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Lymphocytes in barrier tissues play critical roles in host defense and homeostasis. These cells take up residence in tissues during defined developmental windows, when they may demonstrate distinct phenotypes and functions. Here, we utilized mass and flow cytometry to elucidate early features of human skin immunity, demonstrating a unique fetal skin lymphocyte signature. While most conventional αβ T (Tconv) cells in fetal skin have a naive, proliferative phenotype, a subset of CD4+ Tconv and CD8+ cells demonstrate memory-like features and a propensity for IFNγ production. Skin regulatory T cells dynamically accumulate over the second trimester in temporal and regional association with hair follicle development. These fetal skin Tregs demonstrate an effector memory phenotype while differing from their adult counterparts in expression of key effector molecules. Thus, we identify features of prenatal skin lymphocytes that may have key implications for understanding antigen and allergen encounters in utero and in infancy. Competing Interest Statement MDR is a founder and consultant for TRex Bio and Sitryx Bio. KT is currently an employee of Amgen. EGL is currently an employee of SentiBio. All other authors certify that they have no conflict of interest related to the subject matter or materials discussed in this manuscript.

•This is the first-in-human trial of both FMP013 and the ALFQ adjuvant.•The vaccine evinced significant humoral and cell mediated immunogenicity.•The vaccine demonstrated an acceptable safety profile.•The results of this trial have led to an efficacy trial using CHMI. The global burden of malaria remains substantial. Circumsporozoite protein (CSP) has been demonstrated to be an effective target antigen, however, improvements that offer more efficacious and more durable protection are still needed. In support of research and development of next-generation malaria vaccines, Walter Reed Army Institute of Research (WRAIR) has developed a CSP-based antigen (FMP013) and a novel adjuvant ALFQ (Army Liposome Formulation containing QS-21). We present a single center, open-label, dose-escalation Phase 1 clinical trial to evaluate the safety and immunogenicity of the FMP013/ALFQ malaria vaccine candidate. In this first-in-human evaluation of both the antigen and adjuvant, we enrolled ten subjects; five received 20 μg FMP013 / 0.5 mL ALFQ (Low dose group), and five received 40 μg FMP013 / 1.0 mL ALFQ (High dose group) on study days 1, 29, and 57. Adverse events and immune responses were assessed during the study period. The clinical safety profile was acceptable and there were no serious adverse events. Both groups exhibited robust humoral and cellular immunological responses, and compared favorably with historical responses reported for RTS,S/AS01. Based on a lower reactogenicity profile, the 20 μg FMP013 / 0.5 mL ALFQ (Low dose) was selected for follow-on efficacy testing by controlled human malaria infection (CHMI) with a separate cohort. Trial Registration:Clinicaltrials.gov Identifier NCT04268420 (Registered February 13, 2020)

The impact of preexisting immunity on the efficacy of artemisinin combination therapy must be examined to monitor resistance, and for implementation of new treatment strategies. Serum samples obtained from a clinical trial in Western Kenya randomized to receive artemether-lumefantrine (AL) or artesunate-mefloquine (ASMQ) were screened for total immunoglobulin G against preerythrocytic and erythrocytic antigens. The association and correlation between different variables, and impact of preexisting immunity on parasite slope half-life (t½) was determined. There was no significant difference in t½, but the number of individuals with lag phase was significantly higher in the AL than in the ASMQ arm (29 vs 13, respectively; P < .01). Circumsporozoite protein-specific antibodies correlate positively with t½ (AL, P = .03; ASMQ, P = .09), but negatively with clearance rate in both study arms (AL, P = .16; ASMQ, P = .02). The t½ correlated negatively with age in ASMQ group. When stratified based on t½, the antibody titers against circumsporozoite protein and merozoite surface protein 1 were significantly higher in participants who cleared parasites rapidly in the AL group (P = .01 and P = .02, respectively). Data presented here define immunoprofiles associated with distinct responses to 2 different antimalarial drugs, revealing impact of preexisting immunity on the efficacy of artemisinin combination therapy regimens in a malaria-holoendemic area. NCT01976780.

Genetically inactivated, Gram-negative bacteria that express malaria vaccine candidates represent a promising novel self-adjuvanting vaccine approach. Antigens expressed on particulate bacterial carriers not only target directly to antigen-presenting cells but also provide a strong danger signal thus circumventing the requirement for potent extraneous adjuvants. E. coli expressing malarial antigens resulted in the induction of either Th1 or Th2 biased responses that were dependent on both antigen and sub-cellular localization. Some of these constructs induced higher quality humoral responses compared to recombinant protein and most importantly they were able to induce sterile protection against sporozoite challenge in a murine model of malaria. In light of these encouraging results, two major Plasmodium falciparum pre-erythrocytic malaria vaccine targets, the Cell-Traversal protein for Ookinetes and Sporozoites (CelTOS) fused to the Maltose-binding protein in the periplasmic space and the Circumsporozoite Protein (CSP) fused to the Outer membrane (OM) protein A in the OM were expressed in a clinically relevant, attenuated Shigella strain (Shigella flexneri 2a). This type of live-attenuated vector has previously undergone clinical investigations as a vaccine against shigellosis. Using this novel delivery platform for malaria, we find that vaccination with the whole-organism represents an effective vaccination alternative that induces protective efficacy against sporozoite challenge. Shigella GeMI-Vax expressing malaria targets warrant further evaluation to determine their full potential as a dual disease, multivalent, self-adjuvanting vaccine system, against both shigellosis, and malaria.

Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, fltering water, controlling primary producers, and providing food for predators. Their diferences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, eforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specifc taxa to assessing the success of legislative and management restoration eforts.