Humoral Research Articles

Preparation and immunological activity evaluation of an intranasal protein subunit vaccine against ancestral and mutant SARS-CoV-2 with curdlan sulfate/O-linked quaternized chitosan nanoparticles as carrier and adjuvant

Chitosan and its derivatives are ideal nasal vaccine adjuvant to deliver antigens to immune cells. Previously, we successfully used a chitosan derivative, O-(2-Hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (O-HTCC), and a β-glucan derivative, curdlan sulfate (CS), to prepare a nanoparticle adjuvant CS/O-HTCC which could deliver ovalbumin to antigen presenting cells (APCs) through nasal inhalation. In this article, we used SARS-CoV-2 spike receptor binding domain (S-RBD) as the antigen and CS/O-HTCC nanoparticles as the adjuvant to develop a nasal mucosal protein subunit vaccine, CS/S-RBD/O-HTCC. The humoral immunity, cell-mediated immunity and mucosal immunity induced by vaccines were evaluated. The results showed that CS/S-RBD/O-HTCC could induce desirable immunization with single or bivalent antigen through nasal inoculation, giving one booster vaccination with mutated S-RBD (beta) could bring about a broad cross reaction with ancestral and different mutated S-RBD, and vaccination of the BALB/c mice with CS/S-RBD/O-HTCC containing S-RBD mix antigens (ancestral and omicron) could induce the production of binding and neutralizing antibodies against both of the two antigens. Our results indicate that CS/O-HTCC is a promising nasal mucosal adjuvant to prepare protein subunit vaccine for both primary and booster immunization, and the adjuvant is suitable for loading more than one antigen for preparing multivalent vaccines.

Structural Mapping of Polyclonal IgG Responses to HA After Influenza Virus Vaccination or Infection.

Cellular and molecular characterization of immune responses elicited by influenza virus infection and seasonal vaccination have informed efforts to improve vaccine efficacy, breadth, and longevity. Here, we use negative stain electron microscopy polyclonal epitope mapping (nsEMPEM) to structurally characterize the humoral IgG antibody responses to hemagglutinin (HA) from human patients vaccinated with a seasonal quadrivalent flu vaccine or infected with influenza A viruses. Our data show that both vaccinated and infected patients had humoral IgGs targeting highly conserved regions on both H1 and H3 subtype HAs, including the stem and anchor, which are targets for universal influenza vaccine design. Responses against H1 predominantly targeted the central stem epitope in infected patients and vaccinated donors, whereas head epitopes were more prominently targeted on H3. Responses against H3 were less abundant, but a greater diversity of H3 epitopes were targeted relative to H1. While our analysis is limited by sample size, on average, vaccinated donors responded to a greater diversity of epitopes on both H1 and H3 than infected patients. These data establish a baseline for assessing polyclonal antibody responses in vaccination and infection, providing context for future vaccine trials and emphasizing the importance of carefully designing vaccines to boost protective responses towards conserved epitopes.

Humanized Mouse Models of Bacterial Infections.

Bacterial infections continue to represent a significant healthcare burden worldwide, causing considerable mortality and morbidity every year. The emergence of multidrug-resistant bacterial strains continues to rise, posing serious risks to controlling global disease outbreaks. To develop novel and more effective treatment and vaccination programs, there is a need for clinically relevant small animal models. Since multiple bacterial species have human-specific tropism for numerous virulence factors and toxins, conventional mouse models do not fully represent human disease. Several human disease characteristic phenotypes, such as lung granulomas in the case of Mycobacterium tuberculosis infections, are absent in standard mouse models. Alternatively, certain pathogens, such as Salmonella enterica serovar typhi and Staphylococcus aureus, can be well tolerated in mice and cleared quickly. To address this, multiple groups have developed humanized mouse models and observed enhanced susceptibility to infection and a more faithful recapitulation of human disease. In the last two decades, multiple humanized mouse models have been developed to attempt to recapitulate the human immune system in a small animal model. In this review, we first discuss the history of immunodeficient mice that has enabled the engraftment of human tissue and the engraftment methods currently used in the field. We then highlight how humanized mouse models successfully uncovered critical human immune responses to various bacterial infections, including Salmonella enterica serovar Typhi, Mycobacterium tuberculosis, and Staphylococcus aureus.

Precision arbovirus serology with a pan-arbovirus peptidome

Arthropod-borne viruses represent a crucial public health threat. Current arboviral serology assays are either labor intensive or incapable of distinguishing closely related viruses, and many zoonotic arboviruses that may transition to humans lack any serologic assays. In this study, we present a programmable phage display platform, ArboScan, that evaluates antibody binding to overlapping peptides that represent the proteomes of 691 human and zoonotic arboviruses. We confirm that ArboScan provides detailed antibody binding information from animal sera, human sera, and an arthropod blood meal. ArboScan identifies distinguishing features of antibody responses based on exposure history in a Colombian cohort of Zika patients. Finally, ArboScan details epitope level information that rapidly identifies candidate epitopes with potential protective significance. ArboScan thus represents a resource for characterizing human and animal arbovirus antibody responses at cohort scale.

Immune dysfunction prior to and during vaccination in multiple myeloma: a case study based on COVID-19

Infection is the leading cause of death in multiple myeloma (MM). However, the cellular composition associated with immune dysfunction is not defined. We analyzed immune profiles in the peripheral blood of patients with MM (n = 28) and B-cell chronic lymphoproliferative disorders (n = 53) vs. health care practitioners (n = 96), using multidimensional and computational flow cytometry. MM patients displayed altered distribution of most cell types (41/56, 73%), particularly within the B-cell (17/17) and T-cell (20/30) compartments. Using COVID-19 as a case study, we compared the immune response to vaccination based on 64,304 data points generated from the analysis of 1099 longitudinal samples. MM patients showed limited B-cell expansion linked to lower anti-RBD and anti-S antibody titers after the first two doses and booster. The percentages of B cells and CD4+ T cells in the blood, as well as the absolute counts of B cells and dendritic cells, predicted vaccine immunogenicity at different time points. In contrast with the humoral response, the percentage and antigen-dependent differentiation of SARS-CoV-2-specific CD8+ T cells was not altered in MM patients. Taken together, this study defined the cellular composition associated with immune dysfunction in MM and provided biomarkers such as the B-cell percentage and absolute count to individualize vaccination calendars.

A deep learning based cognitive model to probe the relation between psychophysics and electrophysiology of flicker stimulus

The flicker stimulus is a visual stimulus of intermittent illumination. A flicker stimulus can appear flickering or steady to a human subject, depending on the physical parameters associated with the stimulus. When the flickering light appears steady, flicker fusion is said to have occurred. This work aims to bridge the gap between the psychophysics of flicker fusion and the electrophysiology associated with flicker stimulus through a Deep Learning based computational model of flicker perception. Convolutional Recurrent Neural Networks (CRNNs) were trained with psychophysics data of flicker stimulus obtained from a human subject. We claim that many of the reported features of electrophysiology of the flicker stimulus, including the presence of fundamentals and harmonics of the stimulus, can be explained as the result of a temporal convolution operation on the flicker stimulus. We further show that the convolution layer output of a CRNN trained with psychophysics data is more responsive to specific frequencies as in human EEG response to flicker, and the convolution layer of a trained CRNN can give a nearly sinusoidal output for 10 hertz flicker stimulus as reported for some human subjects.

The impact of interferon receptor gene polymorphisms on humoral immunity to influenza and frequency of acute respiratory viral infections; taking into account vaccination status

The impact of interferon receptor gene polymorphisms on humoral immunity to influenza and frequency of acute respiratory viral infections; taking into account vaccination status

Generation of an inflammatory niche in an injectable hydrogel depot through recruitment of key immune cells improves efficacy of mRNA vaccines.

Messenger RNA (mRNA) delivered in lipid nanoparticles (LNPs) rose to the forefront of vaccine candidates during the COVID-19 pandemic due in part to scalability, adaptability, and potency. Yet there remain critical areas for improvements of these vaccines in durability and breadth of humoral responses. In this work, we explore a modular strategy to target mRNA/LNPs to antigen presenting cells with an injectable polymer-nanoparticle (PNP) hydrogel depot technology which recruits key immune cells and forms an immunological niche in vivo. We characterize this niche on a single cell level and find it is highly tunable through incorporation of adjuvants like MPLAs and 3M-052. Delivering commercially available SARS-CoV-2 mRNA vaccines in PNP hydrogels improves the durability and quality of germinal center reactions, and the magnitude, breadth, and durability of humoral responses. The tunable immune niche formed within PNP hydrogels effectively skews immune responses based on encapsulated adjuvants, creating opportunities to precisely modulate mRNA/LNP vaccines for various indications from infectious diseases to cancers.

Long-term humoral and cellular responses elicited by Gam-COVID-Vac vaccine in hemodialysis patients: A prospective cohort study

<b>Purpose: </b>The aim of this study is to assess long-term immunogenicity of the recombinant adenoviruses 26 and 5 vector-based COVID-19 vaccine Gam-COVID-Vac (Sputnik V, developed by N. F. Gamaleya National Research Centre, Russia) in patients receiving maintenance hemodialysis (HD) compared to healthy subjects.<br /> <b>Materials & methods: </b>A prospective cohort study included patients treated with maintenance HD (n=23) and healthy volunteers (n=28). The levels of anti-severe acute respiratory syndrome coronavirus-2 specific IgG as well as specific T-cell responses were quantified in all participants at two time points: one and six months after complete vaccination. All participates were adults, had been vaccinated twice with Gam-COVID-Vac and had no prior history of confirmed COVID-19.<br /> <b>Results: </b>In both groups, IgG levels decreased from month one to six, however, antibodies did not decline more rapidly in HD group (analysis of variance p=0.7214 for the “time×group” interaction, non-adjusted model). At the end of the study, 48.0% of non-HD and 67.0% of HD participants showed T-cell positivity. T-spot counts dropped over time in non-HD controls, but not in HD subjects (p=0.0080 and p=0.1800, respectively).<br /> <b>Conclusions: </b>Patients receiving HD maintain significant long-term humoral response after Gam-COVID-Vac vaccination, which is comparable to that in subjects with normal kidney function. Cellular response turned up to be more sustained over time in HD group.

Humoral and Innate Immunological Profile of Paediatric Recipients of Pfizer-BioNTech BNT162b2 mRNA Vaccine.

The Pfizer-BioNTech vaccine was one of the essential tools in curtailing the COVID-19 pandemic. Unlike conventional vaccines, this newly approved mRNA vaccine is taken up by cells, which leads to the synthesis of the specific viral Spike antigen. The vaccine was initially introduced for adults, and the immunological profile of adult recipients is well-characterized. The vaccine was approved for paediatric use much later after its efficacy and safety had been confirmed in children. However, the complete picture of how the paediatric immune system in children reacts to the vaccine is not well documented. Therefore, in order to better understand the immune response in children, we analysed the humoral response, immune cell count, and interferon signalling in paediatric vaccine recipients ranging between 5 and 17 years of age. Our findings suggest that the paediatric recipients elicit a robust humoral response that is sustained for at least three months. We also found that the vaccine triggered a transient lymphocytopenia similar to that observed during viral infection. Interestingly, we also found that the vaccine may sensitise the interferon signalling pathway, priming the cells to mount a potent response when exposed to interferons during a subsequent infection. The study offers new insights into the workings of the paediatric immune system and innate immunity, thereby opening the doors for further research in this field.

Humoral and Innate Immunological Profile of Paediatric Recipients of Pfizer-BioNTech BNT162b2 mRNA Vaccine

The Pfizer-BioNTech vaccine was one of the essential tools in curtailing the COVID-19 pandemic. Unlike conventional vaccines, this newly approved mRNA vaccine is taken up by cells, which leads to the synthesis of the specific viral Spike antigen. The vaccine was initially introduced for adults, and the immunological profile of adult recipients is well-characterized. The vaccine was approved for paediatric use much later after its efficacy and safety had been confirmed in children. However, the complete picture of how the paediatric immune system in children reacts to the vaccine is not well documented. Therefore, in order to better understand the immune response in children, we analysed the humoral response, immune cell count, and interferon signalling in paediatric vaccine recipients ranging between 5 and 17 years of age. Our findings suggest that the paediatric recipients elicit a robust humoral response that is sustained for at least three months. We also found that the vaccine triggered a transient lymphocytopenia similar to that observed during viral infection. Interestingly, we also found that the vaccine may sensitise the interferon signalling pathway, priming the cells to mount a potent response when exposed to interferons during a subsequent infection. The study offers new insights into the workings of the paediatric immune system and innate immunity, thereby opening the doors for further research in this field.

Childhood PFAS exposure and immunotoxicity: a systematic review and meta-analysis of human studies

BackgroundExposure to poly- and perfluoroalkyl substances (PFAS) may affect infant and childhood health through immunosuppression. However, the findings of epidemiological literature examining relationships between prenatal/childhood PFAS exposure and vaccine response and infection in humans are still inconclusive. The aim of this review was to examine the effects of PFAS exposure on vaccine antibody response and infection in humans.MethodsThe MEDLINE/Pubmed database was searched for publications until 1 February 2023 to identify human studies on PFAS exposure and human health.Eligible for inclusion studies had to have an epidemiological study design and must have performed logistic regression analyses of gestational or childhood exposure to PFAS against either antibody levels for pediatric vaccines or the occurrence of children’s infectious diseases. Information on baseline exposure to PFAS (in ng/mL), the age of PFAS exposure (gestational or in years), and the outcome was measured, potentially leading to multiple exposure-outcome comparisons within each study was collected. Percentage change and standard errors of antibody titers and occurrence of infectious diseases per doubling of PFAS exposure were calculated, and a quality assessment of each study was performed.ResultsSeventeen articles were identified matching the inclusion criteria and were included in the meta-analysis. In general, a small decrease in antibody response and some associations between PFAS exposure and childhood infections were observed.ConclusionsThis meta-analysis summarizes the findings of PFAS effects on infant and childhood immune health. The immunosuppression findings for infections yielded suggestive evidence related to PFAS exposure, particularly PFOS, PFOA, PFHxS, and PFNA but moderate to no evidence regarding antibody titer reduction.Systematic review registrationThe research protocol of this systematic review is registered and accessible at the Open Science Framework (https://doi.org/10.17605/OSF.IO/5M2VU).

Childhood PFAS exposure and immunotoxicity: a systematic review and meta-analysis of human studies

BackgroundExposure to poly- and perfluoroalkyl substances (PFAS) may affect infant and childhood health through immunosuppression. However, the findings of epidemiological literature examining relationships between prenatal/childhood PFAS exposure and vaccine response and infection in humans are still inconclusive. The aim of this review was to examine the effects of PFAS exposure on vaccine antibody response and infection in humans.MethodsThe MEDLINE/Pubmed database was searched for publications until 1 February 2023 to identify human studies on PFAS exposure and human health.Eligible for inclusion studies had to have an epidemiological study design and must have performed logistic regression analyses of gestational or childhood exposure to PFAS against either antibody levels for pediatric vaccines or the occurrence of children’s infectious diseases. Information on baseline exposure to PFAS (in ng/mL), the age of PFAS exposure (gestational or in years), and the outcome was measured, potentially leading to multiple exposure-outcome comparisons within each study was collected. Percentage change and standard errors of antibody titers and occurrence of infectious diseases per doubling of PFAS exposure were calculated, and a quality assessment of each study was performed.ResultsSeventeen articles were identified matching the inclusion criteria and were included in the meta-analysis. In general, a small decrease in antibody response and some associations between PFAS exposure and childhood infections were observed.ConclusionsThis meta-analysis summarizes the findings of PFAS effects on infant and childhood immune health. The immunosuppression findings for infections yielded suggestive evidence related to PFAS exposure, particularly PFOS, PFOA, PFHxS, and PFNA but moderate to no evidence regarding antibody titer reduction.Systematic review registrationThe research protocol of this systematic review is registered and accessible at the Open Science Framework (https://doi.org/10.17605/OSF.IO/5M2VU).

Reverse Vaccinology Approach to Identify Novel and Immunogenic Targets against Streptococcus gordonii.

Streptococcus gordonii is a gram-positive, mutualistic bacterium found in the human body. It is found in the oral cavity, upper respiratory tract, and intestines, and presents a serious clinical problem because it can lead to opportunistic infections in individuals with weakened immune systems. Streptococci are the most prevalent inhabitants of oral microbial communities, and are typical oral commensals found in the human oral cavity. These streptococci, along with many other oral microbes, produce multispecies biofilms that can attach to salivary pellicle components and other oral bacteria via adhesin proteins expressed on the cell surface. Antibiotics are effective against this bacterium, but resistance against antibodies is increasing. Therefore, a more effective treatment is needed. Vaccines offer a promising method for preventing this issue. This study generated a multi-epitope vaccine against Streptococcus gordonii by targeting the completely sequenced proteomes of five strains. The vaccine targets are identified using a pangenome and subtractive proteomic approach. In the present study, 13 complete strains out of 91 strains of S. gordonii are selected. The pangenomics results revealed that out of 2835 pan genes, 1225 are core genes. Out of these 1225 core genes, 643 identified as non-homologous proteins by subtractive proteomics. A total of 20 essential proteins are predicted from non-homologous proteins. Among these 20 essential proteins, only five are identified as surface proteins. The vaccine construct is designed based on selected B- and T-cell epitopes of the antigenic proteins with the help of linkers and adjuvants. The designed vaccine is docked against TLR2. The expression of the protein is determined using in silico gene cloning. Findings concluded that Vaccine I with adjuvant shows higher interactions with TLR2, suggesting that the vaccine has the ability to induce a humoral and cell-mediated response to treat and prevent infection; this makes it promising as a vaccine against infectious diseases caused by S. gordonii. Furthermore, validation of the vaccine construct is required by in vitro and in vivo trials to check its actual potency and safety for use to prevent infectious diseases caused by S. gordonii.

Reverse Vaccinology Approach to Identify Novel and Immunogenic Targets against Streptococcus gordonii

Streptococcus gordonii is a gram-positive, mutualistic bacterium found in the human body. It is found in the oral cavity, upper respiratory tract, and intestines, and presents a serious clinical problem because it can lead to opportunistic infections in individuals with weakened immune systems. Streptococci are the most prevalent inhabitants of oral microbial communities, and are typical oral commensals found in the human oral cavity. These streptococci, along with many other oral microbes, produce multispecies biofilms that can attach to salivary pellicle components and other oral bacteria via adhesin proteins expressed on the cell surface. Antibiotics are effective against this bacterium, but resistance against antibodies is increasing. Therefore, a more effective treatment is needed. Vaccines offer a promising method for preventing this issue. This study generated a multi-epitope vaccine against Streptococcus gordonii by targeting the completely sequenced proteomes of five strains. The vaccine targets are identified using a pangenome and subtractive proteomic approach. In the present study, 13 complete strains out of 91 strains of S. gordonii are selected. The pangenomics results revealed that out of 2835 pan genes, 1225 are core genes. Out of these 1225 core genes, 643 identified as non-homologous proteins by subtractive proteomics. A total of 20 essential proteins are predicted from non-homologous proteins. Among these 20 essential proteins, only five are identified as surface proteins. The vaccine construct is designed based on selected B- and T-cell epitopes of the antigenic proteins with the help of linkers and adjuvants. The designed vaccine is docked against TLR2. The expression of the protein is determined using in silico gene cloning. Findings concluded that Vaccine I with adjuvant shows higher interactions with TLR2, suggesting that the vaccine has the ability to induce a humoral and cell-mediated response to treat and prevent infection; this makes it promising as a vaccine against infectious diseases caused by S. gordonii. Furthermore, validation of the vaccine construct is required by in vitro and in vivo trials to check its actual potency and safety for use to prevent infectious diseases caused by S. gordonii.

Immature dendritic cell-targeting mRNA vaccine expressing PfCSP enhances protective immune responses against Plasmodium liver infection.

Resurgence in malaria has been noted in 2022 with 249 million clinical cases resulting in 608,000 deaths, mostly in children under five. Two vaccines, RTS, S, and more recently R21, targeting the circumsporozoite protein (CSP) are recommended by the WHO but are not yet widely available. Strong humoral responses to neutralize sporozoites before they can infect the hepatocytes are important for vaccine-mediated protection. Suboptimal protection conferred by these first-generation vaccines highlight the need for approaches to improve vaccine-induced immune responses. With the recent success of mRNA-LNP vaccines against COVID-19, there is growing interest in leveraging this approach to enhance malaria vaccines. Here, we present the development of a novel chemokine fusion mRNA vaccine aimed at boosting immune responses to PfCSP by targeting the immunogen to immature dendritic cells (iDC). Vaccination of mice with mRNA encoding full-length CSP fused to macrophage inflammatory protein 3 alpha (MIP3α) encapsulated within lipid nanoparticles (LNP) elicited robust CD4 + T cell responses and enhanced antibody titers against NANP repeat epitopes compared to a conventional CSP mRNA-LNP vaccine. Importantly, the CSP-MIP3α fusion vaccine provided significantly greater protection against liver infection upon challenge with P. berghei PfCSP transgenic sporozoites. This enhanced protection was associated with multifunctional CD4 + T cells levels and anti-NANP repeat titers. This study highlights the potential to augment immune responses to PfCSP through iDC targeting and bolster protection against malaria liver infection.

Assessment of Antibody Titers after 6 Months of Vaccination against SARS-COV-2 in Patients with CKD Stage 4, 5 and CKD 5d

Background: Since the pandemic of COVID-19 started from December 2019, remarkable numbers of infections and deaths associated with COVID-19 have been recorded worldwide. Chronic kidney disease patients are particularly at high risk of infections due to impairments in the innate and adaptive immune systems. Adequate humoral (antibody) and cellular (T cell-driven) immunity are required to minimize pathogen entry and promote pathogen clearance to enable infection control. Vaccination can generate cellular and humoral immunity against this specific pathogen. COVID-19 prevention through successful vaccination is therefore paramount in chronic kidney disease population. But vaccination efficacy is diminished in these patients because premature ageing of the immune system and chronic systemic low- grade inflammation are the main causes of immune alteration in these patients. Therefore, it is urgently necessary to establish a different vaccination strategy for chronic kidney disease and dialysis patient in terms of the dose and administration time. Aims: This study aimed to assessment of antibody titers after vaccination against SARS-COV-2 in patients with chronic kidney disease stage 4, 5 on conservative management and maintenance haemodialysis. Methods: This prospective observational comparative was conducted in Nephrology department of Dhaka Medical College Hospital. Selectionof patients was done by purposive sampling according to inclusion and exclusion criteria. Total 135 patients distributed in three groups: 45 patients of chronic kidney disease (CKD) stage 4, 5 on conservative management, 45 patients on maintenance haemodialysis (MHD) and 45 healthy controls were approached for the study who were receiving SARS-COV-2 vaccination. Demographic, clinical and laboratory data were collected initially. At first a pre vaccination sample or 1st sample was taken for antibody measurement. Then participants from all groups were given 2 doses MODERNA vaccine containing 100 µg in 0.5 ml each in 28 days apart. Then after 14 days of 1st dose of vaccination the 2nd samples were taken, 3rd samples were taken 14 days after the 2nd dose vaccination. Study populations were subdivided into two groups according to pre vaccination SARS-COV-2 antibody titer; seropositive- positive response before vaccination and seronegative- negative response before vaccination. They were also divided into two groups according to quantitive antibody response; positive response- values ≥10 DU/mL were positive Negative response- values of <10 DU/mL were negative. Result: Seroconversion rate was around 20% among study participants before vaccination. 14 days after the 1st dose of vaccination, 90.04% patients had positive immune response in CKD stage 4, 5 on conservative management group whereas in MHD group 84.82% responded to vaccination and immune response in control group was 100%. Immune response is 100% among all the groups after 14 days of 2nd dose of vaccination but the concentration of antibody differs significantly among the study groups. Responders were comparatively younger with normal BMI. Conclusion: Haemodialysis patients as well as patients with chronic kidney disease stage 4, 5 on conservative management showed a favorable but profoundly lower early antibody response, which decreased substantially during follow-up.

Risk Factors for Impaired Cellular or Humoral Immunity after Three Doses of SARS-CoV-2 Vaccine in Healthy and Immunocompromised Individuals.

Background: We aimed to identify the risk factors for impaired cellular and humoral immunity after three doses of the SARS-CoV-2 vaccine. Methods: Six months after the third vaccine dose, T-cell immunity was evaluated using interferon-gamma release assays (IGRAs) in 60 healthy and 139 immunocompromised (IC) individuals, including patients with hematologic malignancy (HM), solid malignancy (SM), rheumatic disease (RD), and kidney transplantation (KT). Neutralizing antibody titers were measured using the plaque reduction neutralization test (PRNT) and surrogate virus neutralization test (sVNT). Results: T-cell immunity results showed that the percentages of IGRA-positive results using wild-type/alpha spike protein (SP) and beta/gamma SP were 85% (51/60) and 75% (45/60), respectively, in healthy individuals and 45.6% (62/136) and 40.4% (55/136), respectively, in IC individuals. IC with SM or KT showed a high percentage of IGRA-negative results. The underlying disease poses a risk for impaired cellular immune response to wild-type SP. The risk was low when all doses were administered as mRNA vaccines. The risk factors for an impaired cellular immune response to beta/gamma SP were underlying disease and monocyte%. In the sVNT using wild-type SP, 12 of 191 (6.3%) individuals tested negative. In the PRNT of 46 random samples, 6 (13%) individuals tested negative for the wild-type virus, and 19 (41.3%) tested negative with omicrons. KT poses a risk for an impaired humoral immune response. Conclusions: Underlying disease poses a risk for impaired cellular immune response after the third dose of the SARS-CoV-2 vaccine; KT poses a risk for impaired humoral immune response, emphasizing the requirement of precautions in patients.

Landslide and flood disaster: Causes and its responses

This paper attempts to overview the practices of human responses and adaptation strategies to natural hazards, particularly from landslides and floods. Moreover, it also aims to find out the appropriate response measures for developing countries like Nepal. This paper is prepared by the systematic reviews of related articles published in different peer-reviewed and scientific journals. Initially, the relevant papers were selected using keywords like hazards, disasters and human response to natural disasters. Then, the 64 papers were chosen and this paper was developed. There are different factors to determine the occurrence of disasters on the earth such as geology, topography, climate, topographic aspects, slope and biological activities. Processes and causes contributing to landslides can be put into three categories such as geological/morphological, physical, and human/anthropogenic causes. This study will be very helpful to entire developing countries in general and Nepal in particular as well as agencies and organizations involved in disaster risk reduction and disaster management. The impact of disasters is exacerbated by the lack of appropriate measures for mitigating their impacts. Hence, it will be the foundation for disaster risk reduction in Nepal.

Covalent isothiocyanate inhibitors of macrophage migration inhibitory factor as potential colorectal cancer treatments.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with roles in innate and adaptive human immune responses, as well as inflammation. MIF exerts its biological activity by binding to the cell surface receptor CD74 as well as intracellular signalling proteins. MIF also possesses keto-enol tautomerase activity. Inhibition of the tautomerase activity has been associated with loss of biological activity of MIF and a potential anticancer target. Isothiocyanates (ITCs) are a class of compounds present in cruciferous vegetables that inhibit the MIF tautomerase activity via covalent modification of the N-terminal proline. A range of substituted ITCs featuring benzyl, phenethyl and phenyl propyl isothiocyanates were designed, synthesised and tested to determine any structure activity relationship for inhibiting MIF. Crystal structures of covalent compounds 8 and 9 in complex with rhMIF revealed key hydrogen bonding and edge-to-face π stacking interactions. Compound 9 and 11 with sub micromolar activity were tested in the NCI60 cancer cell lines panel. Both compounds showed tissue-specific reduced growth in colon and renal cancer cell lines, while one of these showed potent, dose-dependent inhibition of growth against all seven colon cancer cell lines (GI50 < 2.5 µM) and all eight renal cancer cell lines (GI50 < 2.2 µM).