The Age of Cyclic Dinucleotide Vaccine Adjuvants

As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans

Study of a supply chain system with the presence of bullwhip effect

A study has been conducted to understand the effect of bullwhip phenomenon in a supply chain system. The hypothetical data collected from the study is used to make a model which can be used to simulate the operation of the system with moderate complexity. System dynamics approach is used to create an open loop system. The phenomenon used is slightly modified and empirically analysed to bring down its adverse effect on the system. The results obtained graphically are emphasising the effect of bullwhip on the various levels of the supply chain system

Study of a supply chain system with the presence of bullwhip effect

A study has been conducted to understand the effect of bullwhip phenomenon in a supply chain system. The hypothetical data collected from the study is used to make a model which can be used to simulate the operation of the system with moderate complexity. System dynamics approach is used to create an open loop system. The phenomenon used is slightly modified and empirically analysed to bring down its adverse effect on the system. The results obtained graphically are emphasising the effect of bullwhip on the various levels of the supply chain system

Co-Administration of Aluminium Hydroxide Nanoparticles and Protective Antigen Domain 4 Encapsulated Non-Ionic Surfactant Vesicles Show Enhanced Immune Response and Superior Protection against Anthrax

Aluminium salts have been the adjuvant of choice in more than 100 licensed vaccines. Here, we have studied the synergistic effect of aluminium hydroxide nanoparticles (AH np) and non-ionic surfactant-based vesicles (NISV) in modulating the immune response against protective antigen domain 4 (D4) of Bacillus anthracis. NISV was prepared from Span 60 and cholesterol, while AH np was prepared from aluminium chloride and sodium hydroxide. AH np was co-administered with NISV encapsulating D4 (NISV-D4) to formulate AHnp/NISV-D4. The antigen-specific immune response of AHnp/NISV-D4 was compared with that of commercial alhydrogel (alhy) co-administered with NISV-D4 (alhydrogel/NISV-D4), NISV-D4, AHnp/D4, and alhydrogel/D4. Co-administration of NISV-D4 with AH np greatly improved the D4-specific antibody titer as compared to the control groups. Based on IgG isotyping and ex vivo cytokine analysis, AHnp/NISV-D4 generated a balanced Th1/Th2 response. Furthermore, AH np/NISV-D4 showed superior protection against anthrax spore challenge in comparison to other groups. Thus, we demonstrate the possibility of developing a novel combinatorial nanoformulation capable of augmenting both humoral and cellular response, paving the way for adjuvant research

Trimethyl Chitosan Nanoparticles Encapsulated Protective Antigen Protects the Mice Against Anthrax

Anthrax is an era old deadly disease against which there are only two currently available licensed vaccines named anthrax vaccine adsorbed and precipitated (AVP). Though they can provide a protective immunity, their multiple side-effects owing to their ill-defined composition and presence of toxic proteins (LF and EF) of Bacillus anthracis, the causative organism of anthrax, in the vaccine formulation makes their widespread use objectionable. Hence, an anthrax vaccine that contains well-defined and controlled components would be highly desirable. In this context, we have evaluated the potential of various vaccine formulations comprising of protective antigen (PA) encapsulated trimethyl-chitosan nanoparticles (TMC-PA) in conjunction with either CpG-C ODN 2395 (CpG) or Poly I:C. Each formulation was administered via three different routes, viz., subcutaneous (SC), intramuscular (IM), and intraperitoneal in female BALB/c mice. Irrespective of the route of immunization, CpG or Poly I:C adjuvanted TMC-PA nanoparticles induced a significantly higher humoral response (total serum IgG and its isotypes viz., IgG1, IgG2a, and IgG2b), compared to their CpG or Poly I:C PA counterparts. This clearly demonstrates the synergistic behavior of CpG and Poly I:C with TMC nanoparticles. The adjuvant potential of TMC nanoparticles could be observed in all the three routes as the TMC-PA nanoparticles by themselves induced IgG titers (1–1.5 × 105) significantly higher than both CpG PA and Poly I:C PA groups (2–8 × 104). The effect of formulations on T-helper (Th) cell development was assessed by quantifying the Th1-dependant (TNF-α, IFN-γ, and IL-2), Th2-dependant (IL-4, IL-6, and IL-10), and Th17-type (IL-17A) cytokines. Adjuvanation with CpG and Poly I:C, the TMC-PA nanoparticles triggered a Th1 skewed immune response, as suggested by an increase in the levels of total IgG2a along with IFN-γ cytokine production. Interestingly, the TMC-PA group showed a Th2-biased immune response. Upon challenge with the B. anthracis Ames strain, CpG and Poly I:C adjuvanted TMC-PA nanoparticles immunized via the SC and IM routes showed the highest protective efficacy of ~83%. Altogether, the results suggest that CpG or Poly I:C adjuvanted, PA-loaded TMC nanoparticles could be used as an effective, non-toxic, second generation subunit-vaccine candidate against anthrax

Bird Assemblages in a Peri-Urban Landscape in Eastern India

Urbanization plays an important role in biodiversity loss across the globe due to natural habitat loss in the form of landscape conversion and habitat fragmentation on which species depend. To study the bird diversity in the peri-urban landscape, we surveyed four habitats—residential areas, cropland, water bodies, and sal forest; three seasons—monsoon, winter, and summer in Baripada, Odisha, India. We surveyed from February 2018 to January 2019 using point counts set along line transects; 8 transects were established with a replication of 18 each. During the survey, 6963 individuals of 117 bird species belonged to 48 families and 98 genera in the study area, whereas cropland showed rich avian diversity. Based on the non-parametric multidimensional scale (NMDS) and one-way ANOVA, bird richness and abundance differed significantly among the habitats. Cropland showed higher species richness than other habitats; however, water bodies showed more abundance than others. The similarity of bird assemblage was greater between residential areas and cropland than forest and water bodies based on similarity indices. Among seasons, we observed the highest bird species richness in winter and the highest similarity of species richness in monsoon and summer. In conclusion, our study reported that agricultural and degraded landscapes like cropland play important roles in conserving bird diversity in peri-urban landscapes. Our findings highlighted and identified the problems that affect the local biodiversity (e.g., birds) in the peri-urban landscape. It can assist the local government in urban planning and habitat management without affecting the local biodiversity, including birds

Lung IFNAR1(hi) TNFR2(+) cDC2 promotes lung regulatory T cells induction and maintains lung mucosal tolerance at steady state

The lung is a naturally tolerogenic organ. Lung regulatory T cells (T-regs) control lung mucosal tolerance. Here, we identified a lung IFNAR1(hi)TNFR2(+) conventional DC2 (iR2D2) population that induces T-regs in the lung at steady state. Using conditional knockout mice, adoptive cell transfer, receptor blocking antibodies, and TNFR2 agonist, we showed that iR2D2 is a lung microenvironment-adapted dendritic cell population whose residence depends on the constitutive TNFR2 signaling. IFN beta-IFNAR1 signaling in iR2D2 is necessary and sufficient for T-regs induction in the lung. The Epcam(+)CD45(-) epithelial cells are the sole lung IFN beta producer at the steady state. Surprisingly, iR2D2 is plastic. In a house dust mite model of asthma, iR2D2 generates lung T(H)2 responses. Last, healthy human lungs have a phenotypically similar tolerogenic iR2D2 population, which became pathogenic in lung disease patients. Our findings elucidate lung epithelial cells IFN beta-iR2D2-T-regs axis in controlling lung mucosal tolerance and provide new strategies for therapeutic interventions

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<p>Anthrax is an era old deadly disease against which there are only two currently available licensed vaccines named anthrax vaccine adsorbed and precipitated (AVP). Though they can provide a protective immunity, their multiple side-effects owing to their ill-defined composition and presence of toxic proteins (LF and EF) of Bacillus anthracis, the causative organism of anthrax, in the vaccine formulation makes their widespread use objectionable. Hence, an anthrax vaccine that contains well-defined and controlled components would be highly desirable. In this context, we have evaluated the potential of various vaccine formulations comprising of protective antigen (PA) encapsulated trimethyl-chitosan nanoparticles (TMC-PA) in conjunction with either CpG-C ODN 2395 (CpG) or Poly I:C. Each formulation was administered via three different routes, viz., subcutaneous (SC), intramuscular (IM), and intraperitoneal in female BALB/c mice. Irrespective of the route of immunization, CpG or Poly I:C adjuvanted TMC-PA nanoparticles induced a significantly higher humoral response (total serum IgG and its isotypes viz., IgG1, IgG2a, and IgG2b), compared to their CpG or Poly I:C PA counterparts. This clearly demonstrates the synergistic behavior of CpG and Poly I:C with TMC nanoparticles. The adjuvant potential of TMC nanoparticles could be observed in all the three routes as the TMC-PA nanoparticles by themselves induced IgG titers (1–1.5 × 10⁵) significantly higher than both CpG PA and Poly I:C PA groups (2–8 × 10⁴). The effect of formulations on T-helper (T_h) cell development was assessed by quantifying the Th1-dependant (TNF-α, IFN-γ, and IL-2), Th2-dependant (IL-4, IL-6, and IL-10), and Th17-type (IL-17A) cytokines. Adjuvanation with CpG and Poly I:C, the TMC-PA nanoparticles triggered a Th1 skewed immune response, as suggested by an increase in the levels of total IgG2a along with IFN-γ cytokine production. Interestingly, the TMC-PA group showed a Th2-biased immune response. Upon challenge with the B. anthracis Ames strain, CpG and Poly I:C adjuvanted TMC-PA nanoparticles immunized via the SC and IM routes showed the highest protective efficacy of ~83%. Altogether, the results suggest that CpG or Poly I:C adjuvanted, PA-loaded TMC nanoparticles could be used as an effective, non-toxic, second generation subunit-vaccine candidate against anthrax.</p

In vivo reprogramming of pathogenic lung TNFR2 + cDC2s by IFNβ inhibits HDM-induced asthma

Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2 conventional DC2 subset (cDC2s) that induces regulatory T cells (T ) maintaining lung tolerance at steady state but promotes T 2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2 cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed T 2-promoting pathogenic TNFR2 cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2 cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung T induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2 cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy

Cohort profile of the largest health & demographic surveillance system (Dibrugarh-HDSS) from North-East India

Dibrugarh Health and Demographic Surveillance System (Dibrugarh-HDSS), was started in the year 2019 with the objective to create the health and demographic database of a population from a defined geographical area and a surveillance system for providing technical assistance for the implementation of programmes and formulating intervention strategies for reducing disease morbidities and mortalities in the population. Dibrugarh-HDSS adopted a panel design and covered 60 contiguous villages and 20 tea gardens. Line listing of all the households was conducted and a unique identification number detailing State, district, village/tea garden and serial number was provided along with geotagging. Detailed sociodemographic variables, anthropometric measurements (subjects ≥five years) and blood pressure data (subjects ≥18 yr), disease morbidity and mortality were collected. All data were collected in pre-designed and pre-tested questionnaires using a mobile application package developed for this purpose. Dibrugarh-HDSS included a total of 106,769 individuals (rural: 46,762, tea garden: 60,007) with 52,934 males (49.6%) and 53,835 females (50.4%). The number of females per thousand males were significantly higher (1042 in tea garden vs. 985 in rural populations) in the tea-garden community as compared to the village population. More than one-third (35.1%) of tea populations were illiterate compared to the rural population (17.1%). Villagers had significantly higher body mass index than the tea-garden community. The overall prevalence of hypertension (adjusted for age) was 29.4 vs. 28.2 per cent, respectively, for the village and tea-garden population. For both these communities, males (village=30.8%, tea garden=31.1%) showed a higher prevalence of hypertension (adjusted for age) than females (village=28.2%, tea garden=25.8%). The findings of the present study give an insight into the profile of the native rural and tea-garden populations that will help to identify risk factors of different health problems, review the effectiveness of different ongoing programmes, implement intervention strategies for reducing morbidity and mortality and assist the State health authorities in prioritizing their resource allocation and implementation strategies