RESUMO
Typhoid remains one of the major serious health concerns for children in developing countries. With extremely drug-resistant cases emerging, preventative measures like sanitation and vaccination, including typhoid conjugate vaccines (TCV) remain the mainstay in its prevention and control. Different types of TCVs are being developed to meet the global demand. This report outlines the results from a study done to assess the immunogenicity and safety of Vi-Diphtheria toxoid (Vi-DT) TCV in Nepal. The study was a randomized, active-controlled, immunological non-inferiority and safety study. Eligible participants from Sunsari and Morang districts of eastern Nepal were randomized into 4 study groups (A-D) within 3 age strata (6 months to <2 years, 2 to <18 years, and 18 to 45 years). Groups A to C received a single dose (25 µg) of Vi-DT test vaccine from any of the 3 lots, while group D received the comparator, Typbar-TCV®, Vi-tetanus toxoid (Vi-TT) vaccine (25 µg) in 1:1:1:1 ratio and evaluated at 4 weeks postvaccination with 6 months follow-up. Amongst 400 randomized participants, anti-Vi-IgG seroconversion rates for all age strata in Vi-DT pooled groups (A+B+C) were 100.00% (97.5% CI 98.34-100.00) vs 98.99% (97.5% CI 93.99-99.85) in Vi-TT group (D) at 4 weeks. Comparable safety events were reported between the groups. Three serious adverse events (1 in Vi-DT; 2 in Vi-TT group) were reported during the 6 months follow-up, none being related to the investigational product. Thus, Vi-DT vaccine is safe, immunogenic, and immunologically non-inferior to Vi-TT when analyzed at 4 weeks postvaccination.
Assuntos
Febre Tifoide , Vacinas Tíficas-Paratíficas , Criança , Humanos , Lactente , Pré-Escolar , Febre Tifoide/prevenção & controle , Vacinas Conjugadas , Toxoide Tetânico , Nepal , Voluntários Saudáveis , Toxoide Diftérico , Anticorpos AntibacterianosRESUMO
BACKGROUND: This study assessed safety and immunogenicity of Serum Institute of India Pvt Ltd (SIIPL)'s tetanus toxoid (TT), diphtheria toxoid (DT), and acellular pertussis booster vaccine (Tdap). RESEARCH DESIGN AND METHODS: In this Phase II/III, multicenter, randomized, active-controlled, open-label study, 1500 healthy individuals, aged 4-65 years, were randomized to receive a single dose of SIIPL Tdap or comparator Tdap vaccine (Boostrix®; GlaxoSmithKlines, India). Adverse events (AEs) during initial 30 minutes, 7-day, 30-day post-vaccination were assessed. Blood samples were taken before and 30 days post-vaccination for immunogenicity assessment. RESULTS: No significant differences in incidence of local and systemic solicited AEs were observed between the two groups; no vaccine-related serious AEs were reported. SIIPL Tdap was non-inferior to comparator Tdap in achieving booster responses to TT and DT in 75.2% and 70.8% of the participants, respectively, and to pertussis toxoid (PT), pertactin (PRN), and filamentous hemagglutinin (FHA) in 94.3%, 92.6%, and 95.0% of the participants, respectively. Anti-PT, anti-PRN, and anti-FHA antibody geometric mean titers in both the groups, were significantly higher post-vaccination compared to pre-vaccination. CONCLUSIONS: Booster vaccination with SIIPL Tdap was non-inferior to comparator Tdap with respect to immunogenicity against tetanus, diphtheria, and pertussis and was well tolerated.
Assuntos
Vacinas contra Difteria, Tétano e Coqueluche Acelular , Difteria , Tétano , Coqueluche , Adulto , Humanos , Adolescente , Criança , Toxoide Tetânico , Coqueluche/prevenção & controle , Tétano/prevenção & controle , Toxoide Diftérico , Vacina contra Coqueluche , Toxoides , Imunização Secundária/métodos , Difteria/prevenção & controle , Anticorpos AntibacterianosRESUMO
Mucosal vaccines offer several advantages over transdermal vaccines, including the ability to acquire systemic and mucosal immunities. Smoking is a huge public health threat and major risk factor for various diseases that exacerbate or prolong respiratory symptoms and conditions. However, its impact on the efficacy of mucosal vaccines remains partially explored. Thus, this study investigates the effects of smoking on mucosal vaccine reactivity by assessing the induction of Th1 immunity, a vital response in infection defense. Cigarette smoke condensate was prepared as a substitute for mainstream smoke. We intranasally administered diphtheria toxoid as an antigen and natural CpG oligonucleotide G9.1, which enhances the Th1-type antibody (Ab) response in a plasmacytoid dendritic cells (pDCs) dependent manner, as an adjuvant to mice to assess the effect of cigarette smoke condensate on Ab responses. The mechanism of its effect was evaluated using human peripheral blood mononuclear cells and their pDC-rich fraction cultured with or without G9.1. In mice, cigarette smoke condensate tended to decrease diphtheria toxoid-specific Ab response, with a higher reduction in Th1-type IgG2 Ab response than in Th2-type IgG1 Ab response. In human peripheral blood mononuclear cells, cigarette smoke condensate significantly reduced the induction of IFN-α production by G9.1. Moreover, G9.1-induced increases in the CD83 expression in pDCs and the CD80 expression in DCs were suppressed via treatment with cigarette smoke condensate. Among the mechanisms suggested were decreased expression of toll-like receptor 9 mRNA, decreased expression of mRNA for IFN regulatory factor 7, and increased CpG methylation of its promoter region. The analysis of Tbet and GATA3 expressions revealed that cigarette smoke condensate exhibits Th1-directed immunostimulatory activity at a steady state but becomes more Th2-directed under G9.1 stimulation. In conclusion, smoking could reduce mucosal vaccine responses by decreasing pDC activation and, consequently, Th1-dominant immunity.
Assuntos
Fumar Cigarros , Interferon-alfa , Animais , Humanos , Camundongos , Células Dendríticas , Toxoide Diftérico , Leucócitos Mononucleares , RNA Mensageiro/genética , FumarRESUMO
Revaccination against tetanus and diphtheria after allogeneic hematopoietic stem cell transplantation (HCT) is usually effective, but the duration of the immunity is unknown. We conducted this study to evaluate humoral immunity to tetanus and diphtheria in long-term survivors and to provide knowledge regarding the need for boosters. The median time from HCT to blood sampling was 14 years (range, 8 to 40 years). All patients had received at least 3 doses of vaccines against both tetanus and diphtheria, either monovalent or combination vaccines containing a full dose of the diphtheria toxoid component. In addition, 1 or more booster doses were administered to 21 of the 146 patients (14%). On enzyme-linked immunosorbent assay, levels <.1 IU/mL for diphtheria and <.01 IU/mL for tetanus were considered low or seronegative. Values between .01 and .5 IU/mL for tetanus and between .1 and 1.0 IU/mL for diphtheria were considered to represent partial protection, and levels >.5 and >1.0 IU/mL were considered high and protective, respectively. In all, 39% of patients were seronegative against diphtheria, 52% had some protection, and 9% had a high titer. In contrast, no patient had become seronegative to tetanus, 32% had "partial protection" against tetanus and 68% had a high titer. In multivariate analysis, active graft-versus-host-disease, sex, or time from sampling did not affect the probability of becoming seronegative or seropositive. Younger age was associated with lower antibody levels to tetanus toxoid, but age was not correlated with antibody levels against diphtheria toxoid. Tetanus immunity was maintained after vaccination in most long-term survivors, but immunity against diphtheria was poor, and boosters should be considered.
Assuntos
Difteria , Transplante de Células-Tronco Hematopoéticas , Tétano , Humanos , Difteria/prevenção & controle , Tétano/prevenção & controle , Anticorpos Antibacterianos , Toxoide Tetânico , Vacinação , Toxoide Diftérico , CorynebacteriumRESUMO
Pseudomonas aeruginosa is an opportunistic pathogen considered a common cause of nosocomial infection with high morbidity and mortality in burn patients. Immunoprophylaxis techniques may lower the mortality rate of patients with burn wounds infected by P. aeruginosa; consequently, this may be an efficient strategy to manage infections caused by this bacterium. Several pathogenic Gram-negative bacteria like P. aeruginosa release outer membrane vesicles (OMVs), and structurally OMV consists of several antigenic components capable of generating a wide range of immune responses. Here, we evaluated the immunogenicity and efficacy of P. aeruginosa PA-OMVs (PA-OMVs) conjugated with the diphtheria toxoid (DT) formulated with alum adjuvant (PA-OMVs-DT + adj) in a mice model of burn wound infection. ELISA results showed that in the group of mice immunized with PA-OMVs-DT + adj conjugated, there was a significant increase in specific antibodies titer compared to non-conjugated PA-OMVs or control groups. In addition, the vaccination of mice with PA-OMVs-DT + adj conjugated generated greater protective effectiveness, as seen by lower bacterial loads, and eightfold decreased inflammatory cell infiltration with less tissue damage in the mice burn model compared to the control group. The opsonophagocytic killing results confirmed that humoral immune response might be critical for PA-OMVs mediated protection. These findings suggest that PA-OMV-DT conjugated might be used as a new vaccine against P. aeruginosa in burn wound infection.
Assuntos
Queimaduras , Toxoide Diftérico , Vacinas contra Pseudomonas , Pseudomonas aeruginosa , Infecção dos Ferimentos , Animais , Camundongos , Proteínas da Membrana Bacteriana Externa/imunologia , Queimaduras/microbiologia , Toxoide Diftérico/imunologia , Pseudomonas aeruginosa/imunologia , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/prevenção & controle , Vacinas contra Pseudomonas/imunologiaRESUMO
Diphtheria is a potentially fatal respiratory disease caused by toxigenic forms of the Gram-positive bacterium Corynebacterium diphtheriae. Despite the availability of treatments (antitoxin and antimicrobials) and effective vaccines, the disease still occurs sporadically in low-income countries and in higher income where use of diphtheria vaccine is inconsistent. Diphtheria was highly endemic in Vietnam in the 1990s; here, we aimed to provide some historical context to the circulation of erythromycin resistant organisms in Vietnam during this period. After recovering 54 C. diphtheriae isolated from clinical cases of diphtheria in Ho Chi Minh City between 1992 and 1998 we conducted whole genome sequencing and analysis. Our data outlined substantial genetic diversity among the isolates, illustrated by seven distinct Sequence Types (STs), but punctuated by the sustained circulation of ST67 and ST209. With the exception of one isolate, all sequences contained the tox gene, which was classically located on a corynebacteriophage. All erythromycin resistant isolates, accounting for 13â% of organisms in this study, harboured a novel 18 kb erm(X)-carrying plasmid, which exhibited limited sequence homology to previously described resistance plasmids in C. diphtheriae. Our study provides historic context for the circulation of antimicrobial resistant C. diphtheriae in Vietnam; these data provide a framework for the current trajectory in global antimicrobial resistance trends.
Assuntos
Antitoxinas , Corynebacterium diphtheriae , Difteria , Humanos , Corynebacterium diphtheriae/genética , Difteria/epidemiologia , Difteria/microbiologia , Eritromicina/farmacologia , Vietnã/epidemiologia , Corynebacterium , Toxoide DiftéricoRESUMO
Immunization has been considered a successful global health program that saves many persons' lives each year. The vaccines reduce the risk of getting the disease by building immunity in the body. Therefore, the constant availability of essential vaccines is an important factor in community health. One of the most important vaccines is the diphtheria vaccine, which is usually used as Multivalent diphtheria-tetanus-pertussis (DTP) combination vaccines. The production of this vaccine takes about 45 days, from the initial bacterial culture to the end of toxin production. However, the production of this vaccine can be optimized in case the production stages are carried out under normal conditions. In this study, a significant amount of impurities was removed after washing with phosphate buffer saline, and the toxin was then purified by Sephadex G-50. In this method, the toxin was concentrated to be stored in a smaller space (this removes the concerns for the provision of a suitable space). Another problem with the diphtheria vaccine is that it is reversible after detoxification of the toxin using formaldehyde. For this reason, it is suggested to use MPEG for detoxification, which will produce more stable covalent bonds between PEG and the first type of amine groups in the toxin chain. Tests were performed to evaluate factors, such as in vivo cytotoxicity, lack of edemas formation, the neutralizing activity of serum from guinea pigs immunized with the diphtheria toxoid inactivated with MPEG, and the immunogenic activity of the purified and modified toxin. Comparison of this PEG detoxification toxoid with the standard toxoid produced in Razi Vaccine and Serum Institution, Karaj, Iran, showed that washing with PBS and purification with Sephadex G-50 was an efficient method. The stability and reversibility of the toxoid approved by MPEG were acceptable. Therefore, the results of animal tests showed that the obtained product was stable and caused no wound or necrosis in the tested animals.
Assuntos
Toxoide Diftérico , Vacina contra Difteria, Tétano e Coqueluche , Cobaias , Animais , Formaldeído , Fosfatos , AminasRESUMO
Background: Although maternal vaccination with influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines improve health outcomes for pregnant individuals and infants, maternal vaccination rates are low. This study assessed obstetric providers' attitudes and practices related to influenza and Tdap vaccination in four large health systems in New York (NY) and California (CA). Methods: We conducted a cross-sectional survey of all obstetric providers within four health systems (two in NY, two in CA) to evaluate provider attitudes and office systems used for Tdap and influenza vaccination. The survey assessed perceptions of influenza and Tdap vaccination based on the Health Belief Model, and assessed office systems (reminders, prompts, standing orders, and patient education) and communication with pregnant patients related to influenza and Tdap vaccines. Results: We had 112 responses (52% response rate) for analyses. Respondents strongly supported vaccination during pregnancy but viewed influenza disease as less of a concern for newborns than for pregnant individuals (40% vs. 67% considered influenza disease to be very significant, p < 0.001). Only 84% agreed that giving influenza vaccine in the first trimester is very safe. Patient vaccine refusal was the most commonly named barrier for both influenza and Tdap vaccination. Providers frequently used office system prompts, but did not frequently use standing orders, patient educational materials, vaccine champions, and feedback on vaccination rates. Conclusions: While most providers consider influenza and Tdap vaccination important during pregnancy, there is room for improvement in focusing on the importance of maternal vaccination to the health of the infant, and increasing the use of office systems to improve vaccination during pregnancy.
Assuntos
Vacinas contra Difteria, Tétano e Coqueluche Acelular , Vacinas contra Influenza , Influenza Humana , Coqueluche , Estudos Transversais , Toxoide Diftérico , Vacinas contra Difteria, Tétano e Coqueluche Acelular/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Gravidez , Toxoides , Vacinação , Coqueluche/prevenção & controleRESUMO
Formaldehyde detoxification is a process for converting tetanus toxin (TT) and diphtheria toxin (DT) into tetanus toxoid (TTd) and diphtheria toxoid (DTd), respectively. The mechanism of this detoxification process has been investigated by several previous studies based on lab-scale toxoids. To obtain greater insights of the effects induced by formaldehyde, industrial TTd and DTd batches obtained from different detoxification processes were studied in this work. Using liquid chromatography-mass spectrometry (LC-MS), 15 and 20 repeatable formaldehyde-induced modification sites of TTd and DTd were identified, respectively. Toxoid which had a higher formaldehyde-induced modification rate observed by LC-MS, also had larger bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Aggregates which were observed on size exclusion chromatogram (SEC) were confirmed by SDS-PAGE and LC-MS. Formaldehyde detoxification also led to a decrease of isoelectric point (pI) values and an increase of retention on weak anion exchange (WAX) column. Specific toxicity tests were conducted to evaluate toxicity of the TTd and DTd samples obtained with different detoxification conditions. Results from the specific toxicity tests showed that all toxoids used in this study were qualified, including toxoids obtained from mild and drastic detoxification conditions. However, obtained from mild detoxification conditions had less aggregates and may lead to a higher degree of glycosylation in conjugate vaccines than the ones obtained from drastic detoxification conditions. Thus, we suggest that mild detoxification conditions should be used to obtain TTd and DTd. Furthermore, as well as studying the formaldehyde-induced modifications and toxicity in TTd and DTd, the effects of the detoxification process on foreign proteins were also investigated. An increase in foreign proteins were observed in the aggregate than in the monomer of the toxoids. Additionally, some foreign proteins in the monomer of the toxins transferred to the aggregate of toxoids due to the formation of cross-linking. To eliminate the risk of cross-linking foreign proteins to toxoids in vaccination programs, a purification process is necessary before the detoxification process and/or the use of toxoids in vaccines.
Assuntos
Toxoide Diftérico , Toxoide Tetânico , Toxoide Diftérico/química , Formaldeído/química , Formaldeído/toxicidade , Toxina Tetânica/química , Toxoide Tetânico/química , ToxoidesRESUMO
This paper aims to investigate the preparation and characterisation of the alginate nanoparticles (NPs) as antigen delivery system loaded by diphtheria toxoid (DT). For this purpose, both the loading capacity (LC) and Loading efficiency (LE) of the alginate NPs burdened by DT are evaluated. Moreover, the effects of different concentrations of sodium alginate and calcium chloride on the NPs physicochemical characteristics are surveyed in addition to other physical conditions such as homogenization time and rate. To do so, the NPs are characterised using particle size and distribution, zeta potential, scanning electron microscopy, encapsulation efficiency, in vitro release study and FT-IR spectroscopy. Subsequently, the effects of homogenization time and rate on the NPs are assessed. At the meantime, the NPs LC and efficiency in several DT concentrations are estimated. The average size of the NPs was 400.7 and 276.6 nm for unloaded and DT loaded, respectively. According to the obtained results, the zeta potential of the blank and DT loaded NPs are estimated as -23.7 mV and -21.2 mV, respectively. Whereas, the LC and LE were >80% and >90%, in that order. Furthermore, 95% of the releasing DT loaded NPs occurs at 140 h in the sustained mode without any bursting release. It can be concluded that the features of NPs such as morphology and particle size are strongly depended on the calcium chloride, sodium alginate concentrations and physicochemical conditions in the NPs formation process. In addition, appropriate concentrations of the sodium alginate and calcium ions would lead to obtaining the desirable NPs formation associated with the advantageous LE, LC (over 80%) and sustained in vitro release profile. Ultimately, the proposed NPs can be employed in vaccine formulation for the targeted delivery, controlled and slow antigen release associated with the improved antigen stability.
Assuntos
Alginatos , Nanopartículas , Alginatos/química , Cloreto de Cálcio , Toxoide Diftérico , Portadores de Fármacos/química , Nanopartículas/química , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: Diphtheria cases reported in Central Vietnam since 2013 were mainly in children aged 6-15 years, which may reflect an immunity gap. There is little information on population immunity against diphtheria in countries without a school-entry booster dose. We aimed to measure the age-stratified seroprevalence of anti-diphtheria toxoid antibodies, quantify the change in antibody levels in individuals over time, and estimate the length of protective immunity after vaccination in well-vaccinated communities in Vietnam. METHODS: An age-stratified seroprevalence survey among individuals aged 0-55 years was conducted at Nha Trang, Vietnam. The same participants were followed up after two years to quantify the change in antibody levels. IgG was measured using ELISA. The length of protective immunity after vaccination was estimated using a mixed-effect linear regression model with random intercept. RESULTS: Overall seroprevalence was 26% (95%CI:20-32%). Age-stratified seroprevalence was 68% (95%CI:4-11%), 7% (95%CI:4-11%), 12% (95%CI:7-19%), 33% (95%CI:27-40%), and 28% (95%CI:17-43%) among those aged ≤5, 6-15,16-25, 26-35, and 36-55 years, respectively. The antibody levels declined by 47% (95%CI:31-59%) over two years, and the predicted duration of vaccine-derived protective immunity after receiving four doses was 4.3 years (95%CI:3.5-5.3) among participants aged six years or younger. CONCLUSION: Given the low seroprevalence and short period of vaccine protection, a school-entry booster dose (5-7 years) is recommended in Vietnam.
Assuntos
Difteria , Adolescente , Adulto , Anticorpos Antibacterianos , Criança , Pré-Escolar , Difteria/epidemiologia , Difteria/prevenção & controle , Toxoide Diftérico , Humanos , Imunoglobulina G , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Vietnã/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Since 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. METHODS: Residual 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. RESULTS: A 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. CONCLUSIONS: The 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.
Assuntos
Difteria , Migrantes , Adulto , Anticorpos Antibacterianos , Difteria/epidemiologia , Difteria/prevenção & controle , Antitoxina Diftérica , Toxoide Diftérico , Humanos , Imunoglobulina G , Estudos Soroepidemiológicos , Singapura/epidemiologiaRESUMO
BACKGROUND: Prevention of respiratory syncytial virus (RSV) disease in infants is an unmet vaccine need, and maternal immunization is a potential strategy to address this need. This study evaluated concomitant administration of RSV stabilized prefusion F subunit vaccine (RSVpreF) and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap) in healthy, nonpregnant women 18â49 years of age. METHODS: In this phase 2b, multicenter, placebo-controlled, observer-blind, noninferiority study, participants were randomized to receive RSVpreF in a range of doses and formulations with Tdap or alone, or Tdap alone. Safety and immunogenicity were assessed. RESULTS: Local reactions and systemic events were generally similar across vaccine groups. Noninferiority of anti-RSV-A and anti-RSV-B immune responses induced by RSVpreF with Tdap was demonstrated compared to RSVpreF alone. Noninferiority of anti-diphtheria toxoid and anti-tetanus toxoid immune responses after administration of RSVpreF with Tdap was demonstrated compared to Tdap alone; noninferiority was not met for anti-pertussis component responses. CONCLUSIONS: RSVpreF was safe and well tolerated when administered with Tdap or alone in nonpregnant women 18â49 years of age. Immune responses induced by Tdap administered with RSVpreF were noninferior for the tetanus and diphtheria components of Tdap, but not for pertussis. CLINICAL TRIALS REGISTRATION: NCT04071158.
Assuntos
Vacinas contra Difteria, Tétano e Coqueluche Acelular , Imunogenicidade da Vacina , Vacinas contra Vírus Sincicial Respiratório , Adulto , Anticorpos Antibacterianos , Anticorpos Antivirais , Difteria/prevenção & controle , Toxoide Diftérico , Vacinas contra Difteria, Tétano e Coqueluche Acelular/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Tétano/prevenção & controle , Coqueluche/prevenção & controle , Adulto JovemRESUMO
BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) experience hypogammaglobinemia and non-neutropenic infections. In this exploratory proof of concept study, our objective was to determine the prevalence of humoral immunodeficiency in patients with CLL and serum IgG ≥ 400 mg/dL, and to evaluate the efficacy of subcutaneous immunoglobulin (SCIG) in this population. PATIENTS AND METHODS: Patients with CLL with serum IgG ≥ 400 mg/dL were evaluated for serum IgG, IgM, IgA, along with pre/post vaccine IgG titers to diphtheria, tetanus, and Streptococcus pneumoniae. Patients with evidence of humoral dysfunction were treated with SCIG with Hizentra every 7±2 days for 24 weeks. RESULTS: Fifteen patients enrolled with median IgG = 782 mg/dL [IQR: 570 to 827], and 6/15 (40%) responded to vaccination with Td, while 5/15 (33%) responded to vaccination with PPV23. 14/15 (93.3%) demonstrated humoral immunodeficiency as evidenced by suboptimal vaccine responses, and were treated with SCIG. In patients treated with SCIG, serum IgG increased from 670 mg/dL [IQR: 565 to 819] to 1054 mg/dL [IQR: 1040 to 1166] after 24 weeks (95% CI: 271-540). For streptococcus pneumoniae, the median protective serotypes at baseline was 8 [IQR: 4 to 9] and increased to 17 [IQR: 17 to 19] after 24 weeks (95% CI: 6.93-13.72). Non-neutropenic infections (NNI) decreased from 14 to 5 during treatment with SCIG. CONCLUSIONS: Patients with CLL demonstrate humoral immunodeficiency despite IgG > 400 mg/dL. For these patients, SCIG is well tolerated and efficacious in improving serum IgG, specific IgG to streptococcus pneumoniae, and may decrease reliance on antibiotics for the treatment of NNIs. CLINICAL TRIALS REGISTRATION: NCT03730129.
Assuntos
Imunoglobulina G/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Idoso , Idoso de 80 Anos ou mais , Difteria/imunologia , Toxoide Diftérico/administração & dosagem , Toxoide Diftérico/imunologia , Esquema de Medicação , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Infusões Subcutâneas , Leucemia Linfocítica Crônica de Células B/complicações , Masculino , Pessoa de Meia-Idade , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Sorogrupo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/imunologia , Tétano/imunologia , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/imunologiaRESUMO
Peptide conjugates have been widely used for developing vaccines that prevent common bacterial infections for which peptides alone are either ineffective or provide only short-term protection. Among several carrier proteins, diphtheria toxoid and CRM197 (a genetically detoxified diphtheria toxin) are considered safe and have been used in several licensed vaccines. For developing a vaccine against group A streptococcus (GAS), antigens from conserved region of M protein and the IL-8 protease, SpyCEP, have been identified. In this chapter, we describe a method for producing peptide-conjugate subunit GAS vaccines, which involves maleimide conjugation of peptides to a carrier protein and their subsequent characterization.
Assuntos
Streptococcus pyogenes , Anticorpos Antibacterianos , Proteínas de Bactérias/genética , Proteínas de Transporte , Toxoide Diftérico , Peptídeos , Streptococcus pyogenes/genética , Vacinas ConjugadasRESUMO
Sars Cov-2, the pathogen which belongs to the beta coronavirus family that is responsible for COVID-19, uses Angiotensin Converting Enzyme 2 (ACE2) as a receptor, which is responsible for controlling the actions of renin-angiotensin system (RAS). Sars Cov-2 - ACE2 binding leads to a RAS mediated immune response, which targets especially lungs to form ARDS, which in turn, is the most important cause of mortality in COVID-19. CD8+ T cell response dominates over CD4+ T cell response and natural killer cell dysfunction also leads to CD4+ cell dysfunction in COVID-19; this immune dysregulation leads to inappropriate (ARDS) and inadequate (low or quickly waning antibodies) responses to the disease and unfortunately, prepares the patients for re-infections. The peripheral anergy seen in chronic sarcoidosis has much resemblance to COVID-19; CD8+ T cell accumulation is also responsible for inadequate reaction to tuberculin and antigenic stimulus. This article, based on the similarity of COVID-19 and sarcoidosis, discusses a combination of the therapeutic strategy of the tetanus-diphtheria vaccine and dual RAS inhibition, alongside with hydroxychloroquine and antiviral agents, as a solution to overcome the problems described above.
Assuntos
COVID-19 , Sarcoidose , Tétano , Toxoide Diftérico , Humanos , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2RESUMO
BACKGROUND: Despite high childhood immunization coverage, sporadic cases of diphtheria have been reported in Malaysia in recent years. This study aims to evaluate the seroprevalence of diphtheria among the Malaysian population. METHODS: A total of 3317 respondents age 2 years old to 60 years old were recruited in this study from August to November 2017. Enzyme-linked immunosorbent assay (ELISA) was used to measure the level of IgG antibody against the toxoid of C. diphtheriae in the blood samples of respondents. We classified respondent antibody levels based on WHO definition, as protective (≥0.1 IU/mL) and susceptible (< 0.1 IU/mL) to C. diphtheriae infection. RESULTS: Among the 3317 respondents, 57% were susceptible (38.1% of children and 65.4% of adults) and 43% (61.9% of children and 34.6% of adults) had protective antibody levels against diphtheria. The mean antibody level peaked among individuals aged 1-2 years old (0.59 IU/mL) and 6-7 years old (0.64 IU/mL) but generally decreased with age, falling below 0.1 IU/mL at around 4-6 years old and after age 20 years old. There was a significant association between age [Children: χ2 = 43.22(df = 2),p < 0.001)], gender [Adults: χ2 = 5.58(df = 1),p = 0.018] and ethnicity [Adults: χ2 = 21.49(df = 5),p = 0.001] with diphtheria toxoid IgG antibody level. CONCLUSIONS: About 57% of the Malaysian population have inadequate immunity against diphtheria infection. This is apparently due to waning immunity following childhood vaccination without repeated booster vaccination in adults. Children at age 5-6 years old are particularly vulnerable to diphtheria infection. The booster vaccination dose normally given at 7 years should be given earlier, and an additional booster dose is recommended for high-risk adults.
Assuntos
Anticorpos Antibacterianos/sangue , Toxoide Diftérico/imunologia , Difteria/epidemiologia , Imunoglobulina G/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Corynebacterium diphtheriae/metabolismo , Difteria/patologia , Ensaio de Imunoadsorção Enzimática , Humanos , Lactente , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto JovemRESUMO
Currently, animal tests are being used to confirm the potency and lack of toxicity of toxoid vaccines. In a consistency approach, animal tests could be replaced if production consistency (compared to known good products) can be proven in a panel of in vitro assays. By mimicking the in vivo antigen processing in a simplified in vitro approach, it may be possible to distinguish aberrant products from good products. To demonstrate this, heat-exposed diphtheria toxoid was subjected to partial digestion by cathepsin S (an endoprotease involved in antigen processing), and the peptide formation/degradation kinetics were mapped for various heated toxoids. To overcome the limitations associated with the very large number of samples, we used common reference-based tandem mass tag (TMT) labeling. Instead of using one label per condition with direct comparison between the set of labels, we compared multiple labeled samples to a common reference (a pooled sample containing an aliquot of each condition). In this method, the number of samples is not limited by the number of unique TMT labels. This TMT multiplexing strategy allows for a 15-fold reduction of analysis time while retaining the reliability advantage of TMT labeling over label-free quantification. The formation of the most important peptides could be followed over time and compared among several conditions. The changes in enzymatic degradation kinetics of diphtheria toxoid revealed several suitable candidate peptides for use in a quality control assay that can distinguish structurally aberrant diphtheria toxoid from compliant toxoids.
Assuntos
Toxoide Diftérico/metabolismo , Peptídeos/análise , Espectrometria de Massas em Tandem/métodos , Toxoide Diftérico/análise , Espectrometria de Massas em Tandem/normas , TemperaturaRESUMO
The geometry of the channel formed by nontoxic derivative of diphtheria toxin CRM197 in lipid bilayer was determined using the dependence of single-channel conductance upon the hydrodynamic radii of different nonelectrolytes. It was found that the cis entrance of CRM197 channel on the side of membrane to which the toxoid was added at pH 4.8 and the trans entrance on the opposite side at pH 6.0 had effective radii of 3.90 and 3.48 Å, respectively. The 3-alkyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium salts reversibly reduced current via CRM197 channels. The potency of the blockers increased with increasing length of alkyl chain at symmetric pH 6.0 and remained high and stable at pH 4.8 on the cis side. Comparative analysis of CRM197 and amphotericin B pore size with the inhibitory action of thiazolium salts revealed a significant increase in CRM197 pore dimension at pH 6.0. Addition of thiazolium salt with nine carbons alkyl tail increased by â¼30% the viability of human carcinoma cells A431 treated with diphtheria toxin.
Assuntos
Canais Iônicos , Sais , Proteínas de Bactérias/metabolismo , Toxoide Diftérico , Humanos , Potenciais da MembranaRESUMO
We validated a multiplex bead assay for diphtheria toxoid IgG antibodies against the Vero cell toxin neutralization test using 1300 specimens (correlationâ¯=â¯0.88). At the ≥0.01 IU/mL cutoff for minimal seroprotection, sensitivity was 95% and specificity was 83%. Agreement for three categories (<0.01, 0.01-<0.1, ≥0.1 IU/mL) was 81% (kappaâ¯=â¯0.71).
