malERA: An updated research agenda for malaria elimination and eradication

Rabinovich, Regina; Drakeley, Chris; Djimdé, Abdoulaye; Hall, Bradford; Hay, Simon I.; Hemingway, Janet; Kaslow, David C.; Noor, Abdisalan; Okumu, Fredros O.; Steketee, Richard W.; Tanner, Marcel; Wells, Timothy N. C.; Whittaker, Maxine; Winzeler, Elizabeth A.; Wirth, Dyann F.; Whitfield, Kate; Alonso, Pedro L.

doi:10.1371/journal.pmed.1002456

Cited by 235 publications

(197 citation statements)

References 22 publications

(16 reference statements)

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“…There is a clear and urgent need for new tools and strategies if we are to achieve malaria elimination in the Asia-Pacific by the year 2030 (37). P. vivax, the predominant Plasmodium species in the Asia-Pacific, presents a unique challenge to elimination due to the presence of undetectable hypnozoites, representing a hidden burden of infection that contributes to maintaining residual transmission.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Longley

Takashima

et al. 2018

Preprint

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One Sentence Summary: The manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.Abstract: In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of individuals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, individuals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these individuals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of individuals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria. [Main Text: ]

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Section: Discussionmentioning

confidence: 99%

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Longley

Takashima

et al. 2018

Preprint

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“…In summary, we anticipate our approach to be compatible with a broad range of research questions involving the biology of gametocytogenesis as well as human-to-mosquito transmission, with significant potential for integrating into existing research pipelines in addition to identifying novel avenues for target identification and therapeutic intervention. Blocking this stage of the parasite’s life-cycle is predicted to be one of the last remaining hurdles to overcome before we can declare a malaria-free world [1, 2], but for which SMFAs will continue to serve as the penultimate reference.…”

Section: Discussionmentioning

confidence: 99%

“…Incidence of malaria due to Plasmodium falciparum has seen a steady decline in the last 15-20 years, enabled primarily by the synergy between drug-combination therapies for case/disease management and vector control programs [1, 2]. Since transmission to the mosquito is thought to be a severe bottleneck in the parasite’s life history, considerable effort has been channeled towards identifying parasite and vector traits influencing transmission to the mosquito with the aim of designing and testing small molecule inhibitors and vaccines [3-6].…”

Section: Introductionmentioning

confidence: 99%

Cryogenically preserved RBCs support gametocytogenesis ofPlasmodium falciparuminvitroand gametogenesis in mosquitoes

Pathak

Shiau

Thomas

et al. 2018

Preprint

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21Background 22 The malaria Eradication Research Agenda (malERA) has identified human-to-mosquito 23 transmission of Plasmodium falciparum as a major target for eradication. The cornerstone for 24 identifying and evaluating transmission in the laboratory is small membrane feeding assays 25(SMFAs) where mature gametocytes of P. falciparum generated in vitro are offered to 26 mosquitoes as part of a blood-meal. However, propagation of "infectious" gametocytes requires 27 10-12 days with considerable physico-chemical demands imposed on host RBCs and 28 thus, "fresh" RBCs that are ≤1-week old post-collection are generally recommended. However, 29 in addition to the costs, physico-chemical characteristics unique to RBC donors may confound 30 reproducibility and interpretation of SMFAs. Cryogenic storage of RBCs (cryo-preserved RBCs 31 herein) is approved by the European and US FDAs as an alternative to refrigeration (4°C) for 32 preserving RBC quality and while cryo-preserved RBCs have been used for in vitro cultures of 33 other Plasmodia and the asexual stages of P. falciparum, none of the studies required RBCs to 34 support parasite development for >4 days. 35 Results 36Using the standard laboratory strain, P. falciparum NF54, we first demonstrate that cryo-37 preserved RBCs preserved in the gaseous phase of liquid nitrogen and thawed after storage for 38 1, 4, 8 and 12 weeks, supported gametocytogenesis in vitro and subsequent gametogenesis 39 in Anopheles stephensi mosquitoes. Using data from 11 SMFAs and RBCs from 4 separate 40 donors with 3 donors re-tested following various periods of cryo-preservation, we show that 41 overall levels of sporogony in the mosquito, as measured by oocyst prevalence and burdens in 42 the midguts and sporozoites in salivary glands, were similar or better than using ≤1-week old 43 3 refrigerated RBCs. Additionally, the potential for cryo-preserved RBCs to serve as a universal 44 substrate for SMFAs is shown for a Cambodian isolate of P. falciparum. 45 Conclusions 46Considering the suitability of cryo-preserved RBCs for P. falciparum SMFAs, we suggest 47 guidelines for their use and how they can be integrated into an existing laboratory/insectary 48 framework with the potential to significantly reduce running costs and provide greater reliability. 49Finally, we discuss scenarios where cryo-preserved RBCs may be especially useful in 50 enhancing our understanding and/or providing novel insights into the patterns and process 51 underlying human-to-mosquito transmission. 52Background 56Incidence of malaria due to Plasmodium falciparum has seen a steady decline in the last 15-20 57 years, enabled primarily by the synergy between drug-combination therapies for case/disease 58 management and vector control programs [1, 2]. Since transmission to the mosquito is thought 59 to be a severe bottleneck in the parasite's life history, considerable effort has been channeled 60 towards identifying parasite and vector traits influencing transmission to the mosquito with the 61 aim of designing and te...

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“…Significant reductions in malaria burden in recent decades have stimulated malaria elimination initiatives (1). It is widely accepted that malaria elimination with current tools is unlikely for the majority of African settings (2). Therefore, novel interventions are needed and approaches that specifically reduce malaria transmission may be of key importance (3).…”

Section: Introductionmentioning

confidence: 99%

P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

Meibalan

Barry

et al. 2019

Preprint

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Transmission of Plasmodium falciparum depends on the presence of mature gametocytes that can be ingested by mosquitoes taking a bloodmeal when feeding on human skin. It has long been hypothesised that skin sequestration contributes to efficient transmission. Although skin sequestration would have major implications for our understanding of transmission biology and the suitability of mosquito feeding methodologies to measure the human infectious reservoir, it has never been formally tested. In two populations of naturally infected gametocyte carriers from Burkina Faso, we assessed transmission potential to mosquitoes and directly quantified male and female gametocytes and asexual parasites in: i) finger prick blood, ii) venous blood, iii) skin biopsies, and in pools of mosquitoes that fed iv) on venous blood or, v) directly on the skin. Whilst more mosquitoes became infected when feeding directly on the skin compared to venous blood, concentrations of gametocytes in the subdermal skin vasculature were identical to that in other blood compartments. Asexual parasite densities, gametocyte densities and sex ratios were identical in the mosquito blood meals taken directly from the skin of parasite carriers and their venous blood.We also observed sparse gametocytes in skin biopsies from legs and arms of gametocyte carriers by microscopy. Taken together, we provide conclusive evidence for the absence of significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes. Quantifying this human malaria transmission potential is of pivotal importance for the deployment and monitoring of malaria elimination initiatives.IMPORTANCEOur observations settle a long-standing question in the malaria field and close a major knowledge gap in the parasite cycle. By deploying mosquito feeding experiments and stage-specific molecular and immunofluorescence parasite detection methodologies in two populations of naturally infected parasite carriers, we conclusively reject the hypothesis of gametocyte skin sequestration. Our findings provide novel insights in parasite stage composition in human blood compartments, mosquito bloodmeals and their implications for transmission potential. We demonstrate that gametocyte levels in venous or finger prick blood can be used to predict onward transmission potential to mosquitoes. Our findings thus pave the way for methodologies to quantify the human infectious reservoir based on conventional blood sampling approaches to support the deployment and monitoring of malaria elimination efforts for maximum public health impact.

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malERA: An updated research agenda for malaria elimination and eradication

Cited by 235 publications

References 22 publications

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Cryogenically preserved RBCs support gametocytogenesis ofPlasmodium falciparuminvitroand gametogenesis in mosquitoes

P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

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