High-throughput screen identifies non inflammatory small molecule inducers of trained immunity.

Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as ß-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation-a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training.

Progress Toward Eradication of Dracunculiasis - Worldwide, January 2022-June 2023.

The effort to eradicate Dracunculus medinensis, the etiologic agent of dracunculiasis, or Guinea worm disease, commenced at CDC in 1980. In 1986, with an estimated 3.5 million cases worldwide in 20 African and Asian countries, the World Health Assembly called for dracunculiasis elimination. The Guinea Worm Eradication Program (GWEP) was established to help countries with endemic dracunculiasis reach this goal. GWEP is led by The Carter Center and supported by partners that include the World Health Organization, UNICEF, and CDC. In 2012, D. medinensis infections were unexpectedly confirmed in Chadian dogs, and since then, infections in dogs, cats, and baboons have posed a new challenge for GWEP, as have ongoing civil unrest and insecurity in some areas. By 2022, dracunculiasis was endemic in five countries (Angola, Chad, Ethiopia, Mali, and South Sudan), with only 13 human cases identified, the lowest yearly total ever reported. Animal infections, however, were not declining at the same rate: 686 animal infections were reported in 2022, including 606 (88%) in dogs in Chad. Despite these unanticipated challenges as well as the COVID-19 pandemic, countries appear close to reaching the eradication goal. GWEP will continue working with country programs to address animal infections, civil unrest, and insecurity, that challenge the eradication of Guinea worm.

Development of Masitinib Derivatives with Enhanced Mpro Ligand Efficiency and Reduced Cytotoxicity.

Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib's mechanism of Mpro inhibition. To improve the inhibitory efficiency and to increase the ligand selectivity for the viral target, we determined the minimal portion of the molecule (fragment) that is responsible for most of the interactions that arise within the masitinib-Mpro complex. We found that masitinib forms highly stable and specific H-bond interactions with Mpro through its pyridine and aminothiazole rings. Importantly, the interaction with His163 is a key anchoring point of the inhibitor, and its perturbation leads to ligand unbinding within nanoseconds. Based on these observations, a small library of rationally designed masitinib derivatives (M1-M5) was proposed. Our results show increased inhibitory efficiency and highly reduced cytotoxicity for the M3 and M4 derivatives compared to masitinib.

Progress Toward Global Eradication of Dracunculiasis - Worldwide, January 2021-June 2022.

Dracunculiasis (Guinea worm disease), caused by the parasite Dracunculus medinensis, is acquired by drinking water containing small crustacean copepods (water fleas) infected with D. medinensis larvae. Recent evidence suggests that the parasite also appears to be transmitted by eating fish or other aquatic animals. About 1 year after infection, the worm typically emerges through the skin on a lower limb of the host, causing pain and disability (1). No vaccine or medicine is available to prevent or treat dracunculiasis. Eradication relies on case containment* to prevent water contamination and other interventions to prevent infection, including health education, water filtration, treatment of unsafe water with temephos (an organophosphate larvicide), and provision of safe drinking water (1,2). CDC began worldwide eradication efforts in October 1980, and in 1984 was designated by the World Health Organization (WHO) as the technical monitor of the Dracunculiasis Eradication Program (1). In 1986, with an estimated 3.5 million cases† occurring annually in 20 African and Asian countries§ (3), the World Health Assembly called for dracunculiasis elimination. The Guinea Worm Eradication Program (GWEP),¶ led by The Carter Center and supported by partners that include WHO, UNICEF, and CDC, began assisting ministries of health in countries with endemic disease. In 2021, a total of 15 human cases were identified and three were identified during January-June 2022. As of November 2022, dracunculiasis remained endemic in five countries (Angola, Chad, Ethiopia, Mali, and South Sudan); cases reported in Cameroon were likely imported from Chad. Eradication efforts in these countries are challenged by infection in animals, the COVID-19 pandemic, civil unrest, and insecurity. Animal infections, mostly in domestic dogs, some domestic cats, and in Ethiopia, a few baboons, have now surpassed human cases, with 863 reported animal infections in 2021 and 296 during January-June 2022. During the COVID-19 pandemic all national GWEPs remained fully operational, implementing precautions to ensure safety of program staff members and community members. In addition, the progress toward eradication and effectiveness of interventions were reviewed at the 2021 and 2022 annual meetings of GWEP program managers, and the 2021 meeting of WHO's International Commission for the Certification of Dracunculiasis Eradication. With only 15 human cases identified in 2021 and three during January-June 2022, program efforts appear to be closer to reaching the goal of eradication. However, dog infections and impeded access because of civil unrest and insecurity in Mali and South Sudan continue to be the greatest challenges for the program. This report describes progress during January 2021-June 2022 and updates previous reports (2,4).

Liraglutide increases islet Ca2+ oscillation frequency and insulin secretion by activating hyperpolarization-activated cyclic nucleotide-gated channels.

AIM: To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca2+ handling and insulin secretion. METHODS: The impact of liraglutide (GLP-1 analogue) on islet Ca2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated ß-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or ß cells. RESULTS: Liraglutide increased ß-cell Ca2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased ß-cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to ß cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in ß-cell Ca2+ oscillation frequency, ß-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca2+ oscillations. CONCLUSION: The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with ß-cell Ca2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a ß-cell-dependent manner.

Progress Toward Global Eradication of Dracunculiasis, January 2020-June 2021.

Dracunculiasis (Guinea worm disease), caused by the parasite Dracunculus medinensis, is traditionally acquired by drinking water containing copepods (water fleas) infected with D. medinensis larvae, but in recent years also appears increasingly to be transmitted by eating fish or other aquatic animals. The worm typically emerges through the skin on a lower limb of the host 1 year after infection, causing pain and disability (1). There is no vaccine or medicine to prevent or medicine to treat dracunculiasis; eradication relies on case containment* to prevent water contamination and other interventions to prevent infection: health education, water filtration, treatment of unsafe water with temephos (an organophosphate larvicide), and provision of safe drinking water (1,2). The eradication campaign began in 1980 at CDC (1). In 1986, with an estimated 3.5 million cases† occurring annually in 20 African and Asian countries§ (3), the World Health Assembly called for dracunculiasis elimination (4). The Guinea Worm Eradication Program (GWEP), led by The Carter Center and supported by the World Health Organization (WHO), UNICEF, CDC, and other partners, began assisting ministries of health in countries with endemic disease. With 27 cases in humans reported in 2020, five during January-June 2021, and only six countries currently affected by dracunculiasis (Angola, Chad, Ethiopia, Mali, South Sudan, and importations into Cameroon), achievement of eradication appears to be close. However, dracunculiasis eradication is challenged by civil unrest, insecurity, and epidemiologic and zoologic concerns. Guinea worm infections in dogs were first reported in Chad in 2012. Animal infections have now overtaken human cases, with 1,601 reported animal infections in 2020 and 443 during January-June 2021. Currently, all national GWEPs remain fully operational, with precautions taken to ensure safety of program staff and community members in response to the COVID-19 pandemic. Because of COVID-19, The Carter Center convened the 2020 and 2021 annual GWEP Program Managers meetings virtually, and WHO's International Commission for the Certification of Dracunculiasis Eradication met virtually in October 2020. Since 1986, WHO has certified 199 countries, areas, and territories dracunculiasis-free. Six countries are still affected: five with endemic disease and importations into Cameroon. Seven countries (five with endemic dracunculiasis, Democratic Republic of the Congo, and Sudan) still lack certification (4). The existence of infected dogs, especially in Chad, and impeded access because of civil unrest and insecurity in Mali and South Sudan are now the greatest challenges to interrupting transmission. This report describes progress during January 2020-June 2021 and updates previous reports (2,4,5).

Progress Toward Global Eradication of Dracunculiasis, January 2019-June 2020.

Dracunculiasis (Guinea worm disease) is caused by the parasite Dracunculus medinensis and is acquired by drinking water containing copepods (water fleas) infected with D. medinensis larvae. The worm typically emerges through the skin on a lower limb approximately 1 year after infection, resulting in pain and disability (1). There is no vaccine or medicine to treat the disease; eradication efforts rely on case containment* to prevent water contamination. Other interventions to prevent infection include health education, water filtration, chemical treatment of unsafe water with temephos (an organophosphate larvicide to kill copepods), and provision of safe drinking water (1,2). The worldwide eradication campaign began in 1980 at CDC (1). In 1986, with an estimated 3.5 million cases† occurring each year in 20 African and Asian countries§ (3), the World Health Assembly (WHA) called for dracunculiasis elimination (4). The global Guinea Worm Eradication Program (GWEP), led by the Carter Center and supported by the World Health Organization (WHO), United Nations Children's Fund, CDC, and other partners, began assisting ministries of health in countries with dracunculiasis. This report, based on updated health ministry data (4), describes progress made during January 2019-June 2020 and updates previous reports (2,4,5). With only 54 human cases reported in 2019, 19 human cases reported during January 2019-June 2020, and only six countries currently affected by dracunculiasis (Angola, Chad, Ethiopia, Mali, South Sudan, and importations into Cameroon), the achievement of eradication is within reach, but it is challenged by civil unrest, insecurity, and lingering epidemiologic and zoologic concerns, including 2,000 reported animal cases in 2019 and 1,063 animal cases in 2020, mostly in dogs. All national GWEPs remain fully operational, with precautions taken to ensure safety of program staff members and community members in response to the coronavirus disease 2019 (COVID-19) pandemic.

Progress Toward Global Eradication of Dracunculiasis - January 2018-June 2019.

Dracunculiasis (also known as Guinea worm disease) is caused by the parasite Dracunculus medinensis and is acquired by drinking water containing copepods (water fleas) infected with D. medinensis larvae. The worm typically emerges through the skin on a lower limb approximately 1 year after infection, resulting in pain and disability (1). There is no vaccine or medicine to treat the disease; eradication efforts rely on case containment* to prevent water contamination and other interventions to prevent infection, including health education, water filtration, chemical treatment of unsafe water with temephos (an organophosphate larvicide to kill copepods), and provision of safe drinking water (1,2). In 1986, with an estimated 3.5 million cases† occurring each year in 20 African and Asian countries§ (3), the World Health Assembly called for dracunculiasis elimination (4). The global Guinea Worm Eradication Program (GWEP), led by The Carter Center and supported by the World Health Organization (WHO), CDC, the United Nations Children's Fund, and other partners, began assisting ministries of health in countries with dracunculiasis. This report, based on updated health ministry data, describes progress to eradicate dracunculiasis during January 2018-June 2019 and updates previous reports (2,4,5). With only five countries currently affected by dracunculiasis (Angola, Chad, Ethiopia, Mali, and South Sudan), achievement of eradication is within reach, but it is challenged by civil unrest, insecurity, and lingering epidemiologic and zoologic questions.

Progress Toward Global Eradication of Dracunculiasis - January 2017-June 2018.

Dracunculiasis (Guinea worm disease), caused by the parasite Dracunculus medinensis, is acquired by drinking water containing copepods (water fleas) infected with its larvae. The worm typically emerges through the skin on a lower limb approximately 1 year after infection, causing pain and disability (1). The worldwide eradication campaign began at CDC in 1980. In 1986, the World Health Assembly called for dracunculiasis elimination, and the global Guinea Worm Eradication Program (GWEP), led by the Carter Center in partnership with the World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and others, began assisting ministries of health in countries with dracunculiasis. There is no vaccine or medicine to treat the disease; the GWEP relies on case containment* to prevent water contamination and other interventions to prevent infection, including health education, water filtration, chemical treatment of water, and provision of safe drinking water (1,2). In 1986, an estimated 3.5 million cases† occurred each year in 20§ African and Asian countries (3,4). This report, based on updated health ministry data (3), describes progress during January 2017-June 2018 and updates previous reports (1,4). In 2017, 30 cases were reported from Chad and Ethiopia, and 855 infected animals (mostly dogs) were reported from Chad, Ethiopia, and Mali, compared with 25 cases and 1,049 animal infections reported in 2016. During January-June 2018, the number of cases declined to three cases each in Chad and South Sudan and one in Angola, with 709 infected animals reported, compared with eight cases and 547 animal infections during the same period of 2017. With only five affected countries, the eradication goal is near, but is challenged by civil unrest, insecurity, and lingering epidemiologic and zoologic questions.

Progress Toward Global Eradication of Dracunculiasis, January 2016-June 2017.

Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after a person acquires infection from contaminated drinking water, the worm emerges through the skin, usually on a lower limb (1). Pain and secondary bacterial infection can cause temporary or permanent disability that disrupts work and schooling. The campaign to eradicate dracunculiasis worldwide began in 1980 at CDC. In 1986, the World Health Assembly called for dracunculiasis elimination,* and the global Guinea Worm Eradication Program, led by the Carter Center and supported by the World Health Organization (WHO), United Nations Children's Fund, CDC, and other partners, began assisting ministries of health in countries with endemic dracunculiasis. In 1986, an estimated 3.5 million cases occurred each year in 20 countries in Africa and Asia (2). Since then, although the goal of eradicating dracunculiasis has not been achieved, considerable progress has been made. Compared with the 1986 estimate, the annual number of reported cases in 2016 has declined by >99%, and cases are confined to three countries with endemic disease. This report updates published (3-4) and unpublished surveillance data reported by ministries of health and describes progress toward dracunculiasis eradication during January 2016-June 2017. In 2016, a total of 25 cases were reported from three countries (Chad [16], South Sudan [six], Ethiopia [three]), compared with 22 cases reported from the same three countries and Mali in 2015 (Table 1). The 14% increase in cases from 2015 to 2016 was offset by the 25% reduction in number of countries with indigenous cases. During the first 6 months of 2017, the overall number of cases declined to eight, all in Chad, from 10 cases in three countries (Chad [four], South Sudan [four] and Ethiopia [two]) during the same period of 2016. Continued active surveillance, aggressive detection, and appropriate management of cases are essential eradication program components; however, epidemiologic challenges, civil unrest, and insecurity pose potential barriers to eradication.

Progress Toward Global Eradication of Dracunculiasis -January 2015-June 2016.

Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after a person acquires infection from drinking contaminated water, the worm emerges through the skin, usually on the leg. Pain and secondary bacterial infection can cause temporary or permanent disability that disrupts work and schooling. The campaign to eradicate dracunculiasis worldwide began in 1980 at CDC. In 1986, the World Health Assembly called for dracunculiasis elimination (1), and the global Guinea Worm Eradication Program, led by the Carter Center and supported by the World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and other partners, began assisting ministries of health in countries where dracunculiasis was endemic. In 1986, an estimated 3.5 million cases were occurring each year in 20 countries in Africa and Asia (1,2). Since then, although the goal of eradicating dracunculiasis has not been achieved, substantial progress has been made. Compared with the 1986 estimate, the annual number of reported cases in 2015 has been reduced by >99%, and cases are confined to four countries with endemic disease. This report updates published (3-5) and unpublished surveillance data reported by ministries of health and describes progress toward dracunculiasis eradication during January 2015-June 2016. In 2015, a total of 22 cases were reported from four countries (Chad [nine cases], Mali [five], South Sudan [five], and Ethiopia [three]), compared with 126 cases reported in 2014 from the same four countries (Table 1). The overall 83% reduction in cases from 2014 to 2015 is the largest such annual overall reduction ever achieved during this global campaign. During the first 6 months of 2016, however, cases increased 25% compared with the same period in 2015. Continued active surveillance and aggressive detection and appropriate management of cases are essential eradication program components; however, epidemiologic challenges and civil unrest and insecurity pose potential barriers to eradication.

Factors Influencing Community Engagement during Guinea Worm and Polio Eradication Endgames in Chad: Recommendations for "Last Mile" Programming.

Community engagement is a strategy commonly used in health and development programming. Many disease eradication programs engage with communities through different structures and mechanisms to detect, report, contain, and respond to the diseases they target. Qualitative operational research was conducted in a district of Chad co-endemic for both dracunculiasis (i.e., Guinea worm disease) and circulating vaccine-derived poliovirus to reveal factors influencing community engagement behavior in the context of eradication-related programming. Women and men from six communities and stakeholders from the local, district, and central levels were recruited to participate in focus group discussions and semi-structured in-depth interviews. A thematic analysis was performed to identify barriers and facilitators of community engagement. Barriers to community engagement included mistrust in exogenously established health program initiatives (i.e., initiatives designed by partners external to targeted program communities) resulting from negative past experiences with external entities and community groups and the lure of profit-motivating community engagement. Subgroup and intersectionality analyses revealed that gender and other identities influence whether and to what extent certain members of the community engage in a meaningful way. Facilitators of community engagement included leadership and the influence of authorities and leaders in community participation, perceived benefits of being engaged with community-based initiatives, and use of incentives to enhance community participation. Study findings may be used to inform the refinement of community engagement approaches in Chad and learning agendas for other "last mile" disease eradication programs.

The effects of COVID-19 risk, gender, and self-compassion on the workplace cyberbullying and job satisfaction of university faculty.

The purpose of this study is to examine workplace cyberbullying (WPCB) in higher education. Specifically, the study examines the relationship between WPCB and several important factors such as self-compassion, job satisfaction, and gender. The cross-sectional study administered a survey to a convenience sample of 179 faculty members. The regression model showed that self-compassion was positively related to job satisfaction, whereas WPCB was negatively related to job satisfaction after controlling for covariates. The path analysis model results showed that gender and COVID-19 risk of severe illness were related to WPCB. Additionally, self-compassion mediated the inverse relationship between WPCB and job satisfaction.

Potential Impact of a Diagnostic Test for Detecting Prepatent Guinea Worm Infections in Dogs.

Chad has seen a considerable reduction in cases of Guinea worm disease (or dracunculiasis) in domestic dogs in recent years. Tethering of dogs and application of Abate® larvicide to water sources appear to have contributed to this progress, but with 767 reported dog cases in 2021, accelerating elimination of the disease in Chad may require additional tools. We investigate the potential benefits of a hypothetical diagnostic test that could be capable of detecting prepatent infections in dogs. We adapt an agent-based simulation model for forecasting the impact of interventions on guinea worm disease in dogs to examine the interaction of multiple test factors including test accuracy, when the test can detect infection, dog selection, and dog-owner compliance with tethering recommendations. We find that a diagnostic test could be successful if used in conjunction with existing interventions, and elimination can be achieved within 2 years with 80% or higher test sensitivity, 90% or higher specificity, systematic testing of each dog twice per year, and more than 90% long-term tethering compliance when a dog tests positive or a worm is emerging. Because of the long incubation period of Guinea worm disease (10-14 months) and the fact that no treatment exists, the benefits of the test rely on the testing rollout and response of dog owners. If the test could estimate the timing of worm emergence, long-term tethering could be eliminated and infected dogs could be tethered only when the worms are expected, minimizing the related resources (human and financial) to support the intervention.

Slaying the Serpent: A Research Agenda to Expand Intervention Development and Accelerate Guinea Worm Eradication Efforts.

Dracunculiasis, also known as Guinea worm disease, is targeted to become the second human disease and first parasitic infection to be eradicated. The global Guinea Worm Eradication Program (GWEP), through community-based interventions, reduced the burden of disease from an estimated 3.5 million cases per year in 1986 to only 13 human cases in 2022. Despite progress, in 2012 Guinea worm disease was detected in domesticated dogs and later in domesticated cats and baboons. Without previous development of any Guinea worm therapeutics, diagnostic tests to detect pre-patent Guinea worm infection, or environmental surveillance tools, the emergence of Guinea worm disease in animal hosts-a threat to eradication-motivated an assessment of evidence gaps and research opportunities. This gap analysis informed the refinement of a robust research agenda intended to generate new evidence and identify additional tools for national GWEPs and to better align the global GWEP with a 2030 Guinea worm eradication certification target. This paper outlines the rationale for the development and expansion of the global GWEP Research Agenda and summarizes the results of the gap analysis that was conducted to identify Guinea worm-related research needs and opportunities. We describe five work streams informed by the research gap analysis that underpin the GWEP Research Agenda and address eradication endgame challenges through the employment of a systems-informed One Health approach. We also discuss the infrastructure in place to disseminate new evidence and monitor research results as well as plans for the continual review of evidence and research priorities.

Promotion of Th17 Polarized Immunity via Co-Delivery of Mincle Agonist and Tuberculosis Antigen Using Silica Nanoparticles.

Adjuvants and immunomodulators that effectively drive a Th17-skewed immune response are not part of the standard vaccine toolkit. Vaccine adjuvants and delivery technologies that can induce Th17 or Th1/17 immunity and protection against bacterial pathogens, such as tuberculosis (TB), are urgently needed. Th17-polarized immune response can be induced using agonists that bind and activate C-type lectin receptors (CLRs) such as macrophage inducible C-type lectin (Mincle). A simple but effective strategy was developed for codelivering Mincle agonists with the recombinant Mycobacterium tuberculosis fusion antigen, M72, using tunable silica nanoparticles (SNP). Anionic bare SNP, hydrophobic phenyl-functionalized SNP (P-SNP), and cationic amine-functionalized SNP (A-SNP) of different sizes were coated with three synthetic Mincle agonists, UM-1024, UM-1052, and UM-1098, and evaluated for adjuvant activity in vitro and in vivo. The antigen and adjuvant were coadsorbed onto SNP via electrostatic and hydrophobic interactions, facilitating multivalent display and delivery to antigen presenting cells. The cationic A-SNP showed the highest coloading efficiency for the antigen and adjuvant. In addition, the UM-1098-adsorbed A-SNP formulation demonstrated slow-release kinetics in vitro, excellent stability over 12 months of storage, and strong IL-6 induction from human peripheral blood mononuclear cells. Co-adsorption of UM-1098 and M72 on A-SNP significantly improved antigen-specific humoral and Th17-polarized immune responses in vivo in BALB/c mice relative to the controls. Taken together, A-SNP is a promising platform for codelivery and proper presentation of adjuvants and antigens and provides the basis for their further development as a vaccine delivery platform for immunization against TB or other diseases for which Th17 immunity contributes to protection.

Predicting the Environmental Suitability and Identifying Climate and Sociodemographic Correlates of Guinea Worm (Dracunculus medinensis) in Chad.

A comprehensive understanding of the spatial distribution and correlates of infection are key for the planning of disease control programs and assessing the feasibility of elimination and/or eradication. In this work, we used species distribution modeling to predict the environmental suitability of the Guinea worm (Dracunculus medinensis) and identify important climatic and sociodemographic risk factors. Using Guinea worm surveillance data collected by the Chad Guinea Worm Eradication Program (CGWEP) from 2010 to 2022 in combination with remotely sensed climate and sociodemographic correlates of infection within an ensemble machine learning framework, we mapped the environmental suitability of Guinea worm infection in Chad. The same analytical framework was also used to ascertain the contribution and influence of the identified climatic risk factors. Spatial distribution maps showed predominant clustering around the southern regions and along the Chari River. We also identified areas predicted to be environmentally suitable for infection. Of note are districts near the western border with Cameroon and southeastern border with Central African Republic. Key environmental correlates of infection as identified by the model were proximity to permanent rivers and inland lakes, farmlands, land surface temperature, and precipitation. This work provides a comprehensive model of the spatial distribution of Guinea worm infections in Chad 2010-2022 and sheds light on potential environmental correlates of infection. As the CGWEP moves toward elimination, the methods and results in this study will inform surveillance activities and help optimize the allocation of intervention resources.

Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1ß Secretion and T Cell Adjuvanticity.

Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1ß release. Identifying small molecules that induce IL-1ß release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1ß release. We find that ribociclib induces IL-1ß release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.