The Future. Recent studies in Chicago to develop medicines and vaccines, and an intranasal nano-vaccine and a dendrimer RNA vaccine developed by others (I). Part I. A potent tetrahydroquinolone effective against tachyzoites and bradyzoites in vitro, synergistic with atovaquone, eliminates >95% of encysted bradyzoites in vivo,, while active with a single oral dose of a nano formulation against tachyzoite infection and Plasmodium berghei’s three life cycle stages. Specifically reproduced with permission from Frontiers Cell Infection Microbiol : Figure and Legend directly from this paper. “JAG21 is a mature lead that protects against Toxoplasma gondii and Plasmodium berghei in vivo. (A) JAG21 treatment for 14 days protects against T. gondii tachyzoites in vivo. Tachyzoite challenge with Prugneaud luciferase parasites imaged with leuciferin using IVIS demonstrates that treatment with JAG21 eliminates leuciferase expressing parasites and leads to 100% survival of JAG21 treated infected mice. No cysts were found in brains of mice at 30 days after infection when they have been treated with JAG21 for the first 14 days after infection. There were 2 biological replicate experiments with 5 mice per group with similar results. (B) JAG21 and JAG21 plus tafenoquine markedly reduce Me49 strain brain cyst numbers in vivo in Balb/C mice at 30 days after infection. Parasites were quantitated by scanning the entire immunoperoxidase stained slide in an automated manner and by two observers blinded to the experimental treatment using microscopic evaluation. In each of two experiments, the numbers of mice per group were as follows: Experiment 1 had 4 diluent controls, 5 JAG21, 4 JAG21/Tafenoquine treated mice; and Experiment 2 had 5 diluent controls, 5 JAG21, 3 JAG21/Tafenoquine treated mice. Immunoperoxidase staining was performed. Parasite burden was quantitated using a positive pixel count algorithm of Aperio ImageScope software. Positive pixels were normalized to tissue area (mm2). Quantification was by counting positive pixels per square area. The entire brain in one section was scanned for each mouse. The parasite burden was quantitated as units of positive pixels per mm2. The average ± S.E.M. numbers of mm2 per slide quantitated was 30.2±1.6 mm2 per mouse for this quantification. Each high power field of view shown in C is ~0.02 mm2 per field of view. A representative single experiment is presented and the data from the two experiments analyzed together also demonstrated significant differences between the untreated and treated groups (p < 0.01; Supplemental Figure 1). (C) Microscopic evaluation of the slides reveal effect of JAG21 and JAG21 plus tafenoquine having the same pattern as the automated quantitation of immunoperoxidase stained material. There are usual appearing cysts in the DMSO control untreated mice as shown in the top panels, and rare cysts in the treated mice with most of the brown material appearing amorphous (bottom panels). (D) JAG21 nanoformulation dosages administered to P. berghei infected C57Bl6/albino mice compared with vehicle control. Design of single dose and 3 day dose experiments. (E) JAG21 nanoformulation cures P. berghei sporozoites (left panel), blood (middle panel) and liver stages, leading to 100% survival (right panel). This is with oral administration of a single dose of 2.5 mg/kg or 3 doses at 0.625 mg/kg. Single dose causal prophylaxis in 5 C57BL/6 albino mice at 2.5 mpk dosed on day 0, 1 h after intravenous administration of 10,000 P. bergheisporozoites. Shown is 3 dose causal prophylaxis treatment in 5 C57BL/6 albino mice at 0.625 mpk dosed on days −1, 0 and +1. Representative figure showing survival (right panel), luminescence (left panel) and parasitemia quantitated by flow cytometry (middle panel) for 5 mg/kg.” (F) Persisters of a RPS13 Λ strain of Toxoplasma can persist long times by exiting the cell cycle at G1 (G). The nanoformulation highly active in vivo against RH strain tachyzoites indicates that oral formulation in a conventional manner will likely be feasible. Biomarkers of illness, not shown, can also be a measure of efficacy in future studies, including circulating miRs, specific serum proteins and T2 weighted abnormalities in brain MRI. Part II. Vaccines on the horizon in pre-clinical studies. (H) Self assembling nanoparticle immunosense vaccine is potent in protection of mice (134, 137-9). RNA dendrimers also are promising in our vaccine work (Melo, Zhou, Weiss, Irvine, McLeod et al, In preparation, 2022). (I) Protection of primates eliminating death in French zoos with porous nanoparticles loaded with T.gondii lysate administered intranasally [https://www.inrae.fr/actualites/vaccine-contr-toxoplasmose-singes-saimiris]. Additional work of of others is referenced as well [100–135]. (J) Importance of screening and treating during gestation for those who are seronegative, new medicines and vaccines are emphasized in the words and image of J. Morel and her familly. Other images and Figure legend for Part I are reproduced with permission from Frontiers Cell Infect Microbiol, Nature Partners Journal Vaccines, and from Vaxinano