Assays to Support Development of Malaria Transmission Blocking Vaccines

National Institute Of Allergy And Infectious Diseases

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Abstract

We first report here our published findings achieved with our collaborators in Mali and elsewhere: Guindo A et al. 2019. BMC Medical Research Methodology 19(1):149. : Using the example of our malaria transmission blocking vaccine trial, simulations were performed to quantify the impact of spatial heterogeneity and to compare different models (non-spatial Cox Proportional Hazard (Cox-PH) model and four models accounting for spatial heterogeneity-i.e., a Data-Generating Model, a Generalized Additive Model (GAM), and two Stochastic Partial Differential Equation (SPDE) models, one modeling survival time and the other the number of events). Using a Bayesian approach, we estimated the SPDE models with an Integrated Nested Laplace Approximation algorithm. We found that the level of baseline risk did not affect our estimates. However, with a high breeding site density and a strong breeding site effect, the Cox-PH and GAM models underestimated the age and treatment effects (but not the sex effect) with a low confidence interval coverage rate. When population density was low, the Cox-SPDE model slightly overestimated the effect of related factors (age, treatment). The two SPDE models corrected the impact of spatial heterogeneity, thus providing the best estimates. Our results show that when spatial heterogeneity is important but not measured, randomization alone cannot achieve comparability between groups. In such cases, prevention trials should model spatial heterogeneity with an adapted method. We also report below progress this year that has not yet been published: In FY2019, the clinical protocol titled Community Dynamics of Malaria Transmission and Mosquito Feeding in Bancoumana and Doneguebougou, Mali was conducted at two field sites in Mali. The study began enrollment in Bancoumana village in January 2018 and expanded to Doneguebougou village in September 2018. To date, a total of 1680 individuals have been consented of which 1576 participants enrolled across both sites: 1227 in Direct Skin Feeding (DSF) cohort, 305 in Parasite Surveillance (PS) cohort, 44 in genotype cohort. The DSF and PS cohort undergo monthly study visits where they are evaluated by blood smear for any asexual or sexual parasites, have their hemoglobin level measured, provide a small blood sample for molecular analyses at a later date, provide consent for live and spray mosquito catches in their compound and, in the case of the DSF cohort, undergo a DSF. The Genotype cohort undergoes only a single visit at enrollment to provide a small blood sample that may be used at a later date for forensic genotyping of spray caught mosquitoes to determine feeding fidelity. Unlike most vaccine studies, the community study enrolls from all age groups across the community providing valuable date on the contribution of individuals <18 years of age to parasite transmission dynamics. 1033 of the 1576 participants enrolled (66%) were under 18 years old at time of screening. Monthly visits collect blood for blood smears which are read for the presence of asexual and sexual malaria parasites, and have provided useful information on parasite carriage rates through the dry and wet seasons. As expected, parasite burden is higher in children than in adults, with children aged 5-17 years old most particularly affected (Figure 1). Children under 5 years old demonstrate comparatively low burdens of infection which is likely due to them receiving monthly seasonal malaria chemoprophylaxis during the rainy season. For the data collected so far, Doneguebougou participants demonstrate higher rates of parasitemia and gametocytemia, and it will be interesting to see if this is a static observation over time or if it is relatively dynamic from season to season. Participants in the DSF cohort undergo a single DSF every month at the time of their monthly visit and currently 13,486 DSF assays have been completed: 10,220 in Bancoumana; 3266 in Doneguebougou. 59 DSFs have been positive to date (0.4%) note DSFs were not conducted in the transmission season in 2018 due to ongoing vaccine trial activities, so this rate of infection is purely in the dry season. 43 of the positive DSFs are in Bancoumana, 16 in Doneguebougou. 59 positive DSFs have come from 42 unique individuals (28 in Bancoumana; 14 in Doneguebougou) of which 33 are children (median age = 13) illustrating the importance of studying this group as they likely contribute significantly to the community infection reservoir. Live and spray mosquito collections have been conducted coincident with monthly study visits in DSF cohort compounds. To date in Bancoumana, 7118 collections have been completed with 66 huts providing at least one positive mosquito in live catches (0.93%). In Doneguebougou, 2436 collections have been completed with 32 huts providing at least one positive mosquito in live catches (1.3%). Over 2300 blood fed mosquitoes have been collected in spray collections across both sites (spray collections performed in hut post live catch). In August-November 2018, the community study overlapped with the ongoing Pfs230-EPA/AS01 vaccine trial conducted in both Bancoumana and Doneguebougou where a fourth booster dose of this vaccine was administered in August 2018 followed by sixteen weeks of twice weekly DSF assays. In total, 5056 DSF assays were performed of which 88 feeds were positive (1.74%) a total of 671 individual infected mosquitoes. Speciation of infected mosquitoes is ongoing to determine how many of these mosquitoes were infected with P. falciparum. Based on 2017 speciation data, we anticipate approximately 20% to contain additional parasite species. In 2019, a community Pfs230-EPA/AS01 vaccine study was initiated and enrollment is ongoing at this time. Approximately 1500 individuals aged 5 years and older in Doneguebougou are expected to be enrolled. Individuals will be randomized by compound to receive either Pfs230 or placebo vaccine. DSF assays will be performed twice monthly on children aged 9-18 years. In addition, marked release and capture mosquito collections will be performed to examine mosquito movement between compounds.