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The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines. Although several vaccines have received emergency approval through various public health agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning immunity in the vaccinated, evidence that vaccines may not prevent transmission and inequity in vaccine distribution have driven continued development of vaccines against SARS-CoV-2 to address these public health needs. In this report, we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels after six months but were rapidly recalled and conferred protection from disease when the animals were challenged 7 months after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned to undetectable levels.

Pulmonary infections elicit a combination of tissue-resident and circulating T cell responses. Understanding the contribution of these anatomically distinct cellular pools in protective immune responses is critical for vaccine development. Francisella tularensis is a highly virulent bacterium capable of causing lethal systemic disease following pulmonary infection for which there is no currently licensed vaccine. Although T cells are required for survival of F. tularensis infection, the relative contribution of tissue-resident and circulating T cells is not completely understood, hampering design of effective, long-lasting vaccines directed against this bacterium. We have previously shown that resident T cells were not sufficient to protect against F. tularensis, suggesting circulating cells may serve a critical role in host defense. To elucidate the role of circulating T cells, we used a model of vaccination and challenge of parabiotic mice. Intranasally infected naive mice conjoined to immune animals had increased numbers of circulating memory T cells and similar splenic bacterial burdens as vaccinated–vaccinated pairs. However, bacterial loads in the lungs of naive parabionts were significantly greater than those observed in vaccinated–vaccinated pairs, but despite early control of F. tularensis replication, all naive–vaccinated pairs succumbed to infection. Together, these data define the specific roles of circulating and resident T cells in defense against infection that is initiated in the pulmonary compartment but ultimately causes disseminated disease. These data also provide evidence for employing vaccination strategies that elicit both pools of T cells for immunity against F. tularensis and may be a common theme for other disseminating bacterial infections.

BACKGROUND: The ReMIND trial hypothesizes that autologous T-cells specific for three tumor-associated antigens (TAA) -WT1, PRAME, and survivin- will be safe and elicit anti-tumor immunity in pediatric patients with CNS cancer. METHODS: Patients (n=25) received autologous TAA-T for newly-diagnosed DIPG (Stratum A, up to 4x107/m2) or recurrent CNS malignancies (Stratum B, up to 8x107/m2) in this dose-escalation study (NCT03652545) and were monitored for toxicity and response. RESULTS: Autologous TAAT products were successfully manufactured from 28 patients. Using IFN-γ ELISPOT assay, 10/11 evaluable products had specificity for 1-3 TAAs. 25 patients received TAA-T (6 in Stratum A and 19 in Stratum B) and completed the 45-day safety monitoring period. Twenty-four (96%) had no dose limiting toxicities (DLT), but 1 (4%) patient with DIPG experienced a DLT related to potential immune-mediated pseudoprogression. Median overall survival for patients with DIPG (Stratum A) was 14 months (range, 6-32 months). Median progression-free survival (PFS) for Stratum B patients was 8 months (range, 2-26+ months), which exceeded their preceding median duration of disease stability of 2 months (range, 1-5 months). Plasma cytokine profiles demonstrated infusion-related immune cytokine responses. CONCLUSIONS: In summary, TAAT had a favorable toxicity profile (4%) especially compared to CAR-T therapy and may elicit anti-tumor immune responses that contribute to prolonged survival. Immunobiology studies and response assessments are ongoing for both strata. Based on these encouraging preliminary results, we have added a stratum that includes prescribed lymphodepletion pre TAA-T administration at a cell dose of 8x107/m2. Further, we plan to add an additional stratum to allow direct administration of TAA-T into the CNS via an Ommaya reservoir.

Background Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity. Methods Patients (n=18) received autologous tumor antigen-associated T cells (TAAT) (up to 8x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. Results/Discussion 16/18 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Adverse events were minimal despite multiple pretreatments in Group B. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) respectively. Specificity for 1–3 TAAs was demonstrated in 11/18 TAAT by a-IFN-γ ELISPOT. Dose escalation is complete, and clinical and immunologic response assessments are ongoing. Plasma cytokine and proteomic analyses demonstrated dynamic post-infusion immune cytokine and protein responses. Consistent with an infusion-mediated immune response all patients in Grp A showed increased T cell effector, inflammatory and immune-stimulatory cytokines IFN-γ, TNF-α, IL-2, IL-5, IL-7, IL-1β, IL-6, IL-8, IL-12p70, IL-17A and GM-CSF at Weeks 1 and 2 post-infusion (n = 6). Of 9 patients who have been tested, 29/92 plasma proteins showed significant differences between dose levels 1 and 2, including increased IL-7 (p

BACKGROUND Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity. METHODS Patients (n=9) have received autologous tumor antigen-associated T cells (TAAT) (up to 4x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. RESULTS/ DISCUSSION 9/9 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) of the CD3+ cells, respectively. TAAT with specificity for 1–3 TAAs, at varying frequencies, was demonstrated in 8/9 TAAT by anti-IFN-γ ELISPOT. Plasma cytokine profiles demonstrated infusion-related immune cytokine responses. In summary, TAAT are safe and may elicit anti-tumor responses in vivo. To confirm TAAT-driven effects, we are evaluating plasma proteomic profiles for immune-response signatures and assessing unique T cell receptor rearrangements of infused TAAT. Response assessment and dose escalation are ongoing.

This article examines the relationship between the Cape Town Convention (insofar as it relates to aircraft) and the Geneva Convention. The latter continues to apply to rights not constituting international interests under, and to rights in aircraft below the minimum threshold set out in, the former. The Geneva Convention provides that the law of the state of registration of the aircraft in question is the applicable law for rights and interests covered by it but gives no guidance as to whether such law is the domestic law only of that state or includes that state's private international law rules. The Cape Town Convention provides that references in it to applicable law are to the domestic law of the state in question but, in fact, relevant references therein to applicable law are few and international interests under the Cape Town Convention are sui generis interests not dependent on national law.

Although autoantibodies have been used for decades as diagnostic and prognostic markers in type 1 diabetes (T1D), further analysis of developmental abnormalities in B cells could reveal tolerance checkpoint defects that could improve individualized therapy. To evaluate B cell developmental progression in T1D, immunophenotyping was used to classify circulating B cells into transitional, mature naive, mature activated, and resting memory subsets. Then each subset was analyzed for the expression of additional maturation-associated markers. While the frequencies of B cell subsets did not differ significantly between patients and controls, some T1D subjects exhibited reduced proportions of B cells that expressed transmembrane activator and CAML interactor (TACI) and Fas receptor (FasR). Furthermore, some T1D subjects had B cell subsets with lower frequencies of class switching. These results suggest circulating B cells exhibit variable maturation phenotypes in T1D. These phenotypic variations may correlate with differences in B cell selection in individual T1D patients.

ITP is an autoimmune hematologic disorder characterized by immune mediated destruction of platelets. Up to 90% of patients experience disease self-limited to 6 months (2, 3). The majority of patients' platelet counts increase with steroid and/or intravenous immunoglobulin (IVIG) treatment, to prevent complications, within 24-72 hours. (2, 3). ITP may occur in otherwise healthy children or coincide with other autoimmune disorders, such as Hashimoto's thyroiditis. Previous case reports suggest that induction of a euthyroid state with levothyroxine improved patients' platelet response to IVIG and steroids (1). We report the case of a 15 year old female diagnosed with acute ITP, also found to have Hashimoto's thyroiditis, whose ITP proved refractory to first line therapy, despite achieving a euthyroid state on levothyroxine treatment. A 15 year old female presented complaining of prolonged menstrual bleeding and easy bruising, associated with fatigue, for 3 weeks. The patient had a gradually enlarging thyroid gland. Review of systems was otherwise negative and family history was non-contributory. On physical exam, vital signs demonstrated weight at the 97th percentile and tachycardia. The patient had palmar and conjunctival pallor. There was firm, non-tender thyromegaly, without palpable nodules. She had yellow and purple, circular, 3 cm ecchymoses on her right anterior inner thigh and left upper abdominal quadrant. Neurological, cardiovascular, pulmonary, and gastrointestinal exams were otherwise normal. Initial laboratory evaluation demonstrated a microcytic anemia with hemoglobin of 5.3 g/dl, mean corpuscular volume of 76.3 fL, reticulocyte count of 3.2%, and platelet count of 5 x 103/μL, with few large platelets seen on peripheral smear. Peripheral blood flow cytometry proved negative for leukemia and lymphoma. Evaluation for other causes of thrombocytopenia, including infection and familial thrombocytopenia, was negative. She had a normal absolute neutrophil count and a negative direct Coomb's test, ruling out Evan's syndrome. Her thyroid studies suggested hypothyroidism, with a thyroid stimulating hormone (TSH) of 233.40 μ[IU]/mL, free T4 of 0.3 ng/dL, thyroglobulin antibody >1000 [IU]/mL, and thyroid peroxidase antibody >900 [IU]/mL. Neck ultrasound revealed an enlarged, heterogeneous thyroid gland with multiple, small, echogenic, non-shadowing nodules, consistent with Hashimoto's thyroiditis. During the hospital course, the patient received supportive care with 2 courses of IVIG and packed red blood cells (pRBCs). Her hemoglobin improved to 8.7 g/dL, and her platelets reached 34 x 103/μL, prior to discharge. Initially her TSH was 233 μ[IU]/mL, which decreased to 87 μ[IU]/mL after inpatient treatment with 88 mcg of levothyroxine daily. She continued on a steroid taper over 21 days. She continued to experience persistent symptoms of thrombocytopenia and microcytic anemia. She required a second hospitalization for prolonged epistaxis and menorrhagia due to thrombocytopenia, with a platelet count of 2 x 103/μL, while on steroid therapy. Due to refractory response to steroids and IVIG, despite treatment for hypothyroidism, hematology initiated second line treatment with oral eltrombopag. Her goiter did not decrease in size, but the patient's TSH stabilized at 4.51 μ[IU]/mL and free T4 at 0.9 ng/dL. She improved her platelet count to 209 x 103/μL, within 2 weeks of therapy with eltrombopag, and she remained asymptomatic. The adolescent physician also began oral contraceptive pills for menstrual regulation. Since the patient's platelet count improved significantly, hematology decreased her dose of eltrombopag, and the patient maintained a platelet count between 200-400 x 103/μL. This is a rare pediatric case of coexisting ITP and Hashimoto's thyroiditis, in which thrombocytopenia did not improve with first line therapy for ITP, despite the achievement of a euthyroid state with levothyroxine. She initially responded with a transient, minimal improvement in her platelet count, requiring an early decision to initiate second-line management. Second-line therapy is usually reserved for patients with chronic ITP (thrombocytopenia greater than 6 months). Based on our patient's response, we would suggest use of eltrombopag in acute ITP patients who are refractory to first line therapy. Disclosures No relevant conflicts of interest to declare.

Recently a call has gone up for a revival of the “politics of humanity.” But what exactly is the “politics of humanity”? For illumination this paper turns to Hume’s analysis of humanity’s foundational role in morality and modern politics. Its aims in so doing are twofold. First, it aims to set forth a new understanding of the unity of Hume’s practical and epistemological projects in developing his justifications for and the implications of his remarkable and underappreciated claim that humanity is the only sentiment on which a moral system can be founded. Second, by attending to Hume’s substantive definition of humanity and its relationship to benevolence and sympathy in particular, it aims to clarify the relationship between the principal elements of the politics of humanity: “humanism” or secularism, “humane” or other-directed values, and mutual recognition of our shared “humanness.”

Rousseau is famous as an advocate of the politics of “denaturing.” But attention to his conception of the “science of the legislator,” as developed in the Geneva Manuscript and his writings on Poland and Corsica, reveals a more moderate approach to statecraft. Here Rousseau claims that legislative science requires tempering commitment to principles of political right with sensitivity to actual political conditions—a claim that importantly and unexpectedly parallels the better known account of the science of the legislator developed by Adam Smith. In comparing these conceptions, this article draws three conclusions: first, Smith's and Rousseau's shared moderation reveals their common commitment to accommodating the passions and prejudices of modernity; second, their fundamental difference concerns not practical legislative methods but rather differing conceptions of natural justice and political right; and finally, their prudential approach to legislation helps clarify the specific types of “moderation” and “intelligence” required of contemporary nation builders.

I saiah Berlin is remembered for his positive/negative liberty distinction and his value pluralism, but he was also an active participant in the debate over the nature of political inquiry. This essay argues that his neglected contribution to this debate is central to his thought and a valuable resource in today's debate over political science's methods and ends. I first show how Berlin understood the relationship of empirical science to humanistic study. I then demonstrate that his conceptions of political judgment and the “sense of reality” were intended as alternatives to the scientific pursuit of political knowledge. Finally, I argue that his Churchill and Weizmann essays present exemplars of the moral excellence Berlin considered necessary to ennoble liberal society and the political understanding indispensable to comprehensive political inquiry. I conclude by noting how Berlin's critique of scientific political inquiry informs his liberalism and his own methods of political inquiry.

Hume's concern to promote public virtue is a central element of his philosophical project which deserves more attention than it has received. This article examines one of his most focused efforts at public moralism: his largely forgotten autobiography, My Own Life. By attending to its account of how Hume employed his vanity and ambition in his pursuit of fame and fortune—and discovered such virtues as temperance, industry, moderation, and independence in the process—it is argued that My Own Life was intended to serve as a “mirror-for-citizen.” for citizens of modern commercial republics, offering a model of civic virtue and worldly success for them to emulate. To show this Hume's didactic autobiography is compared to that of his friend Benjamin Franklin, which may have served as a model for Hume's.

En este articulo se sostiene que la teoria moral de Adam Smith se entiende mejor como una contribucion a la etica de la virtud que como una contribucion a cualquiera de las dos escuelas rivales de la filosofia moral contemporanea, el utilitarismo y la deontologia. Para demostrarlo, el autor examina la concepcion que tiene Smith de los metodos y fines apropiados de la etica. Se centra aqui en el lugar que Smith le asigna a la retorica en la etica, y en como, para Smith, la etica se relaciona mas con la formacion del caracter que con el establecimiento de reglas y preceptos. Se concluye, sobre esa base, que Smith debe ser considerado junto a Hutcheson y Hume como uno de los fundadores en el siglo XVIII de la etica de la virtud contemporanea, y que, al igual que los cultores de esta ultima, le debe mucho a Aristoteles y, de hecho, bien puede servir de interlocutor en los actuales debates neo-aristotelicos.

Crimean-Congo hemorrhagic fever virus (CCHFV) is widely distributed throughout Africa, the Middle East, Southern Asia, and Southern and Eastern Europe. Spread by Hyalomma ticks or by contact with infected animals, CCHF begins non-specifically but can rapidly progress to severe, sometimes fatal, disease. Due to the non-specific early symptoms and often unrecognized infections, patients often present to healthcare systems exhibiting later stages of disease, when treatment is limited to supportive care. Consequently, simple vaccines are critically needed to protect populations at risk of CCHFV infection. Currently, there are no widely approved vaccines for CCHFV. We have previously reported significant efficacy of a three-dose DNA-based vaccination regimen for CCHFV in cynomolgus macaques (Macaca fasicularis). Here, we show that in cynomolgus macaques, plasmid-expressed CCHFV nucleoprotein (NP) and glycoprotein precursor (GPC) antigens elicit primarily humoral and cellular immunity, respectively. We found that a two-dose vaccination regimen with plasmids expressing the NP and GPC provides significant protection against CCHFV infection. Studies investigating vaccinations with either antigen alone showed that plasmid-expressed NPs could also confer protection. Cumulatively, our data show that this vaccine confers robust protection against CCHFV and suggest that both humoral and cellular immunity contribute to optimal vaccine-mediated protection.