Humoral Research Articles

Electron transport chain capacity expands yellow fever vaccine immunogenicity.

Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.

Humoral responses are enhanced by facilitating B cell viability by Fcrl5 overexpression in B cells.

B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed on naïve B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide (LPS)-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.

Modulating Adjuvant Release Kinetics from Scaffold Vaccines to Tune Adaptive Immune Responses.

Increasing the potency, quality and durability of vaccines represents a major public health challenge. A critical parameter that shapes vaccine immunity is the spatiotemporal context in which immune cells interact with antigen and adjuvant. While various material-based strategies have demonstrated that extended antigen release enhances both cellular and humoral immunity, the effect of adjuvant kinetics on vaccine-mediated immunity remains incompletely understood. Here, we use a previously characterized mesoporous silica rod (MPS) biomaterial vaccine to develop a facile, electrostatics-driven approach to tune in vivo kinetics of the TLR9 agonist CpG. We demonstrate that rapid release of CpG from MPS vaccines, mediated by alterations in MPS chemistry that tune surface charge, generates potent cytotoxic T cell responses and robust, Th1-skewed IgG2a/c antibody titers. Immunophenotyping of lymphoid organs after MPS vaccination with slow or fast CpG release kinetics suggests that differential engagement of migratory dendritic cells and natural killer cells may contribute to the more potent responses observed with rapid adjuvant release. Taken together, these findings suggest that vaccine approaches that pair sustained release of antigen with rapid release of adjuvants with similar characteristics to CpG may drive particularly potent Th1 responses. This article is protected by copyright. All rights reserved.

Baseline characteristics of SARS-CoV-2 vaccine non-responders in a large population-based sample.

Studies indicate that individuals with chronic conditions and specific baseline characteristics may not mount a robust humoral antibody response to SARS-CoV-2 vaccines. In this paper, we used data from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a longitudinal state-wide seroprevalence program that has enrolled more than 90,000 participants, to evaluate the role of chronic diseases as the potential risk factors of non-response to SARS-CoV-2 vaccines in a large epidemiologic cohort. A participant needed to complete an online survey and a blood draw to test for SARS-CoV-2 circulating plasma antibodies at four-time points spaced at least three months apart. Chronic disease predictors of vaccine non-response are evaluated using logistic regression with non-response as the outcome and each chronic disease + age as the predictors. As of April 24, 2023, 18,240 participants met the inclusion criteria; 0.58% (N = 105) of these are non-responders. Adjusting for age, our results show that participants with self-reported immunocompromised status, kidney disease, cancer, and "other" non-specified comorbidity were 15.43, 5.11, 2.59, and 3.13 times more likely to fail to mount a complete response to a vaccine, respectively. Furthermore, having two or more chronic diseases doubled the prevalence of non-response. Consistent with smaller targeted studies, a large epidemiologic cohort bears the same conclusion and demonstrates immunocompromised, cancer, kidney disease, and the number of diseases are associated with vaccine non-response. This study suggests that those individuals, with chronic diseases with the potential to affect their immune system response, may need increased doses or repeated doses of COVID-19 vaccines to develop a protective antibody level.

High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Studying the cellular basis of small bowel enteropathy using high-parameter flow cytometry in mouse models of primary antibody deficiency

BackgroundPrimary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined.MethodsIn this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA-/-, Aicda-/-, CD19-/- and JH-/-) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy).ResultsResults from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively.ConclusionsMultivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.

Advancing molecular modeling and reverse vaccinology in broad-spectrum yellow fever virus vaccine development

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant (β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document}-defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.

A novel microporous biomaterial vaccine platform for long-lasting antibody mediated immunity against viral infection

Current antigen delivery platforms, such as alum and nanoparticles, are not readily tunable, thus may not generate optimal adaptive immune responses. We created an antigen delivery platform by loading lyophilized Microporous Annealed Particle (MAP) with aqueous solution containing target antigens. Upon administration of antigen loaded MAP (VaxMAP), the biomaterial reconstitution forms an instant antigen-loaded porous scaffold area with a sustained release profile to maximize humoral immunity. VaxMAP induced CD4+ T follicular helper (Tfh) cells and germinal center (GC) B cell responses in the lymph nodes similar to Alum. VaxMAP loaded with SARS-CoV-2 spike protein improved the magnitude, neutralization, and duration of anti-receptor binding domain antibodies compared to Alum vaccinated mice. A single injection of Influenza specific HA1-loaded-VaxMAP enhanced neutralizing antibodies and elicited greater protection against influenza virus challenge than HA1-loaded-Alum. Thus, VaxMAP is a platform that can be used to promote adaptive immune cell responses to generate more robust neutralizing antibodies, and better protection upon pathogen challenge.

Studies on the Assessment of Hair Cortisol Concentration in Dogs by Radioimmunoassay (RIA)

Background: Hair cortisol Concentration (HCC) is often used as a measure of chronic stress responses in humans. The use of Radioimmunoassay (RIA) and HCC to assess stress in hospitalized dogs has been poorly reported in the literature in India and Central East Asia. This paper presents a modified protocol for measuring HCC in dog hair samples for stress assessment using RIA. Methods: Estimation of HCC concentrations of healthy (n=20) and hospitalized (n=20) dogs was done using RIA. Hair samples were collected from a dog’s nape region and weighed to measure HCC concentration. The study used RIA-enabled dissevered spiking and detectable concentration-based modifications to measure HCC. Five known cortisol concentration standards (viz 19.0 nmol/l, 47.9 nmol/l, 190 nmol/l, 238.66 nmol/l and 713.33 nmol/l) were used, with the first three readily available with a cortisol RIA kit. The samples were spiked with 50 µL of the standard and analysed in a gamma counter to take counts per minute (CPM). The final concentration of HCC was estimated in nmol/l and derived in pg/mg as per standard methods. Result: Healthy dogs had a mean HCC of 6.24±0.84 pg/mg, while hospitalized dogs had 31.65±5.87 pg/mg. A significant deviation was observed in both groups. A box and whisker graph showed an HCC range of 0.36 to 13.78 pg/mg for healthy dogs and 8.70 to 65.25 pg/mg for hospitalized dogs. The interquartile range (25th to 75th percentile) was 3.55 to 9.24 pg/mg for healthy dogs and 14.43 to 46.22 for hospitalized dogs. The observed median for healthy dogs was 6.16 pg/mg and 22.62 pg/mg for hospitalized dogs. The study shows higher HCC in hospitalized sick dogs compared to clinically healthy ones, suggesting hair sample collection as a simple stress assessment method and RIA as a promising HCC detection technique.

A novel humanized mouse model for HIV and tuberculosis co-infection studies

BackgroundTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to be a major public health problem worldwide. The human immunodeficiency virus (HIV) is another equally important life-threatening pathogen. HIV infection decreases CD4+ T cell levels markedly increasing Mtb co-infections. An appropriate animal model for HIV/Mtb co-infection that can recapitulate the diversity of the immune response in humans during co-infection would facilitate basic and translational research in HIV/Mtb infections. Herein, we describe a novel humanized mouse model.MethodsThe irradiated NSG-SGM3 mice were transplanted with human CD34+ hematopoietic stem cells, and the humanization was monitored by staining various immune cell markers for flow cytometry. They were challenged with HIV and/or Mtb, and the CD4+ T cell depletion and HIV viral load were monitored over time. Before necropsy, the live mice were subjected to pulmonary function test and CT scan, and after sacrifice, the lung and spleen homogenates were used to determine Mtb load (CFU) and cytokine/chemokine levels by multiplex assay, and lung sections were analyzed for histopathology. The mouse sera were subjected to metabolomics analysis.ResultsOur humanized NSG-SGM3 mice were able to engraft human CD34+ stem cells, which then differentiated into a full-lineage of human immune cell subsets. After co-infection with HIV and Mtb, these mice showed decrease in CD4+ T cell counts overtime and elevated HIV load in the sera, similar to the infection pattern of humans. Additionally, Mtb caused infections in both lungs and spleen, and induced granulomatous lesions in the lungs. Distinct metabolomic profiles were also observed in the tissues from different mouse groups after co-infections.ConclusionThe humanized NSG-SGM3 mice are able to recapitulate the pathogenic effects of HIV and Mtb infections and co-infection at the pathological, immunological and metabolism levels and are therefore a reproducible small animal model for studying HIV/Mtb co-infection.

Evaluation of SARS-CoV-2 interferon gamma release assay in BNT162b2 vaccinated healthcare workers.

To predict protective immunity to SARS-CoV-2, cellular immunity seems to be more sensitive than humoral immunity. Through an Interferon-Gamma (IFN-γ) Release Assay (IGRA), we show that, despite a marked decrease in total antibodies, 94.3% of 123 healthcare workers have a positive cellular response 6 months after inoculation with the 2nd dose of BNT162b2 vaccine. Despite the qualitative relationship found, we did not observe a quantitative correlation between IFN-γ and IgG levels against SARS-CoV-2. Using stimulated whole blood from a subset of participants, we confirmed the specific T-cell response to SARS-CoV-2 by dosing elevated levels of the IL-6, IL-10 and TNF-α. Through a 20-month follow-up, we found that none of the infected participants had severe COVID-19 and that the first positive cases were only 12 months after the 2nd dose inoculation. Future studies are needed to understand if IGRA-SARS-CoV-2 can be a powerful diagnostic tool to predict future COVID-19 severe disease, guiding vaccination policies.

Study of humoral and cellular immunity following the immunization of C57Bl/6 mice with a prototype of the inactivated Chikungunya vaccine

Introduction. Chikungunya virus infection is a problem for the health care system of affected regions due to the lack of specific prevention, as well as effective antiviral drugs. The critical role of cellular immunity in viral control and clearance for the Chikungunya fever has been demonstrated in many studies. Therefore, effective stimulation of not only humoral but also cellular immunity is of undeniable importance when assessing the effectiveness of a potential vaccine for the prevention of this infection. The aim of the present study was to investigate the formation of protective immunity after administration of a drug containing inactivated Chikungunya virus (CHIKV) to C57Bl/6 mice. Materials and methods. Inactivated CHIKV (concentrations of 10 μg and 40 μg) was administered intramuscularly to C57Bl/6 mice twice with an interval of 14 days. Indicators of humoral immunity were assessed by ELISA and neutralization test (NT), cellular immunity — by the production of IFN-γ and splenocyte proliferation in vitro. The concentration of cytokines IL-1, IL-2, IL-6, IL-10, IL-12p70 and TNF was determined by ELISA. When assessing the protective immunity in animals, CHIKV was injected into the dorsal surface of the foot of the right hind paw at a dose of 2.89 ± 0.10 lg TCD50 in a volume of 20 μl. Results. The most pronounced immune response was noted to the administration of 40 μg of inactivated CHIKV, which was manifested in the balanced production of the studied cytokines, the formation of specific humoral (according to the results of ELISA and NT) and cellular — specific proliferation of splenocytes in vitro and production of IFN-γ. When assessing efficacy, the development of foot edema in immunized animals was significantly lower than in animals in the control group. Discussion. CHIKV, inactivated by beta-propiolactone, had pronounced immunogenic properties. The balance of production of pro- and anti-inflammatory cytokines, as well as the Th1/Th2 immune response, characterized the formation of adaptive immunity in mice without a pronounced inflammatory response. The formation of a specific humoral and cellular immune response has been demonstrated. A study of protection in a non-lethal animal model confirmed the efficacy of the inactivated vaccine. Conclusion. Double administration of the inactivated CHIKV vaccine at a dose of 40 μg to C57Bl/6 mice demonstrated pronounced immunogenicity, which allows us to evaluate it as a promising prophylactic vaccine.

Aberrant adaptive immune response underlies genetic susceptibility to tuberculosis

Mycobacterium tuberculosis (Mtb) remains a major threat worldwide, although only a fraction of infected individuals develops tuberculosis (TB). TB susceptibility is shaped by multiple genetic factors, and we performed comparative immunological analysis of two mouse strains to uncover relevant mechanisms underlying susceptibility and resistance. C57BL/6 mice are relatively TB-resistant, whereas I/St mice are prone to develop severe TB, partly due to the MHC-II allelic variant that shapes suboptimal CD4+ T cell receptor repertoire. We investigated the repertoires of lung-infiltrating helper T cells and B cells at the progressed stage in both strains. We found that lung CD4+ T cell repertoires of infected C57BL/6 but not I/St mice contained convergent TCR clusters with functionally confirmed Mtb specificity. Transcriptomic analysis revealed a more prominent Th1 signature in C57BL/6, and expression of pro-inflammatory IL-16 in I/St lung-infiltrating helper T cells. The two strains also showed distinct Th2 signatures. Furthermore, the humoral response of I/St mice was delayed, less focused, and dominated by IgG/IgM isotypes, whereas C57BL/6 mice generated more Mtb antigen-focused IgA response. We conclude that the inability of I/St mice to produce a timely and efficient anti-Mtb adaptive immune responses arises from a suboptimal helper T cell landscape that also impacts the humoral response, leading to diffuse inflammation and severe disease.

Effects of injectable trace minerals on the inflammatory cytokines’ response to vaccination in dairy calves

Trace mineral supplementation concurrent with the bovine respiratory diseases complex (BRDC) vaccine boosts antibody production and leukocyte proliferation. However, the mecha­nism underlying this effect is not well understood. On the other hand, cytokines response post-vaccination is an important driver of both humoral and cellular immunity. Therefore, we hypothesized that trace mineral supplementation may improve BRD vaccine immunogenicity and effectiveness by modulating inflammatory cytokines in dairy calves. Our objective was to characterize the effects of injectable trace minerals (ITM) on the cytokines response to the BRD modified-live virus (MLV) vaccine in post-weaning dairy calves.

Spatiotemporal Properties of Common Semantic Categories for Words and Pictures.

The timing of semantic processing during object recognition in the brain is a topic of ongoing discussion. One way of addressing this question is by applying multivariate pattern analysis to human electrophysiological responses to object images of different semantic categories. However, although multivariate pattern analysis can reveal whether neuronal activity patterns are distinct for different stimulus categories, concerns remain on whether low-level visual features also contribute to the classification results. To circumvent this issue, we applied a cross-decoding approach to magnetoencephalography data from stimuli from two different modalities: images and their corresponding written words. We employed items from three categories and presented them in a randomized order. We show that if the classifier is trained on words, pictures are classified between 150 and 430 msec after stimulus onset, and when training on pictures, words are classified between 225 and 430 msec. The topographical map, identified using a searchlight approach for cross-modal activation in both directions, showed left lateralization, confirming the involvement of linguistic representations. These results point to semantic activation of pictorial stimuli occurring at ≈150 msec, whereas for words, the semantic activation occurs at ≈230 msec.

Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.

SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.

Breakthrough Infections in SARS-CoV-2-Vaccinated Multiple Myeloma Patients Improve Cross-Protection against Omicron Variants

Patients with multiple myeloma (MM) are a heterogenous, immunocompromised group with increased risk for COVID-19 morbidity and mortality but impaired responses to primary mRNA SARS-CoV-2 vaccination. The effects of booster vaccinations and breakthrough infections (BTIs) on antibody (Ab) levels and cross-protection to variants of concern (VOCs) are, however, not sufficiently evaluated. Therefore, we analysed humoral and cellular vaccine responses in MM patients stratified according to disease stage/treatment into group (1) monoclonal gammopathy of undetermined significance, (2) after stem cell transplant (SCT) without immunotherapy (IT), (3) after SCT with IT, and (4) progressed MM, and in healthy subjects (prospective cohort study). In contrast to SARS-CoV-2 hu-1-specific Ab levels, Omicron-specific Abs and their cross-neutralisation capacity remained low even after three booster doses in a majority of MM patients. In particular, progressed MM patients receiving anti-CD38 mAb and those after SCT with IT were Ab low responders and showed delayed formation of spike-specific B memory cells. However, MM patients with hybrid immunity (i.e., vaccination and breakthrough infection) had improved cross-neutralisation capacity against VOCs, yet in the absence of severe COVID-19 disease. Our results indicate that MM patients require frequent variant-adapted booster vaccinations and/or changes to other vaccine formulations/platforms, which might have similar immunological effects as BTIs.

A genetically engineered neuronal membrane-based nanotoxoid elicits protective immunity against neurotoxins

Given their dangerous effects on the nervous system, neurotoxins represent a significant threat to public health. Various therapeutic approaches, including chelating agents, receptor decoys, and toxin-neutralizing antibodies, have been explored. While prophylactic vaccines are desirable, it is oftentimes difficult to effectively balance their safety and efficacy given the highly dangerous nature of neurotoxins. To address this, we report here on a nanovaccine against neurotoxins that leverages the detoxifying properties of cell membrane-coated nanoparticles. A genetically modified cell line with constitutive overexpression of the α7 nicotinic acetylcholine receptor is developed as a membrane source to generate biomimetic nanoparticles that can effectively and irreversibly bind to α-bungarotoxin, a model neurotoxin. This abrogates the biological activity of the toxin, enabling the resulting nanotoxoid to be safely delivered into the body and processed by the immune system. When co-administered with an immunological adjuvant, a strong humoral response against α-bungarotoxin is generated that protects vaccinated mice against a lethal dose of the toxin. Overall, this work highlights the potential of using genetic modification strategies to develop nanotoxoid formulations against various biological threats.

Elucidating the Onset of Cross-Protective Immunity after Intranasal Vaccination with the Attenuated African Swine Fever Vaccine Candidate BA71ΔCD2

African swine fever (ASF) is a deadly disease of swine currently causing a worldwide pandemic, leading to severe economic consequences for the porcine industry. The control of disease spread is hampered by the limitation of available effective vaccines. Live attenuated vaccines (LAVs) are currently the most advanced vaccine prototypes, providing strong protection against ASF. However, the significant advances achieved using LAVs must be complemented with further studies to analyze vaccine-induced immunity. Here, we characterized the onset of cross-protective immunity triggered by the LAV candidate BA71ΔCD2. Intranasally vaccinated pigs were challenged with the virulent Georgia 2007/1 strain at days 3, 7 and 12 postvaccination. Only the animals vaccinated 12 days before the challenge had effectively controlled infection progression, showing low virus loads, minor clinical signs and a lack of the unbalanced inflammatory response characteristic of severe disease. Contrarily, the animals vaccinated 3 or 7 days before the challenge just showed a minor delay in disease progression. An analysis of the humoral response and whole blood transcriptome signatures demonstrated that the control of infection was associated with the presence of virus-specific IgG and a cytotoxic response before the challenge. These results contribute to our understanding of protective immunity induced by LAV-based vaccines, encouraging their use in emergency responses in ASF-affected areas.

Humoral responses to multiple SARS-CoV-2 variants after two doses of vaccine in kidney transplant patients

ABSTRACT Background: The COVID-19 pandemic has led to millions of fatalities globally. Kidney transplant (KT) patients, given their comorbidities and under immunosuppressant drugs, are identified as a high-risk group. Though vaccination remains pivotal for pandemic control, some studies indicate that KT exhibits diminished immune reactions to SARS-CoV-2 vaccines. Therefore, evaluating the vaccine responses in KT, especially the humoral responses against emergent variants is crucial. Methods: We developed a multiplexed SARS-CoV-2 variant protein microarray, incorporating the extracellular domain (ECD) and the receptor binding domain (RBD) of the spike proteins from the variants. This was employed to investigate the collective humoral responses after administering two doses of mRNA-1273 and AZD1222 vaccines in KT under immunosuppressive drugs and in healthy controls. Results: After two doses of either mRNA-1273 or AZD1222, the KT generally showed lower surrogate neutralizing and total antibodies against spike ECD in multiple variants compared to healthy controls. Although two doses of mRNA-1273 induced 1.5–2 fold more surrogate neutralizing and total antibodies than AZD1222 in healthy controls, the KT subjects with two doses of mRNA-1273 generally exhibited higher surrogate neutralizing but similar total antibodies against spike ECD in multiple variants. There were moderate to high correlations between the surrogate neutralizing and total antibodies against spike ECDs. Conclusion: This study offers pivotal insights into the relative vulnerability of KT concerning humoral immunity and the evolving mutations of SARS-CoV-2. Such findings are useful for evaluating vaccine responses and recommending vaccine episodes for KT.