RESUMEN
BACKGROUND: Antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae may protect against cholera; however, little is known about this immune response in infected immunologically naïve humans. METHODOLOGY: We measured serum anti-OSP antibodies in adult North American volunteers experimentally infected with V. cholerae O1 Inaba El Tor N16961. We also measured vibriocidal and anti-cholera toxin B subunit (CtxB) antibodies and compared responses to those in matched cholera patients in Dhaka, Bangladesh, an area endemic for cholera. PRINCIPAL FINDINGS: We found prominent anti-OSP antibody responses following initial cholera infection: these responses were largely IgM and IgA, and highest to infecting serotype with significant cross-serotype reactivity. The anti-OSP responses peaked 10 days after infection and remained elevated over baseline for ≥ 6 months, correlated with vibriocidal responses, and may have been blunted in blood group O individuals (IgA anti-OSP). We found significant differences in immune responses between naïve and endemic zone cohorts, presumably reflecting previous exposure in the latter. CONCLUSIONS: Our results define immune responses to O-specific polysaccharide in immunologically naive humans with cholera, find that they are largely IgM and IgA, may be blunted in blood group O individuals, and differ in a number of significant ways from responses in previously humans. These differences may explain in part varying degrees of protective efficacy afforded by cholera vaccination between these two populations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01895855.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Cólera/inmunología , Cólera/microbiología , Inmunidad Humoral , Antígenos O/inmunología , Vibrio cholerae O1/inmunología , Vibrio cholerae O1/aislamiento & purificación , Adolescente , Adulto , Antitoxinas/sangre , Bangladesh , Toxina del Cólera/inmunología , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , América del Norte , Adulto JovenRESUMEN
Pertussis remains a public health concern in most countries. This cross-sectional study aims to investigate the distribution of pertussis toxin antibodies (anti-PT IgG) in Tunisian children and adolescents aged 3-18 years, to define optimal age for booster vaccination. Anti-PT IgG concentrations of enrolled participants were measured using commercial enzyme-linked immunosorbent assay. Concentrations were classified as: indicative of current/recent infection if ⩾100 IU/ml, indicative of recent exposure to Bordetella pertussis within the last year if 40-100 IU/ml and less likely revealing a recent exposure to B. pertussis if <40 IU/ml. Between March and June 2018, a total of 304 participants (mean age: 9.3 years) were included in this study. Overall, 12.8% (95% confidence interval (CI) 9.1%-16.6%) were seropositive (IgG levels ⩾40 IU/ml). Among them, 14.7% (95% CI 2.3%-23.3%) had levels indicative of a current/recent infection. The multivariate Poisson regression analysis suggested associations between female gender, as well as age group 13-18 years and 3-5 years and higher anti-PT IgG concentrations. Our results are consistent with the notion that vaccine-induced immunity decline, as well as circulation of pertussis among school children and adolescents enables them to be reservoirs of infection and disease transmission to vulnerable infants. Booster dose of acellular pertussis vaccine for school entrants is therefore recommended.
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Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Toxina del Pertussis/inmunología , Tos Ferina/epidemiología , Adolescente , Niño , Preescolar , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Estudios Seroepidemiológicos , Túnez/epidemiologíaRESUMEN
Clostridium perfringens type A is the causative agent of gas gangrene and gastroenteric ("yellow lamb disease") disease in ruminants, with C. perfringens alpha toxin (CPA) being the main virulence factor in the pathogenesis of these illnesses. In the present study, we have developed recombinant Escherichia coli bacteria expressing rCPA and used it to vaccinate rabbits and sheep. Doses of up to 200⯵g of rCPA used for inoculation, induced 13.82 IU.mL-1 of neutralizing antitoxin in rabbits, which is three times higher than that recommended by the USDA (4 IU.mL-1). In sheep, recombinant bacteria induced antitoxin titers of 4 IU.mL-1, 56 days after the first dose. rCPA which was expressed, mainly, in inclusion bodies, was not found to influence the immunogenicity of the vaccine. The recombinant Escherichia coli bacterin, produced simply and safely, is capable of affording protection against diseases caused by C. perfringens CPA. The current findings represent a novel production method for CPA vaccines potentially applicable to veterinary medicine.
Asunto(s)
Toxinas Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Proteínas de Unión al Calcio/inmunología , Infecciones por Clostridium/veterinaria , Portadores de Fármacos , Escherichia coli/genética , Fosfolipasas de Tipo C/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Toxinas Bacterianas/genética , Vacunas Bacterianas/administración & dosificación , Proteínas de Unión al Calcio/genética , Infecciones por Clostridium/prevención & control , Conejos , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Ovinos , Fosfolipasas de Tipo C/genética , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunologíaRESUMEN
Regardless of the communal impact of Shiga toxins, till today neither a specific treatment nor licensed vaccine is available. Lactococcus lactis (L. lactis), generally regarded as safe organism, is well known to provide a valuable approach regarding the oral delivery of vaccines. This study was undertaken to evaluate the protective efficacy of Stx2a1 expressed in nisin-inducible L. lactis, against Shiga toxins (Stx1, Stx2) in mouse model. Oral immunization of BALB/c mice with LL-Stx2a1 elicited significant serum antibody titer with elevated fecal and serum IgA, along with minimized intestinal and kidney damage resulting in survival of immunized animals at 84% and 100% when challenged with 10 × LD50 of Escherichia coli O157 and Shigella dysenteriae toxins, respectively. HeLa cells incubated with immune sera and toxin mixture revealed high neutralizing capacity with 90% cell survivability against both the toxins. Mice immunized passively with both toxins and antibody mixture survived the observation period of 15 days, and the controls administered with sham sera and toxins were succumbed to death within 3 days. Our results revealed protective efficacy and toxin neutralization ability of LL-Stx2a1, proposing it as an oral vaccine candidate against Shiga toxicity mediated by E. coli O157 and S. dysenteriae.
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Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/inmunología , Escherichia coli O157/inmunología , Intoxicación/prevención & control , Toxina Shiga/inmunología , Toxina Shiga/toxicidad , Shigella dysenteriae/inmunología , Administración Oral , Animales , Anticuerpos Antibacterianos/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/sangre , Antitoxinas/administración & dosificación , Antitoxinas/sangre , Vacunas Bacterianas/genética , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Escherichia coli O157/genética , Vectores Genéticos/administración & dosificación , Células HeLa , Humanos , Lactococcus lactis/genética , Ratones , Ratones Endogámicos BALB C , Toxina Shiga/genética , Shigella dysenteriae/genética , Análisis de Supervivencia , Resultado del Tratamiento , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
The aim of this study was to evaluate the titers of neutralizing antibodies in cattle inoculated with multivalent commercial clostridial vaccines containing C. botulinum type C (BoNTC), C. botulinum type D (BoNTD), and C. perfringens epsilon (ETX) toxoids for a period of one year. Cattle (Bos taurus), aged 4-6 months and not previously immunized, were vaccinated under four different protocols at days 0 and 30 and followed over one year. Individual serum titration was performed by a serum neutralization test in mice or in MDCK cells. The number of animals with detectable neutralizing antibodies ranged from 40.6% to 78.1%, but only 12.5% of animals showed neutralizing antibodies against all tested antigens. Neutralizing antibodies were found only until 60 days for ETX, 120 days for BoNTC, and 180 days for BoNTD. The absence of detectable neutralizing antibodies against the three antigens before 360 days, suggests that cattle remained unprotected for a long period before the recommended booster vaccination.
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Toxinas Bacterianas/inmunología , Toxinas Botulínicas/inmunología , Inmunidad Humoral , Toxoides/inmunología , Animales , Antitoxinas/sangre , Bovinos , Perros , Células de Riñón Canino Madin Darby , Ratones , Pruebas de Neutralización , Factores de Tiempo , Toxoides/administración & dosificaciónRESUMEN
BACKGROUND: Protection induced by acellular pertussis (aP) vaccines is partial and short-lived, especially in teenagers, calling for novel immunization strategies. METHODS: We conducted an investigator-driven proof-of-concept randomized controlled trial in aP-primed adolescents in Geneva to assess the immunogenicity and reactogenicity of a novel recombinant aP (r-aP) vaccine including recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) coadministered with tetanus-diphtheria toxoids (Td), compared to a licensed tetanus-diphtheria-aP vaccine containing chemically detoxified PT (cd/Tdap). The primary immunological endpoints were day 28/365 geometric mean concentrations (GMCs) of total and neutralizing anti-PT antibodies. Memory B cells were assessed. RESULTS: Sixty-two aP-primed adolescents were randomized and vaccinated with r-aP + Td or cd/Tdap. Reactogenicity, adverse events, and baseline GMCs were similar between the groups. Day 28 PT-neutralizing GMCs were low after cd/Tdap (73.91 [95% confidence interval {CI}, 49.88-109.52] IU/mL) and approximately 2-fold higher after r-aP + Td (127.68 [95% CI, 96.73-168.53] IU/mL; P = .0162). Anti-PT GMCs were also low after cd/Tdap (52.43 [95% CI, 36.41-75.50] IU/mL) and 2-fold higher after r-aP + Td (113.74 [95% CI, 88.31-146.50] IU/mL; P = .0006). Day 28 anti-FHA GMCs were similar in both groups. Day 365 anti-PT (but not PT-neutralizing) GMCs remained higher in r-aP + Td vaccinees. PT-specific memory B cells increased significantly after r-aP + Td but not cd/Tdap boosting. CONCLUSIONS: Boosting aP-primed adolescents with r-aP induced higher anti-PT and PT-neutralizing responses than cd/Tdap and increased PT-specific memory B cells. Despite this superior immunogenicity, r-aP may have to be given repeatedly, earlier, and/or with novel adjuvants to exert an optimal influence in aP-primed subjects. CLINICAL TRIALS REGISTRATION: NCT02946190.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Inmunización Secundaria/métodos , Toxina del Pertussis/inmunología , Vacuna contra la Tos Ferina/inmunología , Tos Ferina/prevención & control , Adhesinas Bacterianas/genética , Adhesinas Bacterianas/inmunología , Adolescente , Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Subgrupos de Linfocitos B/inmunología , Niño , Femenino , Humanos , Memoria Inmunológica , Masculino , Toxina del Pertussis/genética , Vacuna contra la Tos Ferina/administración & dosificación , Suiza , Vacunas Acelulares/administración & dosificación , Vacunas Acelulares/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Factores de Virulencia de Bordetella/genética , Factores de Virulencia de Bordetella/inmunologíaRESUMEN
BACKGROUND: It is about 4 decades from the identification of Enterohemorrhagic Escherichia coli (EHEC) as a food-borne pathogen. There are many shreds of evidence that the bacteria are significant sources of intestinal infections and outbreaks even in developed countries. Developing an effective vaccine against O157 and non-O157 serotypes of EHEC is a good strategy to combat the bacteria. Raising antibody against main toxicity, adhering and colonizing apparatus of the bacteria using a multi-antigenic protein can be hopefully applicable. MATERIAL AND METHODS: A synthetic cassette consists of HcpA-EspA-Tir-Stx2B (HETS) subunit proteins were constructed and sub-cloned in pET32a (+). The protein was expressed and purified with Ni-NTA column and the BALB/c mice were immunized by the purified protein. HETS protein efficacy to elicit immune responses, O157 fecal shedding and immunity against Stx toxin were assessed. In addition, the cellular assays were performed to investigate the immune sera capability for neutralizing of Stx toxin and bacterial attachment apparatus. RESULTS: The HETS protein (611 amino acid length) was expressed and validated by Western blotting. Exerted EHEC bacteria ratio in the immunized mice was reduced close to 60% in shedding test. Cellular assays revealed that the sera of the immunized animals were able to neutralize Stx holotoxin in an extent of 70%; also, immunized mice were able to tolerate up to 200 LD50 of the active toxin. Moreover, toxin neutralization assay showed the capability of the immunized sera to block the cell adhesion. CONCLUSION: Regarding a lack of an efficient vaccine against EHEC, the proposed candidate immunogen, which consists of main adhesion and invasion factors, can overcome the lack of a vaccine against the bacteria.
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Infecciones por Escherichia coli/prevención & control , Escherichia coli O157/inmunología , Proteínas de Escherichia coli/inmunología , Vacunas contra Escherichia coli/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Anticuerpos Neutralizantes/sangre , Antitoxinas/sangre , Adhesión Bacteriana , Derrame de Bacterias , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/inmunología , Escherichia coli O157/genética , Proteínas de Escherichia coli/administración & dosificación , Proteínas de Escherichia coli/genética , Vacunas contra Escherichia coli/administración & dosificación , Vacunas contra Escherichia coli/genética , Femenino , Ratones Endogámicos BALB C , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaAsunto(s)
Antitoxinas/sangre , Toxinas Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Enfermedades de los Bovinos/prevención & control , Infecciones por Clostridium/veterinaria , Enfermedades de las Ovejas/prevención & control , Toxemia/veterinaria , Animales , Toxinas Bacterianas/administración & dosificación , Toxinas Bacterianas/genética , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/genética , Bovinos , Infecciones por Clostridium/prevención & control , Femenino , Conejos , Ovinos , Toxemia/prevención & control , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
BACKGROUND: The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. METHODS: We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12-17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64-88) participants in the aP(PTgen/FHA) group and 41 (81%, 70-92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1-16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71-93 and 64%, 51-77, respectively) and TdaP(PTgen/FHA) group (75%, 63-87 and 56%, 42-70, respectively) than in the Tdap group (4%, 0-9, p<0·0001, and 28%, 16-41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. INTERPRETATION: A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. FUNDING: BioNet-Asia.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Toxina del Pertussis/inmunología , Vacuna contra la Tos Ferina/inmunología , Adolescente , Asia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Toxina del Pertussis/genética , Vacuna contra la Tos Ferina/administración & dosificación , Vacuna contra la Tos Ferina/efectos adversos , Vacuna contra la Tos Ferina/genética , Seroconversión , Método Simple Ciego , Factores de Tiempo , Vacunas Acelulares/administración & dosificación , Vacunas Acelulares/efectos adversos , Vacunas Acelulares/genética , Vacunas Acelulares/inmunología , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/efectos adversos , Vacunas Combinadas/genética , Vacunas Combinadas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
The epsilon toxin (Etx) produced by Clostridium perfringens type B and D causes severe enterotoxaemia associated with a general edema and neurological alterations, leading to subsequent death and is listed as one of the most lethal toxins. Currently employed vaccines against C. perfringens epsilon toxin include toxoid based vaccines. Use of peptide vaccines has become an interesting approach for vaccination after the successful licensing of peptide vaccines against Haemophilus influenza, Neisseria meningitides and Streptococcus pneumonia that have demonstrated the potential and effectiveness of these vaccines. Therefore, the present study was undertaken to develop a peptide based vaccine against epsilon toxin. Peptides were selected on the basis of epitope mapping by making 35 overlapping peptides of 15 amino acid residues in length specific to the primary amino acid sequence of the toxin, with a 7 amino acid residues overlaps between sequential peptides. Chemically synthesized peptides that were recognised by the antibody against the full length epsilon toxin were further assessed for vaccine potential. The selected peptides were chemically conjugated to partially reduced tetanus toxoid (TT) using of N-succinimidyl-3(2-pyridyldithio) propionate. Immunization of BALB/c mice with TT-peptide conjugates by sub-cutaneous route induced sustained high level mixed immune response as analyzed by antibody isotyping. Immunoblot analysis and ELISA clearly indicated generation of Etx-specific antibodies. Further, neutralization studies with the antisera generated against the TT-conjugated peptide(s) demonstrated that the antisera were able to neutralize the lethal dose of epsilon toxin in vitro demonstrating its potential as a promising vaccine candidate against enterotoxaemia.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Toxinas Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Toxoide Tetánico/farmacología , Toxemia/prevención & control , Adyuvantes Inmunológicos/química , Animales , Anticuerpos Antibacterianos/sangre , Anticuerpos Neutralizantes/sangre , Antitoxinas/sangre , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/síntesis química , Vacunas Bacterianas/genética , Infecciones por Clostridium/prevención & control , Ensayo de Inmunoadsorción Enzimática , Femenino , Immunoblotting , Inyecciones Subcutáneas , Ratones Endogámicos BALB C , Pruebas de Neutralización , Toxoide Tetánico/química , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/química , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
Many countries including Japan have adapted acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP). DTaP vaccine coverage is approximately >90%, but pertussis re-emergence has been observed since 2000 in Japan. In the present study, anti-pertussis antibodies were investigated among school-age children and adolescents from 2013 to 2015. The positive rate of anti-pertussis toxin (PT) antibodies was higher among children aged 12-13â¯years (60.0%. 95%CI; 56.0-63.9%) in 2014 and 18-19â¯years (73.0%. 95%CI; 61.4-82.6%) in 2013, compared with 6-7â¯years (47.1%. 95%CI; 40.7-53.6%). The mean PT antibody titer was higher among children aged 12-13â¯years (23.8â¯EU/ml. 95%CI; 21.9-25.8) in 2014 and 18-19â¯years (29.3â¯EU/ml. 95%CI; 23.0-35.6) in 2013, compared with 6-7â¯years (18.3â¯EU/ml. 95%CI; 15.5-21.2). Distributions of pertussis antibodies and mean titers at their same grade of school-age were similar from 2013 to 2015. Although school-age children were immunized with 4 doses of DTaP, the data suggested the decay of vaccine-acquired immunity and possibility of asymptomatic infection in school age, indicating the additional DTaP vaccination before the entry of elementary school, preventing household contact.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/administración & dosificación , Toxina del Pertussis/inmunología , Tos Ferina/epidemiología , Tos Ferina/inmunología , Adolescente , Factores de Edad , Niño , Femenino , Humanos , Japón/epidemiología , Masculino , Encuestas y Cuestionarios , Tos Ferina/prevención & control , Adulto JovenRESUMEN
BACKGROUND: Increasing evidence shows that protection induced by acellular pertussis vaccines is short-lived, requiring repeated booster vaccination to control pertussis disease. We aimed to assess the safety and immunogenicity of a recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin and filamentous haemagglutinin, as either a monovalent vaccine (aP[PTgen/FHA]) or in combination with tetanus and reduced-dose diphtheria vaccines (TdaP[PTgen/FHA]), versus a licensed tetanus and reduced-dose diphtheria and acellular pertussis combination vaccine (Tdap). METHODS: We did this phase 2/3, randomised controlled non-inferiority trial at two sites in Bangkok, Thailand. Healthy adolescents (aged 12-17 years) were randomly assigned (1:1:1), via a computer-generated randomisation list with block sizes of three, to receive one dose (0·5 mL) of aP(PTgen/FHA), TdaP(PTgen/FHA), or Tdap (comparator). Clinical research staff responsible for participant randomisation, vaccine preparation and administration, and accountability were aware of group allocation. However, allocation was concealed from all other site study staff, data management personnel, statisticians, laboratory staff, and study participants. The primary outcome was non-inferior immunogenicity of TdaP(PTgen/FHA) to Tdap based on seroconversion rates (a four-fold increase or more) for pertussis toxin and filamentous haemagglutinin IgG antibodies 28 days after vaccination, with a predefined 10% margin of equivalence. We did analysis by per protocol. This study is registered with the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between July 6 and Aug 20, 2015, we allocated 450 participants to receive one dose of TdaP(PTgen/FHA) (n=150), aP(PTgen/FHA) (n=150), or comparator Tdap (n=150). 28 days after vaccination, seroconversion rates for anti-pertussis toxin IgG were 96·6% (95% CI 93·8-99·5; n=144) in the TdaP(PTgen/FHA) group and 55·0% (47·1-63·0; n=82) in the comparator Tdap group (difference 41·6%, 95% CI 33·1-50·1; p<0·0001). Seroconversion rates for anti-filamentous haemagglutinin were 82·6% (95% CI 76·5-88·6; n=123) in the TdaP(PTgen/FHA) group and 54·4% (46·4-62·4; n=81) in the comparator group (difference 28·2%, 95% CI 18·1-38·2 p<0·0001). 28 days after vaccination, seroconversion rates in the aP(PTgen/FHA) group were 96·0% (95% CI 92·8-99·1; n=142) for anti-pertussis toxin IgG and 93·2% (89·2-97·3; n=138) for anti-filamentous haemagglutinin IgG. These findings support the non-inferior immunogenicity of TdaP(PTgen/FHA) over comparator Tdap. Reactogenicity and incidence of adverse events were similar between groups. INTERPRETATION: The new TdaP(PTgen/FHA) vaccine is safe and induces higher pertussis responses 28 days after vaccination than does the available licensed Tdap booster vaccine. Results of our trial led to the licensure of new acellular pertussis vaccines containing genetically inactivated pertussis toxin in Thailand. The availability of recombinant monovalent pertussis vaccines that induce high antibody responses provides the medical community and consumers with the opportunity to vaccinate against pertussis when immunisation against diphtheria and tetanus is not required or not desired. Studies are underway to pave the way for licensure studies of this acellular pertussis vaccine in other countries. FUNDING: BioNet-Asia.
Asunto(s)
Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/administración & dosificación , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/inmunología , Tos Ferina/prevención & control , Adolescente , Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Niño , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Voluntarios Sanos , Humanos , Masculino , Tailandia , Resultado del Tratamiento , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunologíaRESUMEN
Clostridium difficile is the number one cause of nosocomial antibiotic-associated diarrhea in developed countries. Historically, pathogenesis was attributed two homologous glucosylating toxins, toxin-A (TcdA) and toxin-B (TcdB). Over the past decade, however, highly virulent epidemic strains of C. difficile (B1/NAP1/027) have emerged and are linked to an increase in morbidity and mortality. Increased virulence is attributed to multiple factors including: increased production of A- and B-toxins; production of binary toxin (CDT); and the emergence of more toxic TcdB variants (TcdB(027)). TcdB(027) is more cytotoxicity to cells; causes greater tissue damage and toxicity in animals; and is antigenically distinct from historical TcdB (TcdB(003)). Broadly protective vaccines and therapeutic antibody strategies, therefore, may target TcdA, TcdB variants and CDT. To facilitate the generation of multivalent toxin-based C. difficile vaccines and therapeutic antibodies, we have generated fusion proteins constructed from the receptor binding domains (RBD) of TcdA, TcdB(003), TcdB(027) and CDT. Herein, we describe the development of a trivalent toxin (T-toxin) vaccine (CDTb/TcdB(003)/TcdA) and quadravalent toxin (Q-toxin) vaccine (CDTb/TcB(003)/TcdA/TcdB(027)) fusion proteins that retain the protective toxin neutralizing epitopes. Active immunization of mice or hamsters with T-toxin or Q-toxin fusion protein vaccines elicited the generation of toxin neutralizing antibodies to each of the toxins. Hamsters immunized with the Q-toxin vaccine were broadly protected against spore challenge with historical C. difficile 630 (toxinotype 0/ribotype 003) and epidemic NAP1 (toxinotype III/ribotype 027) strains. Fully human polyclonal antitoxin IgG was produced by immunization of transgenic bovine with these fusion proteins. In passive transfer studies, mice were protected against lethal toxin challenge. Hamsters treated with human antitoxin IgG were completely protected when challenged with historical or epidemic strains of C. difficile. The use of chimeric fusion proteins is an attractive approach to producing multivalent antitoxin vaccines and therapeutic polyclonal antibodies for prevention and treatment of C. difficile infections (CDI).
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Vacunas Bacterianas/inmunología , Clostridioides difficile/inmunología , Infecciones por Clostridium/prevención & control , Protección Cruzada , Inmunotoxinas/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/uso terapéutico , Antitoxinas/sangre , Antitoxinas/uso terapéutico , Toxinas Bacterianas/genética , Toxinas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/genética , Clostridioides difficile/genética , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/uso terapéutico , Inmunotoxinas/genética , Masculino , Mesocricetus , Ratones Endogámicos C57BL , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Resultado del Tratamiento , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
Botulinum toxin is the most poisonous substance known, and is believed to be a highly lethal as a biological weapon; researchers of the toxin are exposed to this hazard. Botulinum toxoid vaccines have been produced and used in Japan. However, since clinical studies involving these vaccines were conducted before establishment of the Ethical Guidelines for Clinical Research in Japan, their immunogenicity and safety were not systematically assessed. In this study, we produced a new tetravalent (type A, B, E, and F) botulinum toxoid vaccine, the first ever to be derived from M toxin, and conducted quality control tests with reference to the Minimum Requirements in Japan for adsorbed tetanus toxoid vaccine. Subsequently, a clinical study using the new vaccine in 48 healthy adult volunteers was conducted according to the guidelines in Japan. No clinically serious adverse event was noted. Neutralizing antibody titers for each type of toxin in the participants' sera, 1 month after the 4th injection were more than 0.25 IU/mL, indicating sufficient protection. This study demonstrated that the vaccine has marked immunogenicity and is safe for use in humans.
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Vacunas Bacterianas/inmunología , Toxinas Botulínicas/inmunología , Botulismo/prevención & control , Toxoides/inmunología , Adulto , Animales , Antitoxinas/sangre , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/efectos adversos , Vacunas Bacterianas/aislamiento & purificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Cobayas , Voluntarios Sanos , Humanos , Japón , Masculino , Ratones , Persona de Mediana Edad , Toxoides/administración & dosificación , Toxoides/efectos adversos , Toxoides/aislamiento & purificación , Resultado del Tratamiento , Adulto JovenRESUMEN
The use of Soluplus® polymeric micelles as a novel adjuvant for tetanus toxoid (TTxd) in transcutaneous immunisation was evaluated. TTxd was added to Soluplus® polymeric micelles to form TTxd-Soluplus® nano-aggregates with a size of 68nm. Non-adjuvanted TTxd commonly induces very poor antibody response by the transcutaneous route. However, in this study, the use of TTxd-Soluplus® resulted in a significant increase in the antibody response to TTxd, which was similar to that induced in the presence of CPG-oligodeoxynucleotides (CPG-ODNs) adjuvant. The toxin neutralising potency of the immune sera induced by TTxd-Soluplus® was also much stronger than that from TTxd alone, in a passive transfer experiment in mice. Soluplus® also enhanced the immunogenicity of the toxoid when TTxd-Soluplus® was stored at 4°C for 4weeks, but not at higher temperatures. Confocal microscopy imaging showed a much higher uptake of TTxd in the epidermis and dermis layers of the skin when it was associated with Soluplus®, suggesting that the mechanism for Soluplus® adjuvanticity is through enhanced uptake of the TTxd through the skin. Overall, our findings demonstrated that Soluplus® is an effective novel adjuvant for transcutaneous immunisation.
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Adyuvantes Inmunológicos/administración & dosificación , Formación de Anticuerpos , Antitoxinas/sangre , Nanopartículas/administración & dosificación , Polietilenglicoles/administración & dosificación , Polivinilos/administración & dosificación , Toxoide Tetánico/inmunología , Administración Cutánea , Animales , Anticuerpos Neutralizantes/sangre , Modelos Animales de Enfermedad , Femenino , Inmunización Pasiva , Ratones , Ratas Sprague-Dawley , Tétanos/prevención & control , Toxoide Tetánico/administración & dosificaciónRESUMEN
Anthrax is caused by Bacillus anthracis, a zoonotic bacterial pathogen affecting humans and livestock worldwide. The current human anthrax vaccine, anthrax vaccine adsorbed (AVA), is an injected vaccine with a cumbersome administration schedule and fails to promote mucosal immunity. Bacterial enterotoxins, which stimulate production of the cyclic nucleotide cAMP are effective experimental mucosal vaccine adjuvants, but their inherent toxicity has precluded their use in humans. We investigated whether cyclic dinucleotides that target Stimulator of Interferon Gamma Genes (STING) in mammalian cells could represent an alternative to bacterial enterotoxins as adjuvant for sublingual immunization and promotion of mucosal immunity and secretory IgA responses in addition to systemic immunity. We found that sublingual immunization of mice with Bacillus anthracis protective antigen (PA) and the STING ligand 3'3'-cGAMP promotes PA-specific serum IgG Ab responses of the same magnitude as those induced after immunization with PA and the experimental adjuvant cholera toxin (CT). Interestingly, this STING ligand also promoted serum anti-PA IgA and IgA-producing cells in the bone marrow. Furthermore, the saliva of mice immunized with the STING ligand exhibited similar levels of PA-specific IgA Abs as groups immunized with CT as adjuvant. The adjuvant activity of 3'3'-cGAMP was associated with mixed Th1, Th2, and Th17 responses. This STING ligand also induced rapid IFN-ß and IL-10 responses in sublingual tissues and cervical lymph nodes, and TGF-ß responses in the cervical lymph nodes, which could contribute to promoting IgA responses after sublingual immunization.
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Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra el Carbunco/inmunología , Antígenos Bacterianos/inmunología , Toxinas Bacterianas/inmunología , Proteínas de la Membrana/metabolismo , Nucleótidos Cíclicos/administración & dosificación , Administración Sublingual , Animales , Vacunas contra el Carbunco/administración & dosificación , Antígenos Bacterianos/administración & dosificación , Antitoxinas/sangre , Toxinas Bacterianas/administración & dosificación , Citocinas/metabolismo , Femenino , Inmunidad Mucosa , Inmunoglobulina A/análisis , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Leucocitos Mononucleares/inmunología , Ganglios Linfáticos/inmunología , Ratones Endogámicos C57BL , Saliva/inmunologíaRESUMEN
This study aimed to investigate serologic immunity to diphtheria and tetanus in army personnel and a sample population of adult civilians in Mashhad, Iran. Army personnel (n = 180) and civilians (n = 83) who presented at Mashhad army hospital participated in this study. Diphtheria and tetanus antitoxin levels were determined by enzyme-linked immunosorbent assay. Approximately 77% and 94% of army personnel aged 18-34 years had at least basic protection against diphtheria (antitoxin level ≥0.1 IU/mL) and tetanus (antitoxin level >0.1 IU/mL), respectively. For civilians in this age group, the proportions were 76% for both diseases. Antitoxin levels waned with age. Thus, participants older than 50 years had lower immunity; this decrease in immunity was more pronounced for tetanus than for diphtheria in both army personnel and civilians. For both diseases, geometric mean antitoxin titers and the proportion of participants with at least basic protection were higher in subjects with a history of vaccination in the last 10 years (P < 0.001), higher in men than women, and in army personnel than civilians in each age group. Young army personnel and civilians (18-34 years old) had adequate immunity to diphtheria and tetanus. However, the large number of susceptible older adults (>50 years old) calls for improved booster vaccination protocols.
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Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Difteria/inmunología , Tétanos/inmunología , Adolescente , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Irán , Masculino , Persona de Mediana Edad , Personal Militar , Estudios Seroepidemiológicos , Adulto JovenRESUMEN
PURPOSE: This study was planned to collect evidences of familial pertussis transmission to infants younger than 6 months of age. Understanding the dynamics of transmission of pertussis in families is essential to plan effective prevention strategies that could be integrated in pertussis control. METHODS: The seroprevalence of IgG antibodies to pertussis toxin (PT-IgG) and prolonged cough symptoms were evaluated in parents of 55 infants aged <6 months hospitalized for confirmed pertussis. Parents of 33 infants with lower respiratory tract infection (LRTI) and parents of 57 healthy infants admitted as outpatients for hip ultrasound examination (HE) were enrolled as controls. RESULTS: Parents of pertussis cases had PT-IgG levels significantly higher as compared to LRTI and HE parents. More than 40 % were compatible as transmitters of pertussis to their babies, since they had a level of PT-IgG ≥ 100 IU/ml, which is considered diagnostic for a recent pertussis episode. Based on serology, the percentage of pertussis cases that had at least one parent as source of infection was 49.1 %. When cough symptoms were taken into account, the percentage of parents putative transmitters of the infection to their infants increased to 56.4 %. CONCLUSIONS: Parents are scarcely aware of the household transmission of pertussis to their newborns. Our study highlights the need to advise parents about the likelihood of transmission to the newborn and to be particularly aware of coughing symptoms in the household. Since infection can be asymptomatic, a serological survey of family members should also be considered.
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Salud de la Familia , Transmisión Vertical de Enfermedad Infecciosa , Padres , Tos Ferina/transmisión , Anticuerpos Antibacterianos/sangre , Antitoxinas/sangre , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina G/sangre , Lactante , Recién Nacido , Masculino , Estudios SeroepidemiológicosRESUMEN
PURPOSE: This report describes the safety, immunogenicity, and pharmacokinetic results of obiltoxaximab treatment in healthy subjects from 5 clinical trials. METHODS: Healthy men and women were enrolled in randomized, double-blind studies of obiltoxaximab versus placebo (studies 1-3), an open-label, parallel-group study of obiltoxaximab alone versus obiltoxaximab and ciprofloxacin (study 4), or a randomized, double-blind, placebo-controlled study involving administration of a second dose of obiltoxaximab 13 or 119 days after an initial dose (study 5). Obiltoxaximab was administered intravenously in all studies. The safety profile was characterized by physical examinations, including focused examinations of the skin and infusion sites; study drug infusion discontinuations; and assessment of adverse events, vital signs, electrocardiographic findings, laboratory parameters, and immunogenicity. Studies 3 to 5 were the primary safety profile studies. Pharmacokinetic parameters were calculated using noncompartmental methods. FINDINGS: Results of 2 multiple dose studies (studies 1 and 2) revealed that obiltoxaximab exposure increased proportionally. Pharmacokinetic results were consistent across studies. After administration of 16 mg/kg of obiltoxaximab, serum concentrations decreased in a biexponential or multiexponential fashion with a terminal half-life of 17 to 23 days. Mean volume of distribution was approximately 6.3 to 7.5 L, suggesting obiltoxaximab distribution outside the vascular compartment and potentially into tissues. Mean systemic clearance was approximately 0.27 L/d, suggesting that hepatic metabolism and/or renal excretion are not critical to obiltoxaximab elimination. Obiltoxaximab was generally well tolerated. Hypersensitivity reactions were the most common adverse reactions in the safety profile clinical trials, occurring in 34 of 320 subjects (10.6%) receiving obiltoxaximab and 4 of 70 subjects (5.7%) receiving placebo. The most common adverse events were headache, pruritus, upper respiratory tract infection, cough, infusion site swelling, bruising and/or pain, nasal congestion, urticaria, and extremity pain. Of the 320 subjects in the primary safety profile studies who received ≥1 dose of 16 mg/kg of obiltoxaximab, 8 (2.5%) tested positive for a exposure-emergent antiobiltoxaximab response; however, quantitative titers were low (1:20-1:320). IMPLICATIONS: On the basis of consistent results of 5 clinical trials in healthy volunteers, the pharmacokinetic properties of obiltoxaximab after a 16-mg/kg IV infusion can be considered adequately characterized, a criteria of the Animal Rule. Obiltoxaximab appears to be generally well tolerated. ClinicalTrials.gov identifiers: NCT00829582, NCT01453907, NCT01929226, NCT01952444, NCT01932242.
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Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/sangre , Antitoxinas/efectos adversos , Antitoxinas/sangre , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Antitoxinas/administración & dosificación , Área Bajo la Curva , Método Doble Ciego , Esquema de Medicación , Hipersensibilidad a las Drogas/etiología , Femenino , Semivida , Cefalea/inducido químicamente , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Anthrax vaccines containing recombinant PA (rPA) as the only antigen face a stability issue: rPA forms aggregates in solution after exposure to temperatures ⩾40°C, thus losing its ability to form lethal toxin (LeTx) with Lethal Factor. To study rPA aggregation's impact on immune response, we subjected rPA to several time and temperature combinations. rPA treated at 50°C for 30min formed high mass aggregates when analyzed by gel electrophoresis and failed to form LeTx as measured by a macrophage lysis assay (MLA). Aggregated rPA-formed LeTx was about 30 times less active than LeTx containing native rPA. Mice immunized with heat-treated rPA combined with Al(OH)3 developed antibody titers about 49 times lower than mice immunized with native rPA, as measured by a Toxicity Neutralization Assay (TNA). Enzyme Linked Immunosorbent Assay (ELISA) of the same immune sera showed anti-rPA titers only 2-7 times lower than titers elicited by native rPA. Thus, rPA's ability to form LeTx correlates with its production of neutralizing antibodies, and aggregation significantly impairs the protein's antibody response. However, while these findings suggest MLA has some value as an in-process quality test for rPA in new anthrax vaccines, they also confirm the superiority of TNA for use in vaccine potency.