Journal of Tropical Medicine and Hygiene. 2012;86(3): Beshir KB, Hallett RL, Eziefula AC, et al. Measuring the efficacy of anti-malarial drugs in vivo: quantitative PCR measurement of parasite clearance. Malaria Journal. 2010;9: Iseki H, Kawai S, Takahashi N, et al. Evaluation of a loop-mediated isothermal amplification method as a tool for diagnosis of infection by the zoonotic simian malaria parasite Plasmodium knowlesi. Journal of Clinical Microbiology. 2010;48(7): Schneider P, Schoone G, Schallig H, et al. Quantification of Plasmodium falciparum gametocytes in differential stages of development by quantitative nucleic acid sequence-based amplification. Molecular and Biochemical Parasitology. 2004;137(1): B-3

8 14. Ouedraogo AL, Bousema T, Schneider P, et al. Substantial contribution of submicroscopical Plasmodium falciparum gametocyte carriage to the infectious reservoir in an area of seasonal transmission. PLoS One. 2009;4(12):e Marangi M, Di TR, Mens PF, et al. Prevalence of Plasmodium spp. in malaria asymptomatic African migrants assessed by nucleic acid sequence based amplification. Malaria Journal. 2009;8:12. B-4

9 Appendix C: Pf Antigen Attributes and Analysis Description Density Appearance Clearance PfHRP2 1-6 PfHRP3 2 PfALD 7 PfLDH 8 PfMSP PfGLURP 10 Six to 11 (*10 4 ) g/l. Equivalent to more than parasites/ml blood. Also present in saliva at 17 to more than 1,000 (*10-15 ) g/l (highly variable, technology dependent). Unknown? (Publications not found) Abundant, but variable. Abundant, but variable. Correlated with parasite density. Correlated with parasite density. Expressed by all parasite stages. Unknown? (Publications not found) In all metabolizing parasites. In all metabolizing parasites. Expressed by merozoite. Expressed in all blood stages, not in liver stages. Half-life is approximately 4 days (since elimination of the last schizont, including sequestered, may be detectable for several weeks after treatment). Unknown? (Publications not found) Immediate after parasites are cleared. Immediate after parasites are cleared. Correlated with presence of parasite. Correlated with presence of parasite? Associated sensitivity Adequate for control settings, likely inadequate for elimination settings. Assuming similarity to HRP2. Abundant metabolic enzyme. Abundant metabolic enzyme. Abundant bloodstage surface antigen (Ag). Associated specificity Assisted by cross reaction of interrogating antibody (Ab) with PfHRP3? Assisted by cross reaction of interrogating Ab with PfHRP2? Specific to Plasmodium, some homology between species. Specific to Plasmodium, some homology between species. Not all variants are equally informative may require tailored in-vitro diagnostics (IVD). Biomarker utility Except in regions where variably expressed or deleted completely. Except in regions where variably expressed or deleted completely. Extant Ab cross reaction between subtypes. C-1

10 Description Density Appearance Clearance PfAMA PfMSP-3 11,14 PfMSP-2 11,15 Correlated with parasite density. Correlated with parasite density. Correlated with parasite density. Expressed in asexual blood stages. Expressed by merozoite. Expressed by merozoite. Correlated with presence of parasite. Correlated with presence of parasite. Correlated with presence of parasite. Associated sensitivity Blood-stage surface Ag. Blood-stage surface Ag. Blood-stage surface Ag. Associated specificity Not all variants are equally informative may require tailored IVD. Not all variants are equally informative may require tailored IVD. Biomarker utility Short half-life in some populations. Short half-life in some populations. C-2

11 References 1. Baker J, McCarthy J, Gatton M, et al. Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests. Journal of Infectious Diseases. 2005;192(5): Baker J, Ho MF, Pelecanos A, et al. Global sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: implications for the performance of malaria rapid diagnostic tests. Malaria Journal. 2010;9: Dondorp AM, Desakorn V, Pongtavornpinyo W, et al. Estimation of the Total Parasite Biomass in Acute Falciparum Malaria from Plasma PfHRP2. PLoS Med. 2005;2(8):e Hendriksen IC, White LJ, Veenemans J, et al. Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration. The Journal of Infectious Diseases. 2013;207(2): Fung AO, Damoiseaux R, Grundeen S, et al. Quantitative detection of PfHRP2 in saliva of malaria patients in the Philippines. Malaria Journal. 2012;11 6. Mayxay M, Pukrittayakamee S, Chotivanich K, Looareesuwan S, White NJ. Persistence of Plasmodium falciparum HRP-2 in successfully treated acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2001;95(2): Palmer CJ, Lindo JF, Klaskala WI, et al. Evaluation of the OptiMAL test for rapid diagnosis of Plasmodium vivax and Plasmodium falciparum malaria. Journal of Clinical Microbiology. 1998;36(1): Cooke AH, Chiodini PL, Doherty T, Moody AH, Ries J, Pinder M. Comparison of a parasite lactate dehydrogenase-based immunochromatographic antigen detection assay (OptiMAL) with microscopy for the detection of malaria parasites in human blood samples. The American Journal of Tropical Medicine and Hygiene. 1999;60(2): Dent AE, Moormann AM, Yohn CT, et al. Broadly reactive antibodies specific for Plasmodium falciparum MSP-1(19) are associated with the protection of naturally exposed children against infection. Malaria Journal. 2012; Cook J, Speybroeck N, Sochanta T, et al. Sero-epidemiological evaluation of changes in Plasmodium falciparum and Plasmodium vivax transmission patterns over the rainy season in Cambodia. Malaria Journal. 2012; Kinyanjui SM, Conway DJ, Lanar DE, Marsh K. IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life. Malaria Journal. 2007;6. C-3

12 12. Cook J, Reid H, Iavro J, et al. Using serological measures to monitor changes in malaria transmission in Vanuatu. Malaria Journal. 2010;9: Bousema T, Youssef RM, Cook J, et al. Serologic markers for detecting malaria in areas of low endemicity, Somalia, Emerg Infect Dis. 2010;16(3): Ibison F, Olotu A, Muema DM, et al. Lack of Avidity Maturation of Merozoite Antigen-Specific Antibodies with Increasing Exposure to Plasmodium falciparum amongst Children and Adults Exposed to Endemic Malaria in Kenya. PLoS One. 2012;7(12). 15. Reddy SB, Anders RF, Beeson JG, et al. High Affinity Antibodies to Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Malaria. PLoS One. 2012;7(2). C-4

13 Appendix D: Pf Antibody Attributes and Analysis Description Density Appearance Clearance Associated sensitivity Associated specificity Biomarker utility α-pfemp mg/ml Typical values for antibody (Ab) response. Not quantified specifically. Highly variable. Highly variable with age and exposure. Months to years. Highly variable antigen (Ag). Not adequately Good subtype specificity can enable mapping of hotspots. Best candidate among serological markers? α-msp α-glurp 2 α-ama α-msp-3 3,6 α-msp-2 3, mg/ml Typical values for Ab response. Not quantified specifically. Highly variable mg/ml Typical values for Ab response. Not quantified specifically. Highly variable mg/ml Typical values for Ab response. Not quantified specifically. Highly variable mg/ml Typical values for Ab response. Not quantified specifically. Highly variable mg/ml Typical values for Ab response. Not quantified specifically. Highly variable. Highly variable with age and exposure. Highly variable with age and exposure. Highly variable with age and exposure. Highly variable with age and exposure. Highly variable with age and exposure. Response to abundant bloodstage surface Ag is associated with acquired immunity (vaccine candidate). Months. Higher rates of seroreversion than expected during periods of low transmission. Months to years. Response to this abundant blood-stage surface Ag is associated with acquired immunity. Response to Ag is associated with acquired immunity. Shows some avidity maturation. Low avidity? Low avidity? Not all variants are equally informative may require tailored in-vitro diagnostic (IVD). Not all variants are equally informative may require tailored IVD. Not all variants are equally informative may require tailored IVD. Short half-life in some populations. Cross reaction between subtypes. Sero-reversion suggests possible utility. Not adequately Cross reaction between subtypes. Short half-life in some populations. Not adequately Short half-life in some populations. Not adequately D-1

14 References 1. Bejon P, Turner L, Lavstsen T, et al. Serological evidence of discrete spatial clusters of Plasmodium falciparum parasites. PLoS One. 2011;6(6):e Cook J, Speybroeck N, Sochanta T, et al. Sero-epidemiological evaluation of changes in Plasmodium falciparum and Plasmodium vivax transmission patterns over the rainy season in Cambodia. Malaria Journal. 2012; Kinyanjui SM, Conway DJ, Lanar DE, Marsh K. IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life. Malaria Journal. 2007;6. 4. Cook J, Reid H, Iavro J, et al. Using serological measures to monitor changes in malaria transmission in Vanuatu. Malaria Journal. 2010;9: Bousema T, Youssef RM, Cook J, et al. Serologic markers for detecting malaria in areas of low endemicity, Somalia, Emerging Infectious Diseases. 2010;16(3): Ibison F, Olotu A, Muema DM, et al. Lack of avidity maturation of merozoite antigen-specific antibodies with increasing exposure to Plasmodium falciparum amongst children and adults exposed to endemic malaria in Kenya. PLoS One. 2012;7(12). 7. Reddy SB, Anders RF, Beeson JG, et al. High affinity antibodies to Plasmodium falciparum merozoite antigens are associated with protection from malaria. PLoS One. 2012;7(2). D-2

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