Cholera toxin and O-specific polysaccharide immune responses after oral cholera vaccination with Dukoral in different age groups of Bangladeshi participants.

Vaccination is important to prevent cholera. There are limited data comparing anti-O-specific polysaccharide (OSP) and anti-cholera toxin-specific immune responses following oral whole-cell with cholera toxin B-subunit (WC-rBS) vaccine (Dukoral, Valneva) administration in different age groups. An understanding of the differences is relevant because young children are less well protected by oral cholera vaccines than older children and adults. We compared responses in 50 adults and 49 children (ages 2 to <18) who were administered two doses of WC-rBS at a standard 14-day interval. All age groups had significant IgA and IgG plasma-blast responses to the OSP and cholera toxin B-subunit (CtxB) antigens that peaked 7 days after vaccination. However, in adults and older children (ages 5 to <18), antibody responses directed at the OSP antigen were largely IgA and IgG, with a minimal IgM response, while younger children (ages 2 to <5) mounted significant increases in IgM with minimal increases in IgA and IgG antibody responses 30 days after vaccination. In adults, anti-OSP and CtxB memory B-cell responses were detected after completion of the vaccination series, while children only mounted CtxB-specific IgG memory B-cell responses and no OSP-memory B-cell responses. In summary, children and adults living in a cholera endemic area mounted different responses to the WC-rBS vaccine, which may be a result of more prior exposure to Vibrio cholerae in older participants. The absence of class-switched antibody responses and memory B-cell responses to OSP may explain why protection wanes more rapidly after vaccination in young children compared to older vaccinees.IMPORTANCEVaccination is an important strategy to prevent cholera. Though immune responses targeting the OSP of V. cholerae are believed to mediate protection against cholera, there are limited data on anti-OSP responses after vaccination in different age groups, which is important as young children are not well protected by current oral cholera vaccines. In this study, we found that adults mounted memory B-cell responses to OSP, which were not seen in children. Adults and older children mounted class-switched (IgG and IgA) serum antibody responses to OSP, which were not seen in young children who had only IgM responses to OSP. The lack of class-switched antibody responses and memory B-cell responses to OSP in younger participants may be due to lack of prior exposure to V. cholerae and could explain why protection wanes more rapidly after vaccination in young children.

Esculetin unveiled: Decoding its anti-tumor potential through molecular mechanisms-A comprehensive review.

BACKGROUND: The growing complexity of cancer has made it a significant concern in the medical community. Although cancer research has advanced, it is still challenging to create new effective medications due to the limitations and side effects of existing treatment strategies. These are enforcing the development of some alternative drugs from natural compounds with fewer drawbacks and side effects. AIM: Therefore, this review aims to provide up-to-date, crucial, and all-encompassing data on esculetin's anticancer activity, including all relevant molecular and cellular processes based on in vivo and in vitro investigations. RESULTS: According to the literature review, esculetin is available in nature and is effective against 16 different types of cancer. The general mechanism shown by esculetin is modulating signaling cascades and its related pathways, like cell proliferation, cell growth, autophagy, apoptosis, necrosis, inflammation, angiogenesis, metastasis, invasion, and DNA damage. Nanoformulation of esculetin improves this natural product's efficacy by improving water solubility. Esculetin's synergistic effects with both natural substances and conventional treatments have been shown, and this method aids in reversing resistance mechanisms by modulating resistance-related proteins. In addition, it has fewer side effects on humans than other phytochemicals and standard drugs with some good pharmacokinetic features. CONCLUSION: Therefore, until standard chemotherapeutics are available in pharmaceutical markets, esculetin should be used as a therapeutic drug against various cancer types.

The Fatal Clinical Outcome of Severe COVID-19 in Hospitalized Patients: Findings from a Prospective Cohort Study in Dhaka, Bangladesh.

Background and Objectives: The morbidity and mortality associated with COVID-19 have burdened worldwide healthcare systems beyond their capacities, forcing them to promptly investigate the virus characteristics and its associated outcomes. This clinical analysis aimed to explore the key factors related to the fatal outcome of severe COVID-19 cases. Materials and Methods: Thirty-five adult severe COVID-19 patients were enrolled from two COVID-19 hospitals in Dhaka, Bangladesh. Clinical manifestation, comorbid conditions, medications, SARS-CoV-2 RT-PCR related cycle threshold (CT) value, hematology, biochemical parameters with SARS-CoV-2 specific IgG and IgM responses at enrollment were compared between the survivors and deceased participants. Results: Total 27 patients survived and 8 patients died within 3 months of disease onset. Deceased patients suffered longer from shortness of breath than the survived (p = 0.049). Among the severe cases, 62% of the deceased patients had multiple comorbid condition compared to 48% of those who survived. Interestingly, the anti-viral was initiated earlier among the deceased patients [median day of 1 (IQR: 0, 1.5) versus 6.5 (IQR: 6.25, 6.75)]. Most of the survivors (55%) received a combination of anticoagulant (p = 0.034). Liver enzymes, creatinine kinase, and procalcitonin were higher among the deceased patients during enrollment. The median CT value among the deceased was significantly lower than the survivors (p = 0.025). A significant difference for initial IgG (p = 0.013) and IgM (p = 0.030) responses was found between the survivor and the deceased groups. Conclusions: The factors including older age, male gender, early onset of respiratory distress, multiple comorbidities, low CT value, and poor antibody response may contribute to the fatal outcome in severe COVID-19 patients. Early initiation of anti-viral and a combination of anticoagulant treatment may prevent or lower the fatality among severe COVID-19 cases.

Determining clinical biomarkers to predict long-term SARS-CoV-2 antibody response among COVID-19 patients in Bangladesh.

Background: Information on antibody responses following SARS-CoV-2 infection, including the magnitude and duration of responses, is limited. In this analysis, we aimed to identify clinical biomarkers that can predict long-term antibody responses following natural SARS-CoV-2 infection. Methodology: In this prospective study, we enrolled 100 COVID-19 patients between November 2020 and February 2021 and followed them for 6 months. The association of clinical laboratory parameters on enrollment, including lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP), ferritin, procalcitonin (PCT), and D-dimer, with predicting the geometric mean (GM) concentration of SARS-CoV-2 receptor-binding domain (RBD)-specific IgG antibody at 3 and 6 months post-infection was assessed in multivariable linear regression models. Result: The mean ± SD age of patients in the cohort was 46.8 ± 14 years, and 58.8% were male. Data from 68 patients at 3 months follow-up and 55 patients at 6 months follow-up were analyzed. Over 90% of patients were seropositive against RBD-specific IgG till 6 months post-infection. At 3 months, for any 10% increase in absolute lymphocyte count and NLR, there was a 6.28% (95% CI: 9.68, -2.77) decrease and 4.93% (95% CI: 2.43, 7.50) increase, respectively, in GM of IgG concentration, while any 10% increase for LDH, CRP, ferritin, and procalcitonin was associated with a 10.63, 2.87, 2.54, and 3.11% increase in the GM of IgG concentration, respectively. Any 10% increase in LDH, CRP, and ferritin was similarly associated with an 11.28, 2.48, and 3.0% increase in GM of IgG concentration at 6 months post-infection. Conclusion: Several clinical biomarkers in the acute phase of SARS-CoV-2 infection are associated with enhanced IgG antibody response detected after 6 months of disease onset. The measurement of SARS-CoV-2 specific antibody responses requires improved techniques and is not feasible in all settings. Baseline clinical biomarkers can be a useful alternative as they can predict antibody response during the convalescence period. Individuals with an increased level of NLR, CRP, LDH, ferritin, and procalcitonin may benefit from the boosting effect of vaccines. Further analyses will determine whether biochemical parameters can predict RBD-specific IgG antibody responses at later time points and the association of neutralizing antibody responses.

A snap-shot of a diarrheal epidemic in Dhaka due to enterotoxigenic Escherichia coli and Vibrio cholerae O1 in 2022.

Background: Enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae O1 are most common bacterial causes of diarrheal diseases in Bangladesh. This analysis projected distribution of ETEC and V. cholerae O1 among diarrheal patients of icddr,b, Dhaka hospital in two diarrheal peaks of 2022. Methodology: Under the 2% systematic surveillance system, stool samples collected from diarrheal patients of icddr,b hospital were cultured and diagnostic testing was done for ETEC and V. cholerae O1. Comparison of positive cases was done between first peak (March-April) and second peak (October-November) in 2022. Results: A total of 2,937 stool specimens were tested of which 12% were ETEC and 20% were V. cholerae O1. About 40% of the severe dehydration cases were infected with V. cholerae O1. Predominant ETEC enterotoxin type was 'LT/ST' (41%). The LT enterotoxin significantly increased from 13% to 28% in the second peak (p = 0.015). The predominant colonization factors (CFs) on ETEC were CS5 + CS6 (23%), followed by CS6 (15%). CF-positive isolates was significantly higher in the second peak (36%) than in the first peak (22%) (p = 0.043). Total 14% cases were co-infected with ETEC and V. cholerae O1. Significant differences in the distribution of enterotoxin types were observed (p = 0.029) among the co-infection cases. Conclusion: Changing patterns of enterotoxin and CFs observed in ETEC pathogens should be taken into consideration for ETEC vaccine development. Considering cholera and ETEC biannual trends in causing diarrheal epidemics and outbreaks, emphasizes the need for thoughts on combination vaccine strategies for preventing acute watery diarrhea due to the two major bacterial pathogens.

Appearance of tolerance-induction and non-inflammatory SARS-CoV-2 spike-specific IgG4 antibodies after COVID-19 booster vaccinations.

Background: Understanding the characteristics of the humoral immune responses following COVID-19 vaccinations is crucial for refining vaccination strategies and predicting immune responses to emerging SARS-CoV-2 variants. Methods: A longitudinal analysis of SARS-CoV-2 spike receptor binding domain (RBD) specific IgG antibody responses, encompassing IgG subclasses IgG1, IgG2, IgG3, and IgG4 was performed. Participants received four mRNA vaccine doses (group 1; n=10) or two ChAdOx1 nCoV-19 and two mRNA booster doses (group 2; n=19) in Bangladesh over two years. Results: Findings demonstrate robust IgG responses after primary Covishield or mRNA doses; declining to baseline within six months. First mRNA booster restored and surpassed primary IgG responses but waned after six months. Surprisingly, a second mRNA booster did not increase IgG levels further. Comprehensive IgG subclass analysis showed primary Covishield/mRNA vaccination generated predominantly IgG1 responses with limited IgG2/IgG3, Remarkably, IgG4 responses exhibited a distinct pattern. IgG4 remained undetectable initially but increased extensively six months after the second mRNA dose, eventually replacing IgG1 after the 3rd/4th mRNA doses. Conversely, initial Covishield recipients lack IgG4, surged post-second mRNA booster. Notably, mRNA-vaccinated individuals displayed earlier, robust IgG4 levels post first mRNA booster versus Covishield counterparts. IgG1 to IgG4 ratios decreased with increasing doses, most pronounced with four mRNA doses. This study highlights IgG response kinetics, influenced by vaccine type and doses, impacting immunological tolerance and IgG4 induction, shaping future vaccination strategies. Conclusions: This study highlights the dynamics of IgG responses dependent on vaccine type and number of doses, leading to immunological tolerance and IgG4 induction, and shaping future vaccination strategies.

Longevity of memory B cells and antibodies, as well as the polarization of effector memory helper T cells, are associated with disease severity in patients with COVID-19 in Bangladesh.

The longevity of immune responses induced by different degrees of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection provides information important to understanding protection against coronavirus disease 2019 (COVID-19). Here, we report the persistence of SARS-CoV-2 spike receptor-binding domain (RBD) specific antibodies and memory B cells recognizing this antigen in sequential samples from patients in Bangladesh with asymptomatic, mild, moderate and severe COVID-19 out to six months following infection. Since the development of long-lived memory B cells, as well as antibody production, is likely to be dependent on T helper (Th) cells, we also investigated the phenotypic changes of Th cells in COVID-19 patients over time following infection. Our results show that patients with moderate to severe COVID-19 mounted significant levels of IgG antibodies out to six months following infection, while patients with asymptomatic or mild disease had significant levels of IgG antibodies out to 3 months following infection, but these then fell more rapidly at 6 months than in patients with higher disease severity. Patients from all severity groups developed circulating memory B cells (MBCs) specific to SARS-CoV-2 spike RBD by 3 months following infection, and these persisted until the last timepoint measured at 6 months. A T helper cell response with an effector memory phenotype was observed following infection in all symptomatic patients, while patients with asymptomatic infection had no significant increases in effector Th1, Th2 and Th17 effector memory cell responses. Our results suggest that the strength and magnitude of antibody and memory B cells induced following SARS-CoV-2 infection depend on the severity of the disease. Polarization of the Th cell response, with an increase in Th effector memory cells, occurs in symptomatic patients by day 7 following infection, with increases seen in Th1, Th2, Th17 and follicular helper T cell subsets.

Correlation of antigen-specific immune response with disease severity among COVID-19 patients in Bangladesh.

Coronavirus disease 2019 (COVID-19) is a protean disease causing different degrees of clinical severity including fatality. In addition to humoral immunity, antigen-specific T cells may play a critical role in defining the protective immune response against SARS-CoV-2, the virus that causes this disease. As a part of a longitudinal cohort study in Bangladesh to investigate B and T cell-specific immune responses, we sought to evaluate the activation-induced marker (AIM) and the status of different immune cell subsets during a COVID-19 infection. We analyzed a total of 115 participants, which included participants with asymptomatic, mild, moderate, and severe clinical symptoms. We observed decreased mucosal-associated invariant T (MAIT) cell frequency on the initial days of the COVID-19 infection in symptomatic patients compared to asymptomatic patients. However, natural killer (NK) cells were found to be elevated in symptomatic patients just after the onset of the disease compared to both asymptomatic patients and healthy individuals. Moreover, we found a significant increase of AIM+ (both OX40+CD137+ and OX40+CD40L+) CD4+ T cells in moderate and severe COVID-19 patients in response to SARS-CoV-2 peptides (especially spike peptides) compared to pre-pandemic controls who are unexposed to SARS-CoV-2. Notably, we did not observe any significant difference in the CD8+ AIMs (CD137+CD69+), which indicates the exhaustion of CD8+ T cells during a COVID-19 infection. These findings suggest that patients who recovered from moderate and severe COVID-19 were able to mount a strong CD4+ T-cell response against shared viral determinants that ultimately induced T cells to mount further immune responses to SARS-CoV-2.

Disease characteristics and serological responses in patients with differing severity of COVID-19 infection: A longitudinal cohort study in Dhaka, Bangladesh.

BACKGROUND: COVID-19 caused by SARS-CoV-2 ranges from asymptomatic to severe disease and can cause fatal and devastating outcome in many cases. In this study, we have compared the clinical, biochemical and immunological parameters across the different disease spectrum of COVID-19 in Bangladeshi patients. METHODOLOGY/PRINCIPAL FINDINGS: This longitudinal study was conducted in two COVID-19 hospitals and also around the community in Dhaka city in Bangladesh between November 2020 to March 2021. A total of 100 patients with COVID-19 infection were enrolled and classified into asymptomatic, mild, moderate and severe cases (n = 25/group). In addition, thirty age and sex matched healthy participants were enrolled and 21 were analyzed as controls based on exclusion criteria. After enrollment (study day1), follow-up visits were conducted on day 7, 14 and 28 for the cases. Older age, male gender and co-morbid conditions were the risk factors for severe COVID-19 disease. Those with moderate and severe cases of infection had low lymphocyte counts, high neutrophil counts along with a higher neutrophil-lymphocyte ratio (NLR) at enrollment; this decreased to normal range within 42 days after the onset of symptom. At enrollment, D-dimer, CRP and ferritin levels were elevated among moderate and severe cases. The mild, moderate, and severe cases were seropositive for IgG antibody by day 14 after enrollment. Moderate and severe cases showed significantly higher IgM and IgG levels of antibodies to SARS-CoV-2 compared to mild and asymptomatic cases. CONCLUSION/SIGNIFICANCE: We report on the clinical, biochemical, and hematological parameters associated with the different severity of COVID-19 infection. We also show different profile of antibody response against SARS-CoV-2 in relation to disease severity, especially in those with moderate and severe disease manifestations compared to the mild and asymptomatic infection.

A non-inferiority trial comparing two killed, whole cell, oral cholera vaccines (Cholvax vs. Shanchol) in Dhaka, Bangladesh.

Bangladesh remains cholera endemic with biannual seasonal peaks causing epidemics. At least 300,000 severe cases and over 4,500 deaths occur each year. The available oral cholera vaccineshave not yet been adopted for cholera control in Bangladesh due to insufficient number of doses available for endemic control. With a public private partnership, icddr,b initiated a collaboration between vaccine manufacturers in Bangladesh and abroad. A locally manufactured Oral Cholera Vaccine (OCV) named Cholvax became available for testing in Bangladesh. We evaluated the safety and immunogenicity of this locally produced Cholvax (Incepta Vaccine Ltd) inexpensive OCV comparatively to Shanchol (Shantha Biotechnics-Sanofi Pasteur) which is licensed in several countries. We conducted a randomized non-inferiority clinical trial of bivalent, killed oral whole-cell cholera vaccine Cholvax vs. Shanchol in the cholera-endemic area of Mirpur, Dhaka, among three different age cohorts (1-5, 6-17 and 18-45 years) between April 2016 and April 2017. Two vaccine doses were given at 14 days apart to 2,052 healthy participants. No vaccine-related serious adverse events were reported. There were no significant differences in the frequency of solicited (7.31% vs. 6.73%) and unsolicited (1.46% vs. 1.07%) adverse events reported between the Cholvax and Shanchol groups. Vibriocidal antibody responses among the overall population for O1 Ogawa (81% vs. 77%) and O1 Inaba (83% vs. 84%) serotypes showed that Cholvax was non-inferior to Shanchol, with the non-inferiority margin of -10%. For O1 Inaba, GMT was 462.60 (Test group), 450.84 (Comparator group) with GMR 1.02(95% CI: 0.92, 1.13). For O1 Ogawa, GMT was 419.64 (Test group), 387.22 (Comparator group) with GMR 1.12 (95% CI: 1.02, 1.23). Cholvax was safe and non-inferior to Shanchol in terms of immunogenicity in the different age groups. These results support public use of Cholvax to contribute for reduction of the cholera burden in Bangladesh. ClinicalTrials.gov number: NCT027425581.

Hematological and immunological responses to naturally occurring bovine respiratory disease in newly received beef calves in a commercial stocker farm.

The objective was to determine temporal changes in hematological and immune parameters in response to naturally occurring bovine respiratory disease (BRD) in commercially managed stocker calves. Forty newly weaned beef steers purchased from auction markets were housed at a commercial stocker operation in Crossville, TN. Blood samples, rectal temperature, and thoracic ultrasonography (TUS; 1: normal to 3: severe) were collected on days 0, 7, 14, and 21. Castration status (FC: freshly castrated; PC: previously castrated) was determined on arrival based on presence of a fresh castration site at the scrotum. Calves received antibiotics for BRD based on clinical severity scoring (CSS; 0: moribund, 4: moribund) and rectal temperature. Complete blood counts (CBC) were performed. Calves were categorized based on the number of treatments (NumTrt) received (0x, 1x, and 2x). Temporal variations in CBC and immune parameters were analyzed using mixed model repeated measure ANOVA (Proc GLIMMIX; SAS 9.4). Variation of CBCs and immune parameters based on TUS was determined using mixed model ANOVA. There was a NumTrt by day interaction effect on the responses of white blood cells (WBC) (P = 0.04) and haptoglobin (HPT) (P = 0.04). On day 21, WBC were greater in the 2x NumTrt group than other groups, but there were no differences in WBC between NumTrt levels on other days. Haptoglobin was greater in the 2x group on days 14 and 21 than 0x or 1x. Red blood cells (RBC) (P = 0.02) and WBC (P = 0.04) differed between FC and PC groups, and lower RBC and WBC were observed in the FC group. A castration status × day effect for mean corpuscular volume (MCV; P = 0.04) was observed where FC group had higher MCV at days 14 and 21 than the PC group. Tumor necrosis factor-α differed based on NumTrt (P = 0.03) and higher concentrations were found in 2x group. We observed a day effect for IL-1ß (P = 0.009) and TNF-α (P = 0.001). Significant effect of TUS on HPT at day 14 (P = 0.0004) and day 21 (P = 0.002) was observed. Combining HPT and platelet explained 15% of the variability in treatment status on a given day, whereas HPT and hemoglobin explained 10% of the variability in lung consolidation status. Although hematological and immunological parameters varied largely in our study, the potential of combining HPT with hematological variables should be studied further. Results from this study would help in understanding temporal changes in CBC and immune parameters in newly received stocker cattle.

Blood and immune parameters are altered during bovine respiratory disease (BRD) progression and can be used for predicting disease status. We aimed looking at the dynamics of hematology and immunology in newly received stocker cattle in naturally occurring BRD. Forty newly received stocker cattle were managed by a local producer and monitored for BRD occurrence for 21 d after receiving during the high-risk period. Newly weaned calves were monitored as they experience several stress factors and become prone to BRD. Additionally, there are limited data related to immunological changes that occur in high-risk stocker cattle. Since there is no perfect diagnostic test for BRD, the diagnosis of BRD is likely missed when only visual signs are used. We observed that haptoglobin (HPT) was the most important parameter to differentiate BRD severity. The combination of HPT with blood parameters (hemoglobin and platelets) was useful to predict treatment and lung infection status. Therefore, measuring hematological and immunological parameters might be helpful to determine BRD status and facilitate treatment decisions in newly received stocker cattle.

Long-term sialidase-specific immune responses after natural infection with cholera: Findings from a longitudinal cohort study in Bangladesh.

Background: Immune responses that target sialidase occur following natural cholera and have been associated with protection against cholera. Sialidase is a neuraminidase that facilitates the binding of cholera toxin (CT) to intestinal epithelial cells. Despite this, little is known about age-related sialidase-specific immune responses and the impact of nutritional status and co-infection on sialidase-specific immunity. Methods: We enrolled 50 culture-confirmed Vibrio cholerae O1 cholera cases presenting to the icddr,b Dhaka hospital with moderate to severe dehydration. We evaluated antibody responses out to 18 months (day 540) following cholera. We assessed immune responses targeting sialidase, lipopolysaccharide (LPS), cholera toxin B subunit (CtxB), and vibriocidal responses. We also explored the association of sialidase-specific immune responses to nutritional parameters and parasitic co-infection of cases. Results: This longitudinal cohort study showed age-dependent differences in anti-sialidase immune response after natural cholera infection. Adult patients developed plasma anti-sialidase IgA and IgG responses after acute infection (P<0.05), which gradually decreased from day 30 on. In children, no significant anti-sialidase IgA, IgM, and IgG response was seen with the exception of a late IgG response at study day 540 (p=0.05 compared to adults). There was a correlation between anti-sialidase IgA with vibriocidal titers, as well as anti-sialidase IgA and IgG with anti-LPS and anti-CtxB antibody responses in adult patients, whereas in children, a significant positive correlation was seen only between anti-sialidase IgA and CtxB IgA responses. Stunted children showed significantly lower anti-sialidase IgA, IgG, and IgM antibody responses and higher LPS IgG and IgM antibody responses than healthy children. The anti-sialidase IgA and IgG responses were significantly higher in cases with concomitant parasitic infection. Conclusion: Our data suggest that cholera patients develop age-distinct systemic and mucosal immune responses against sialidase. The stunted children have a lower anti-sialidase antibody response which may be associated with gut enteropathy and the neuraminidase plays an important role in augmented immune response in cholera patients infected with parasites.

A non-inferiority trial comparing two recombinant vaccines (Hepa-B vs. Engerix-B) for hepatitis B among adults in Dhaka, Bangladesh.

Worldwide Hepatitis B is known as one of the imperative causes of mortality and morbidity as well as occupational health hazard among health workers. Bangladesh is intermediate endemic country for Hepatitis B infection for which the government has introduced hepatitis B vaccination into the Expanded Programme on Immunization (EPI) nationwide since 2009 for new born children. However, the people who were born before 2009, was dependent on imported hepatitis B vaccine as there was no locally manufactured hepatitis B vaccine in Bangladesh. Hence, we conducted a randomized observer blinded non-inferiority clinical trial to assess the immunogenicity and safety of the locally manufactured Hepa-B vaccine in comparison with World Health Organization prequalified Engerix-B vaccine. Total 158 eligible adult participants were enrolled in this study with mean age of 30 and 29 years old in Hepa-B and Engerix-B groups, respectively. Both the vaccines were administered intramuscularly at 0, 1 and 6 months schedule. Baseline and post vaccination anti-HBs titers were measure at different time points. Seroconversion rate post three doses of Hepa-B vaccine was 98.67% similar to the comparator Engerix-B vaccine which was 100%. The geometric mean test ratios of both vaccines at all analysis time points were found > 0.5 predefined non-inferiority margin. Soreness at the injection site was the most common symptom for both the vaccines which resolved without any complication. No serious adverse event was reported throughout the study period. These results suggest that locally manufactured hepatitis B vaccine 'Hepa-B' vaccine is non-inferior to the well-known licensed 'Engerix-B' vaccine. ClinicalTrials.gov NCT03627507.

A phase I/II study to evaluate safety, tolerability and immunogenicity of Hillchol®, an inactivated single Hikojima strain based oral cholera vaccine, in a sequentially age descending population in Bangladesh.

BACKGROUND: The World Health Organization (WHO) recommends the use of oral cholera vaccines (OCVs) as part of an integrated control program, both in highly endemic settings and during cholera epidemics. The available and internationally recommended WHO-prequalified OCVs (Dukoral, Shanchol, Euvichol) contain multiple heat and formalin-killed V. cholerae strains of Inaba and Ogawa serotypes. MSD Wellcome Trust Hilleman Laboratories Pvt. Ltd. in technical collaboration with University of Gothenburg, Sweden has developed a new single strain OCV, Hillchol. This vaccine consists of formaldehyde-inactivated whole cell El Tor V. cholerae O1 bacteria engineered into the Hikojima serotype for stable expression of both the Ogawa (AB) and Inaba (AC) LPS antigens on the bacterial surface. We evaluated the safety and immunogenicity of this novel and potentially much less expensive OCV in comparison with Shanchol. METHODS: We conducted a randomized, non-inferiority, age-descending clinical trial of OCV (Hillchol vs. Shanchol) in the Mirpur area of Dhaka city from July 2016 to May 2017. This study was carried out in three different age cohorts (1-<5, 5-17 and ≥18 years old). Two doses of vaccine were given at 14 days intervals to 560 healthy participants. FINDINGS: No serious adverse events were reported. There were no significant differences in the rates of adverse events between the test vaccine (Hillchol) and the comparator (Shanchol) group. Serum vibriocidal antibody responses in all age groups combined were comparable for all the O1 Ogawa (59% vs. 67%; 90% CI of difference: -14.55, -0.84) and Inaba (70% vs. 71%; 90% CI of difference: -7.24, 5.77) serotypes, showing that the Hillchol vaccine was non-inferior to Shanchol. This new vaccine was also non-inferior to Shanchol in the different age strata. CONCLUSION: The safety and immunogenicity profile of the new OCV Hillchol is comparable to Shanchol in persons residing in a cholera-endemic setting. ClinicalTrials.gov number: NCT02823899.

Role of Pyroptosis in Diabetes and Its Therapeutic Implications.

Pyroptosis is mainly considered as a new pro-inflammatory mediated-programmed cell death. In addition, pyroptosis is described by gasdermin-induced pore formation on the membrane, cell swelling and rapid lysis, and several pro-inflammatory mediators interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) release. Extensive studies have shown that pyroptosis is commonly involved by activating the caspase-1-dependent canonical pathway and caspase-4/5/11-dependent non-canonical pathway. However, pyroptosis facilitates local inflammation and inflammatory responses. Current researches have reported that pyroptosis promotes the progression of several diabetic complications. Emerging studies have suggested that some potential molecules targeting the pyroptosis and inflammasome signaling pathways could be a novel therapeutic avenue for managing and treating diabetes and its complications in the near future. Our narrative review concisely describes the possible mechanism of pyroptosis and its progressive understanding of the development of diabetic complications.

Role of pyroptosis in diabetic retinopathy and its therapeutic implications.

Pyroptosis has recently been established as a term of programmed-inflammatory cell death. Pyroptosis is mainly divided into two molecular signaling pathways, including caspase-1-dependent canonical and caspase-4/5/11-dependent non-canonical inflammasome pathways. Extensive investigations have reported inflammasome activation facilitates the maturation and secretion of the inflammatory factors interleukin-1ß/18 (IL-1ß/18), cleavage of gasdermin D (GSDMD), and leading to the stimulation of pyroptosis-mediated cell death. Furthermore, accumulating studies report NLRP3 inflammasome activation plays a significant role in triggering the pyroptosis-mediated cell death and promotes the pathogenesis of diabetic retinopathy (DR). Our current review elaborates on the molecular mechanisms of pyroptosis-signaling pathways and their potential roles in the pathogenesis and impact of DR development. We also emphasize several investigational molecules regulating key steps in pyroptotic-cell death to create new comprehensions and findings to explore the pathogenesis of DR advancement. Our narrative review concisely suggests these potential pharmacological agents could be promising therapies to treat and manage DR in the future.

Advances in immunotherapy for the treatment of spinal cord injury.

Spinal cord injury (SCI) is a leading cause of morbidity and disability in the world. Over the past few decades, the exact molecular mechanisms describing secondary, persistent injuries, as well as primary and transient injuries, have attracted massive attention to the clinicians and researchers. Recent investigations have distinctly shown the critical roles of innate and adaptive immune responses in regulating sterile neuroinflammation and functional outcomes after SCI. In past years, some promising advances in immunotherapeutic options have efficaciously been identified for the treatment of SCI. In our narrative review, we have mainly focused on the new therapeutic strategies such as the maturation and apoptosis of immune cells by several agents, mesenchymal stem cells (MSCs) as well as multi-factor combination therapy, which have recently provided novel ideas and prospects for the future treatment of SCI. This article also illustrates the latest progress in clarifying the potential roles of innate and adaptive immune responses in SCI, the progression and specification of prospective immunotherapy and outstanding issues in the area.

Role of NLRP3 inflammasome in liver disease.

Inflammasomes have become an important natural sensor of host immunity, and can protect various organs against pathogenic infections, metabolic syndromes, cellular stress and cancer metastasis. Inflammasomes are intracellular multi-protein complexes found in both parenchymal and non-parenchymal cells, stimulating the initiation of caspase-1 and interleukin (IL)-1ß and IL-18 in response to cell danger signals. Inflammasomes induce cell death mechanisms. The potential role of NOD-like receptor protein 3 (NLRP3) inflammasome in alcoholic and non-alcoholic steatohepatitis, hepatitis, nanoparticle-induced liver injury and other liver diseases has recently attracted widespread attention from clinicians and researchers. In this review we summarize the role played by the NLRP3 inflammasome in molecular and pathophysiological mechanisms in the pathogenesis and progression of liver disease. This article aims to establish that targeting the NLRP3 inflammasome and other inflammasome components may make a significant therapeutic approach to the treatment of liver disease.

Immunogenicity of a killed bivalent whole cell oral cholera vaccine in forcibly displaced Myanmar nationals in Cox's Bazar, Bangladesh.

After the large influx of Rohingya nationals (termed Forcibly Displaced Myanmar National; FDMN) from Rakhine State of Myanmar to Cox's Bazar in Bangladesh, it was apparent that outbreaks of cholera was very likely in this setting where people were living under adverse water and sanitation conditions. Large campaigns of oral cholera vaccine (OCV) were carried out as a preemptive measure to control cholera epidemics. The aim of the study was to evaluate the immune responses of healthy adults and children after administration of two doses of OCV at 14 days interval in FDMN population and compare with the response observed in Bangladeshi's vaccinated earlier. A cross-sectional immunogenicity study was conducted among FDMNs of three age cohort; in adults (18+years; n = 83), in older children (6-17 years; n = 63) and in younger children (1-5 years; n = 80). Capillary blood was collected at three time points to measure vibriocidal antibodies using either plasma or dried blood spot (DBS) specimens. There was a significant increase of responder frequency of vibriocidal antibody titer at day 14 in all groups for Vibrio cholerae O1 (Ogawa/Inaba: adults-64%/64%, older children-70%/89% and younger children-51%/75%). There was no overall difference of vibriocidal antibody titer between FDMN and Bangladeshi population at baseline (p = 0.07-0.08) and at day 14, day 28 in all age groups for both serotypes. The seroconversion rate and geometric mean titer (GMT) of either serotype were comparable using both plasma and DBS specimens. These results showed that OCV is capable of inducing robust immune responses in adults and children among the FDMN population which is comparable to that seen in Bangladeshi participants in different age groups or that reported from other cholera endemic countries. Our results also suggest that the displaced population were exposed to V. cholerae prior to seeking shelter in Bangladesh.