Postbooster Antibodies from Humans as Source of Diphtheria Antitoxin.
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ABSTRACT:
SUBMITTER: Bermejo-Martin JF
PROVIDER: S-EPMC4918160 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSince the last local case of diphtheria in 1992, there had not been any case in Singapore until an autochthonous case was reported in 2017. This fatal diphtheria case of a migrant worker raised concerns about the potential re-emergence of locally transmitted toxigenic diphtheria in Singapore. We conducted a seroprevalence study to assess the immunity levels to diphtheria among migrant workers in Singapore.MethodsResidual sera from migrant workers who hailed from Bangladesh, China, India, Indonesia, Malaysia, Myanmar and the Philippines were tested for anti-diphtheria toxoid immunoglobulin G (IgG) antibodies. These migrant workers previously participated in a survey between 2016 and 2019 and had provided blood samples as part of the survey procedure.ResultsA total of 2176 migrant workers were included in the study. Their overall mean age was 27.1 years (standard deviation 5.0), range was 20-43 years. The proportion having at least basic protection against diphtheria (antitoxin titres ≥ 0.01 IU/ml) ranged from 77.9% (95% confidence interval [CI] 72.8 - 82.3%) among migrant workers from Bangladesh to 96.7% (95% CI 92.5 - 98.6%) in those hailing from Malaysia. The proportion showing full protection (antitoxin titres ≥ 0.10 IU/ml) ranged from 10.1% (95% CI 6.5 - 15.4%) in Chinese workers to 23.0% (95% CI 17.1 - 30.3%) in Malaysian workers. There were no significant differences in the proportion with at least basic protection across birth cohorts, except for those from Bangladesh where the seroprevalence was significantly lower in younger migrant workers born after 1989.ConclusionsThe proportions having at least basic protection against diphtheria in migrant workers from five out of seven Asian countries (India, Indonesia, Malaysia, Myanmar and the Philippines) were higher than 85%, the threshold for diphtheria herd immunity. Seroprevalence surveys should be conducted periodically to assess the level of immunity against diphtheria and other vaccine preventable diseases in migrant worker population, so that appropriate interventions such as booster vaccination can be implemented proactively to prevent sporadic outbreaks.
| S-EPMC8761332 | biostudies-literature
Project description:BackgroundDiphtheria has re-emerged over the past several years. There is a paucity of data on the administration and safety of diphtheria antitoxin (DAT), the standard treatment for diphtheria. The 2017-2018 outbreak among Rohingya refugees in Bangladesh was the largest in decades. We determined the outcomes of DAT-treated patients and describe the occurrence and risk factors associated with adverse reactions to DAT.MethodsWe conducted a retrospective study at the Médecins Sans Frontières Rubber Garden Diphtheria Treatment Center from December 2017-September 2018. Diphtheria was diagnosed based on the World Health Organization clinical case criteria. High-acuity patients were eligible for DAT. Safety precautions were meticulously maintained. We calculated the presence of adverse events by age, duration of illness, and DAT dosage using bivariate comparisons.ResultsWe treated 709 patients with DAT; 98% (n = 696) recovered and were discharged. One-fourth (n = 170) had at least 1 adverse reaction. Common reactions included cough (n = 115, 16%), rash (n = 66, 9%), and itching (n = 37, 5%). Three percent (n = 18) had severe hypersensitivity reactions. Five patients died during their DAT infusion or soon afterwards, but no deaths were attributed to DAT.ConclusionsOutcomes for DAT-treated patients were excellent; mortality was <1%. Adverse reactions occurred in one-quarter of all patients, but most reactions were mild and resolved quickly. DAT can be safely administered in a setting with basic critical care, provided there is continuous patient monitoring during the infusion, staff training on management of adverse effects, and attention to safety precautions.
| S-EPMC8561263 | biostudies-literature
Project description:Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.
| S-EPMC3811848 | biostudies-literature
Project description:Diphtheria is an infectious disease caused by Corynebacterium diphtheriae. The bacterium primarily infects the throat and upper airways and the produced diphtheria toxin (DT), which binds to the elongation factor 2 and blocks protein synthesis, can spread through the bloodstream and affect organs, such as the heart and kidneys. For more than 125 years, the therapy against diphtheria has been based on polyclonal horse sera directed against DT (diphtheria antitoxin; DAT). Animal sera have many disadvantages including serum sickness, batch-to-batch variation in quality and the use of animals for production. In this work, 400 human recombinant antibodies were generated against DT from two different phage display panning strategies using a human immune library. A panning in microtiter plates resulted in 22 unique in vitro neutralizing antibodies and a panning in solution combined with a functional neutralization screening resulted in 268 in vitro neutralizing antibodies. 61 unique antibodies were further characterized as scFv-Fc with 35 produced as fully human IgG1. The best in vitro neutralizing antibody showed an estimated relative potency of 454 IU/mg and minimal effective dose 50% (MED50%) of 3.0 pM at a constant amount of DT (4x minimal cytopathic dose) in the IgG format. The targeted domains of the 35 antibodies were analyzed by immunoblot and by epitope mapping using phage display. All three DT domains (enzymatic domain, translocation domain and receptor binding domain) are targets for neutralizing antibodies. When toxin neutralization assays were performed at higher toxin dose levels, the neutralizing capacity of individual antibodies was markedly reduced but this was largely compensated for by using two or more antibodies in combination, resulting in a potency of 79.4 IU/mg in the in vivo intradermal challenge assay. These recombinant antibody combinations are candidates for further clinical and regulatory development to replace equine DAT.
| S-EPMC6969050 | biostudies-literature
Project description:The spore-forming bacterium Clostridium difficile represents the principal cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. C. difficile infection (CDI) is mediated by 2 bacterial toxins, A and B; neutralizing these toxins with monoclonal antibodies (mAbs) provides a potential nonantibiotic strategy for combating the rising prevalence, severity, and recurrence of CDI. Novel antitoxin mAbs were generated in mice and were humanized. The humanized antitoxin A mAb PA-50 and antitoxin B mAb PA-41 have picomolar potencies in vitro and bind to novel regions of the respective toxins. In a hamster model for CDI, 95% of animals treated with a combination of humanized PA-50 and PA-41 showed long-term survival relative to 0% survival of animals treated with standard antibiotics or comparator mAbs. These humanized mAbs provide insight into C. difficile intoxication and hold promise as potential nonantibiotic agents for improving clinical management of CDI.
| S-EPMC3491748 | biostudies-literature
Project description:BackgroundRespiratory diphtheria is a toxin-mediated disease caused by Corynebacterium diphtheriae. Diphtheria-like illness, clinically indistinguishable from diphtheria, is caused by Corynebacterium ulcerans, a zoonotic bacterium that can also produce diphtheria toxin. In the United States, respiratory diphtheria is nationally notifiable: specimens from suspected cases are submitted to the Centers for Disease Control and Prevention (CDC) for species and toxin confirmation, and diphtheria antitoxin (DAT) is obtained from CDC for treatment. We summarize the epidemiology of respiratory diphtheria and diphtheria-like illness and describe DAT use during 1996-2018 in the United States.MethodsWe described respiratory diphtheria cases reported to the National Notifiable Diseases Surveillance System (NNDSS) and C. ulcerans-related diphtheria-like illness identified through specimen submissions to CDC during 1996-2018. We reviewed DAT requests from 1997 to 2018.ResultsFrom 1996 to 2018, 14 respiratory diphtheria cases were reported to NNDSS. Among these 14 cases, 1 was toxigenic and 3 were nontoxigenic C. diphtheriae by culture and Elek, 6 were culture-negative but polymerase chain reaction (PCR)-positive for diphtheria toxin gene, 1 was culture-positive without further testing, and the remaining 3 were either not tested or tested negative. Five cases of respiratory diphtheria-like illness caused by toxigenic C. ulcerans were identified. DAT was requested by healthcare providers for 151 suspected diphtheria cases between 1997 and 2018, with an average of 11 requests per year from 1997 to 2007, and 3 per year from 2008 to 2018.ConclusionsRespiratory diphtheria remains rare in the United States, and requests for DAT have declined. Incidental identification of C. ulcerans-related diphtheria-like illness suggests surveillance of this condition might be warranted.
| S-EPMC8876369 | biostudies-literature
Project description:In Haiti, measles, rubella, and maternal and neonatal tetanus have been eliminated, but a diphtheria outbreak is ongoing as of 2019. We conducted a nationally representative, household-based, two-stage cluster survey among children aged 5-7 years in 2017 to assess progress toward maintenance of control and elimination of selected vaccine-preventable diseases (VPDs). We stratified Haiti into West region (West department, including the capital city) and non-West region (all other departments). We obtained vaccination history and dried blood spots, and measured antibody concentrations to VPDs on a multiplex bead assay. Among 1,146 children, national seropositivity was 83% (95% CI: 80-86%) for tetanus, 83% (95% CI: 81-85%) for diphtheria, 87% (95% CI: 85-89%) for measles, and 84% (95% CI: 81-87%) for rubella. None of the children had long-term immunity to tetanus or diphtheria (IgG concentration ≥ 1 international unit/mL). Seropositivity in the West region was lower than that in the non-West region. Vaccination coverage was 68% (95% CI: 61-74%) for ≥ 3 doses of tetanus- and diphtheria-containing vaccine (DTP3), 84% (95% CI: 80-87%) for one dose of measles-rubella vaccine (MR1), and 20% (95% CI: 16-24%) for MR2. The seroprevalence of measles, rubella, and diphtheria antibodies is lower than population immunity levels needed to prevent disease transmission, particularly in the West region; reintroduction of these diseases could lead to an outbreak. To maintain VPD control and elimination, Haiti should achieve DTP3 and MR2 coverage ≥ 95%, and include tetanus and diphtheria booster doses in the routine immunization schedule.
| S-EPMC7543806 | biostudies-literature
Project description:Diphtheria is a vaccine-preventable disease, yet immunization can wane over time to non-protective levels. We have developed a low-cost, miniaturized electroanalytical biosensor to quantify anti-diphtheria toxin (DTx) immunoglobulin G (anti-DTx IgG) antibody to minimize the risk for localized outbreaks. Two epitopes specific to DTx and recognized by antibodies generated post-vaccination were selected to create a bi-epitope peptide, biEP, by synthesizing the epitopes in tandem. The biEP peptide was conjugated to the surface of a pencil-lead electrode (PLE) integrated into a portable electrode holder. Captured anti-DTx IgG was measured by square wave voltammetry from the generation of hydroquinone (HQ) from the resulting immunocomplex. The performance of the biEP reagent presented high selectivity and specificity for DTx. Under the optimized working conditions, a logarithmic calibration curve showed good linearity over the concentration range of 10-5-10-1 IU mL-1 and achieved a limit of detection of 5 × 10-6 IU mL-1. The final device proved suitable for interrogating the immunity level against DTx in actual serum samples. Results showed good agreement with those obtained from a commercial enzyme-linked immunosorbent assay. In addition, the flexibility for conjugating other capture molecules to PLEs suggests that this technology could be easily adapted to the diagnoses of other pathogens.
| S-EPMC8699316 | biostudies-literature
Project description:The exotoxins TcdA and TcdB are the major virulence factors of Clostridium difficile. Circulating neutralizing antitoxin antibodies are protective in C. difficile infection (CDI), as demonstrated, in part, by the protective effects of actoxumab and bezlotoxumab, which bind to and neutralize TcdA and TcdB, respectively. The question of how systemic IgG antibodies neutralize toxins in the gut lumen remains unresolved, although it has been suggested that the Fc receptor FcRn may be involved in active antibody transport across the gut epithelium. In this study, we demonstrated that genetic ablation of FcRn and excess irrelevant human IgG have no impact on actoxumab-bezlotoxumab-mediated protection in murine and hamster models of CDI, suggesting that Fc-dependent transport of antibodies across the gut wall is not required for efficacy. Tissue distribution studies in hamsters suggest, rather, that the transport of antibodies depends on toxin-induced damage to the gut lining. In an in vitro two-dimensional culture system that mimics the architecture of the intestinal mucosal epithelium, toxins on the apical side of epithelial cell monolayers are neutralized by basolateral antibodies, and antibody transport across the cell layer is dramatically increased upon addition of toxin to the apical side. Similar data were obtained with F(ab')2 fragments, which lack an Fc domain, consistent with FcRn-independent paracellular, rather than transcellular, transport of antibodies. Kinetic studies show that initial damage caused by apical toxin is required for efficient neutralization by basolateral antibodies. These data may represent a general mechanism of humoral response-mediated protection against enteric pathogens.
| S-EPMC4288887 | biostudies-literature
Project description:VLP Vaccination in humans induced antigen-specific B cells with broad reactivity and protection in mouse models of infection
2023-03-31 | GSE218843 | GEO