title: Utilizing direct skin feeding assays for development of vaccines that interrupt malaria transmission: A systematic review of methods and case study.
abstract: Shifting the malaria priorities from a paradigm of control and elimination to a goal of global eradication calls for renewed attention to the interruption of malaria transmission. Sustained progress toward eradication will require both improved understanding of infectious reservoirs and efficient development of novel transmission-blocking interventions, such as rapidly acting and highly efficacious therapeutics and vaccines. Here, we review the direct skin feeding assay (DSF), which has been proposed as a valuable tool for measuring the in natura transmission of malaria parasites from human hosts to mosquito vectors across heterogeneous populations. To capture the methodological breadth of this assay's use, we first systematically review and qualitatively synthesize previously published investigations using DSFs to study malaria transmission in humans. Then, using a recent Phase 1 trial in Mali of the Pfs25H-EPA/Alhydrogel® vaccine candidate (NCT01867463) designed to interrupt Plasmodium falciparum transmission as a case study, we describe the potential opportunities and current limitations of utilizing the endpoints measured by DSF in making early clinical decisions for individually randomized transmission-interrupting intervention candidates. Using simulations based on the data collected in the clinical trial, we demonstrate that the capacity of the DSF to serve as an evaluative tool is limited by the statistical power constraints of the "effective sample size" (i.e. the number of subjects that are capable of transmitting at the time of feeding). Altogether, our findings suggest DSFs have great potential utility for assessing the public health impacts of emerging antimalarial tools, but additional research is needed to address issues of scalability and to establish correlation with community-wide clinical endpoints as well as complementary in vitro measures, such as standard membrane feeding assays.
authors: Laboratory of Malaria Immunology and Vaccinology, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Twinbrook 1, 5640 Fishers Lane, Rockville, MD 20852, United States; Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, Cambridgeshire CB1 8RN, United Kingdom; Department of Epidemiology, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, 7927 Rubin Building, Lebanon, NH 03756, United States. Electronic address: elizabeth.b.brickley@dartmouth.edu.
authors: Elizabeth B
authors: EB
authors: Brickley
authors: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy & Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako, P.O. Box 1805, Mali. Electronic address: doudou@icermali.org.
authors: Mamadou
authors: M
authors: Coulibaly
authors: Biostatistics Research Branch, National Institute for Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Lane, Rockville, MD 20852, United States. Electronic address: erin.gabriel@nih.gov.
authors: Erin E
authors: EE
authors: Gabriel
authors: Laboratory of Malaria Immunology and Vaccinology, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Twinbrook 1, 5640 Fishers Lane, Rockville, MD 20852, United States. Electronic address: sara.healy@nih.gov.
authors: Sara A
authors: SA
authors: Healy
authors: Laboratory of Malaria Immunology and Vaccinology, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Twinbrook 1, 5640 Fishers Lane, Rockville, MD 20852, United States. Electronic address: jennifer.hume@nih.gov.
authors: Jen C C
authors: JCC
authors: Hume
authors: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy & Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako, P.O. Box 1805, Mali. Electronic address: isagara@icermali.org.
authors: Issaka
authors: I
authors: Sagara
authors: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy & Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako, P.O. Box 1805, Mali. Electronic address: cheick@icermali.org.
authors: Sekou F
authors: SF
authors: Traore
authors: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy & Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako, P.O. Box 1805, Mali. Electronic address: okd@icermali.org.
authors: Ogobara
authors: O
authors: Doumbo
authors: Laboratory of Malaria Immunology and Vaccinology, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Twinbrook 1, 5640 Fishers Lane, Rockville, MD 20852, United States. Electronic address: patrick.duffy@nih.gov.
authors: Patrick E
authors: PE
authors: Duffy
mesh_terms: D000328:Adult; D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D002986:Clinical Trials as Topic; D005247:Feeding Behavior; D005260:Female; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission*; D008297:Male; D008875:Middle Aged; D000072138:Mosquito Vectors / Q000469:parasitology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology; D012867:Skin / Q000276:immunology; D055815:Young Adult
chemical_list: D017780:Malaria Vaccines; C071284:Pfs25 protein, Plasmodium falciparum; D015800:Protozoan Proteins
keywords: Direct skin feed; Malaria; Transmission-blocking vaccine; Trial design; Vaccine activity