7. Field studies of TBVs and Malian experiences

Field clinical trials are a major component of TBV development. TBV candidates are generally discovered in laboratories in the North with extensive infrastructure for modern biological sciences to conduct discovery research. After passing preclinical evaluations, TBV candidates must be tested in humans to qualify as viable vaccines. Safety and tolerability of the products are assessed first, generally in malaria-naïve individuals in non-endemic countries during a first-in-human phase 1 study. If the product meets acceptable safety and tolerability criteria, then it advances to Phases I, II, and III field clinical trials, which often means evaluation in malaria-endemic settings. Field studies are essential for assessing interruption of malaria transmission in the communities living in malaria-endemic areas.

(Figure 2A). Feeding occurs through various types of membranes, such as pig intestine or Parafilm®, to access infected blood housed in a heated chamber that attracts mosquitoes. This method takes the diversity of infection in the population into account. The standard membrane-feeding assay (SMFA) is the gold-standard technique for functional evaluation of antibodies in TBV studies, given its use of a well-characterized laboratory parasite isolate and mosquito line that lend themselves to standardization. Mosquitoes feed on cultured gametocytes together with either volunteer serum or purified immunoglobulin (Figure 2B). SMFA is similar to DMFA in the machinery and process for feeding but fails to capture parasite

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In DSF assays, cups of field-adapted, laboratory-reared mosquitoes are fed on the skin of human volunteers to assess the ability of vaccine antibody responses to block malaria transmission in near-natural conditions (Figure 3). In a recent advance, the Malaria Research and Training Center (MRTC) in Bamako (Mali) and the Laboratory of Malaria Immunology and Vaccinology (LMIV) at NIAID/NIH, in Rockville, MD (USA) have established the infrastructure, logistics, and safety database to support scale up of DSF assays on a community-wide basis (Figure 3). These DSF assays use a line of locally caught Anopheles coluzzii recently adapted for breeding in a contained insectary. In these studies [52], uninfected mosquitoes (generally 30–60 per assay) are fed on study volunteers on a regular basis during the malaria transmission season, with the expectation that an effective vaccine will reduce the number of infected mosquitoes compared to controls. We believe DSFs, in which insectary-raised clean mosquitoes are directly fed on infected individuals, may be more likely to be predictive of an

Figure 2. Membrane-feeding assays. (A) Overall setup of a direct membrane-feeding assay (DMFA). DMFA was performed at the Malaria Research and Training Center (MRTC), Mali with mosquitoes feeding through a membrane on whole venous blood taken in citrate-phosphate-dextrose or heparin from infected donors. The mosquitoes used were F1 or F2 progeny of wild-caught mosquitoes, or MRTC colony-bred mosquitoes (Anopheles coluzzii) maintained for many generations after local capture. The gametocyte source was fresh venous blood collected from infected study volunteers in Mali. (B) Standard membrane-feeding assay (SMFA) showing an individual feeding chamber. SMFA performed at the Laboratory of Malaria Immunology and Vaccinology (LMIV), National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), Rockville, MD, USA with mosquitoes feeding through a membrane on laboratory-cultured parasites (gametocytes) suspended in media with immune or nonimmune serum/plasma or IgG.

The mosquitoes used were an established laboratory strain (commonly Anopheles stephensi).

diversity effects on vaccine activity.

intervention's impact on transmission than membrane feeds.

A field clinical trial is not just a simple study but rather a multifaceted activity that builds on strong partnerships between research institutions and affected communities. Various capabilities are required for successful clinical trials, including confidence-based collaborative research teams, facilities, equipment, written procedures, training programs, community engagement, collaboration with ethics review committees, and collaborations with health and political authorities. The partnerships include vaccine inventors, developers, sponsors/funders, and institutions that have appropriate capacities and experience in conducting field clinical trials of malaria vaccines.

The main components of a TBV field clinical trial comprise immunization of study volunteers with prime and boost doses, intensive safety follow-up and reporting, mosquito-feeding assays, and the measurement of antibody responses using enzyme-linked immunosorbent assay (ELISA) for titers and standard membrane-feeding assay (SMFA) for activity. The immunization of volunteers is a major event that involves professionals with sundry expertise. The professionals include clinicians who assess volunteers for inclusion/exclusion criteria and monitor their health after receiving the vaccination, pharmacists who manage the randomization list as well as vaccine preparation, physicians who administer the vaccines, and intensivists who provide care for any post-immunization emergency. Medical biologists ensure proper biological sample collection, processing, transport, and storage as well as immediate measurement of biological parameters. Medical entomologists perform mosquito-feeding assays and associated dissections for endpoint analysis, and data managers enter and ensure quality of data according to established procedures.
