Repeat controlled human Plasmodium falciparum infections delay bloodstream patency and reduce symptoms.

Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants' second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.

Model-based estimates of chikungunya epidemiological parameters and outbreak risk from varied data types.

Assessing the factors responsible for differences in outbreak severity for the same pathogen is a challenging task, since outbreak data are often incomplete and may vary in type across outbreaks (e.g., daily case counts, serology, cases per household). We propose that outbreaks described with varied data types can be directly compared by using those data to estimate a common set of epidemiological parameters. To demonstrate this for chikungunya virus (CHIKV), we developed a realistic model of CHIKV transmission, along with a Bayesian inference method that accommodates any type of outbreak data that can be simulated. The inference method makes use of the fact that all data types arise from the same transmission process, which is simulated by the model. We applied these tools to data from three real-world outbreaks of CHIKV in Italy, Cambodia, and Bangladesh to estimate nine model parameters. We found that these populations differed in several parameters, including pre-existing immunity and house-to-house differences in mosquito activity. These differences resulted in posterior predictions of local CHIKV transmission risk that varied nearly fourfold: 16% in Italy, 28% in Cambodia, and 62% in Bangladesh. Our inference method and model can be applied to improve understanding of the epidemiology of CHIKV and other pathogens for which outbreaks are described with varied data types.

Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIß).

Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC50s against in vitro cultured asexual P. falciparum parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77 ± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7_0509800, annotated as a phosphatidylinositol 4 kinase (Pf PI4KIIIß). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing Pf PI4KIIIß. Both lines were also resistant to other Pf PI4K inhibitors. In addition NCATS-SM3710 inhibited purified Pf PI4KIIIß with an IC50 of 2.0 ± 0.30 nM. Together the results demonstrate that Pf PI4KIIIß is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.