Assays to Support Development of Malaria Transmission Blocking Vaccines

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

We first report here our published findings in FY2021 achieved with our collaborators: 1. Coelho CH, Tang WK, Burkhardt M, Galson JD, Muratova O, Salinas ND, Alves ESTL, Reiter K, MacDonald NJ, Nguyen V, et al: A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes. Nat Commun 2021, 12:1750. We characterized B cell receptor responses among Malian adults vaccinated against Pfs230D1, our leading TBV candidate. As part of this work, we developed the first competitive ELISA to measure the epitope-specific responses to a TBV vaccine. This approach can be developed for any future TBV candidate. 2. Duffy PE: Transmission-Blocking Vaccines: Harnessing Herd Immunity for Malaria Elimination. Expert Rev Vaccines 2021, 20:185-198. We described the concept and biology behind TBV, and provided an update on clinical development of the leading vaccine candidate antigens including Pfs25, Pvs25, Pfs230, and Pfs48/45, as well as the appropriate endpoints for TBV trials and the need to develop novel assays to support vaccine development. 3. Coelho CH, Jore MM, Canepa GE, Barillas-Mury C, Bousema T, Duffy PE: Antibody Therapy Goes to Insects: Monoclonal Antibodies Can Block Plasmodium Transmission to Mosquitoes. Trends Parasitol 2020, 36:880-883. In this publication, we discussed targets of monoclonal antibodies in mosquito sexual stages of Plasmodium. These antibodies will be useful to consider for the development of novel assays to measure TBV activity. 4. Coelho CH, Nadakal ST, Gonzales Hurtado P, Morrison R, Galson JD, Neal J, Wu Y, King CR, Price V, Miura K, et al: Antimalarial antibody repertoire defined by plasma IG proteomics and single B cell IG sequencing. JCI Insight 2020, 5. Plasma antimalarial Ab can mediate antiparasite immunity but has not previously been characterized at the molecular level. We developed an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IGs) or Abs with those expressed on B cells as part of the B cell receptor. We applied this strategy to define plasma IG and to determine variable (V) gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25. This approach will be useful in fuiture to characterize the serum antibody response to vaccines in general, including malaria TBV. 5. Faiman R, Krajacich B, Dao A, Yaro AS, Yossi O, Lamissa Z, Diallo M, Samake D, Sylla D, Moribo C, Salifou MK, Goita S, Coulibaly M, Muratova O, McCormack A, Goncalves B, Hume JCC, Duffy PE, Lehmann T. A novel fluorescence and DNA combination for versatile, long-term marking of mosquitoes. 2021. Methods in Ecology and Evolution. 12(6):1008-1016. Current markreleaserecapture methodologies are limited in their ability to address complex problems in vector biology, such as studying multiple groups overlapping in space and time. LMIV and its Mali partners deployed a novel marking method developed by colleagues at LMVR,using a fluorescent dye (SmartWater) combined with synthetic DNA tags to informatively and efficiently mark adult mosquitoes using an airbrush pump and nebulizer. Using a handheld UV flashlight, the fluorescent marking enabled quick and simple initial detection of recaptures in a field-ready and non-destructive approach that when combined with an extraction-free PCR on individual mosquito legs provides potentially unlimited marking information.The studies established that this method can be readily deployed in the field for marking multiple groups of mosquitoes or other insects, and we predict may be useful to support trials of transmission blocking interventions such as vaccines. 6. Reichert EN, Hume JCC, Sagara I, Healy SA, Assadou MH, Guindo MA, Barney R, Rashid A, Yang IK, Golden D, Domingo GJ, Duffy PE, Slater HC (2020) Ultra-sensitive RDT performance and antigen dynamics in a high-transmission Plasmodium falciparum setting in Mali. Malaria Journal Sept 3; 19(1): 323 With colleagues at PATH, we characterized the performance of the ultra-sensitive RDT and demonstrated the potential for emerging antigen-quantifying technologies in the field of malaria diagnostics to be helpful tools in distinguishing between active versus recently cleared malaria infections. This diagnostic capability may be useful to characterize malaria infections in the context of interventional trials. We also report below progress this year that has not yet been published: In 2019, a community Pfs230-EPA/AS01 vaccine study was initiated and a booster vaccine dose administered in 2020. Approximately 1500 individuals aged 1 year and older in Doneguebougou were enrolled. Individuals were randomized by compound and individuals aged five years and older received either Pfs230D1-EPA/AS01 or comparator vaccine. Vaccine efficacy was measured by the direct skin feeding assay (DSF) which was performed on children aged 9-18 year old at time of enrollment (N=314 in 2019; N=386 in 2020). In the first season, DSFs were performed every 2 weeks for 16 weeks (total of 8 DSF per participant); a total of 2,914 DSFs were performed with 70 positive assays (2.4%) recorded in 45 unique individuals. In the second season, DSFs were performed every 2 weeks for 20 weeks (total of 10 DSF per participant); a total of 3,030 DSFs were performed with 84 positive assays (2.8%) in 43 unique individuals. In the primary efficacy analysis, DSFs were aggregated over study years one and two and fitted to a poisson regression model for the number of positive DSF results per participant versus assignment to Pfs230 or comparator, with an offset for the total number of DSFs per person. The model was fit using generalized estimating equations, clustering on vaccine unit, and using an independence working correlation. Over the two year study, we found that the vaccine significantly reduced the rate of parasite transmission to mosquitoes. The study was unblinded to participants and by group in March 2021 and further analyses are ongoing. The final study visit for participants was completed July-August 2021.