title: Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay.
abstract: Malaria transmission-blocking vaccines (TBVs) are potentially helpful tools for malaria eradication. The standard membrane-feeding assay (SMFA) is considered one of the "gold standard" assays for TBV development. However, lack of consensus in reporting results from SMFA has made it very challenging to compare results from different studies. Two main readouts, % inhibition in mean oocyst count per mosquito (TRA) and % inhibition in prevalence of infected mosquitoes (TBA), have been used widely. In this study, we statistically modeled the oocyst data in SMFA using data from 105 independent feeding experiments including 9804 mosquitoes. The model was validated using an independent data set that included 10,790 mosquitoes from 110 feeding studies. The model delineates a relationship between TRA, the mean oocyst count in the control mosquitoes (mo-contl), and TBA. While TRA was independent from mo-contl, TBA values changed depending on mo-contl. Regardless of monoclonal or polyclonal antibodies tested, there were strong concordances between observed TBA and predicted TBA based on the model using mo-contl and observed TRA. Simulations showed that SMFA with lower true control means had increased uncertainty in TRA estimates. The strong linkage between TBA, TRA and mo-contl inspired creation of a standardized TBA, a model-based TBA standardized to a target control mean, which allows comparison across multiple feeds regardless of mo-contl. This is the first study showing that the observed TBA can be reasonably predicted by mo-contl and the TRA of the test antibody using independent experimental data. This study indicates that TRA should be used to compare results from multiple feeds with different levels of mo-contl. If a measure of TBA is desired, it is better to report standardized TBA rather than observed TBA. These recommendations support rational comparisons of results from different studies, thus benefiting future TBV development.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Lane, Rockville, MD 20852, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Swihart
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Deng
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Luwen
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Thao P
authors.initials: TP
authors.lastname: Pham
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Ababacar
authors.initials: A
authors.lastname: Diouf
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Burton
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Lane, Rockville, MD 20852, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fay
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D001681:Biological Assay; D004772:Entomology / Q000379:methods; D005247:Feeding Behavior; D005260:Female; D017780:Malaria Vaccines / Q000276:immunology; D016778:Malaria, Falciparum / Q000517:prevention & control / Q000635:transmission*; D008567:Membranes, Artificial; D015233:Models, Statistical; D000072138:Mosquito Vectors / Q000469:parasitology; D033661:Oocysts; D010963:Plasmodium falciparum; D012015:Reference Standards
chemical_list: D017780:Malaria Vaccines; D008567:Membranes, Artificial
keywords: Malaria; Standard membrane-feeding assay; Transmission-blocking vaccine