Vaccine Mediated Immunity To Malaria

Malaria infects millions of people every year, and despite recent advances in controlling disease spread, it remains a global health concern. Decades of research into both naturally acquired and vaccine mediated immunity have given a broad range of correlates of protection. RTS,S, the only licensed anti-malarial vaccine, has implicated antibodies against the circumsporozoite protein (CSP) as a key correlate. Not to be discounted, CD8+ T cells targeting liver-stage (LS) antigens were associated with protection in attenuated sporozoite vaccination. Clearly there is no panacea for malarial immunity, and a broad range of responses against multiple antigens is crucial. In this work we develop novel synthetic DNA vaccines targeting antigens in multiple Plasmodium pre-erythrocytic life cycle stages, and evaluate the immunity elicited by each in the context of murine models of malaria. To further evaluate protection mediated by Liver stage antigens, we focused on the exported pre-erythrocytic proteins EXP1, PFN, EXP2, ICP, TMP21, and UIS3. SynDNA antigen cocktails were tested with and without the molecular adjuvant plasmid IL-33. Immunized animals developed robust T cell responses including induction of antigen-specific liver-localized CD8+ T cells, which were enhanced by the co-delivery of plasmid IL-33. In total, 100% of mice in adjuvanted groups and 71%–88% in non-adjuvanted groups were protected from disease following Plasmodium yoelii challenge. To further evaluate protection mediated by sporozoite antigens, five synDNA vaccines encoding variations of CSP were designed and studied: 3D7, GPI1, ΔGPI, TM, and DD2. ΔGPI generated the most robust immunity, and was the most efficacious in an IV sporozoite challenge. We then compared the immunity generated by ΔGPI vs synDNA mimics for two leading malaria vaccine candidates (RTS,S and R21). They demonstrated similar anti-CSP antibody responses, however ΔGPI induced a more focused T cell response. In an infectious mosquito challenge all three of these constructs generated potent inhibition of liver stage infection, with ΔGPI appearing to also provide the best sterilizing immunity from blood stage parasitemia. Together these studies demonstrated that synDNA vaccines encoding malaria immunogens can provide substantial protection from disease, and highlighted the importance of targeting the pre-erythrocytic life cycle stages to combat malaria

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The White-Nose Syndrome Transcriptome: Exploring the Putative Fungal Virulence Genes of Pseudogymnoascus destructans.

White-nose syndrome (WNS) in North American bats is caused by an invasive cutaneous infection by the psychrophilic fungus Pseudogymnoascus destructans (P. destructans). In a previous study, we used a dual RNA-Seq approach, which allowed us to gain insight into the gene expression of both the host and the pathogen simultaneously, and we observed differences in P. destructans gene expression that suggest host-pathogen interactions that might determine WNS progression. More recently we compared transcriptome-wide changes in gene expression levels in P. destructans grown on and actively infecting the wing of a bat (infecting pathogen) with P. destructans grown in culture (free pathogen). We predicted that some of the putative virulence factors seen in the previous dual RNA-seq study would be more highly expressed in the infecting P. destructans grown on bat wings as compared to free P. destructans grown in culture. We identified several classes of potential virulence factors that are expressed in P. destructans during WNS, including metal-ion transporters to assist in resisting nutritional immunity, factors involved in cell repair and protection, and factors involved in microbiome competition. These putative virulence factors may provide novel targets for treatment or prevention of WNS

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

ImportanceThe prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.ObservationsWe describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science.Conclusions and relevanceRECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions.Clinical trials.gov identifierClinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011