المؤلفون: Lima CP; Laboratory of Biopharmaceuticals, Butantan Institute, Sao Paulo 05503-900, Brazil.; Interunits Graduate Program in Biotechnology, University of Sao Paulo, Sao Paulo 05508-270, Brazil., Barreiros GM; Laboratory of Biopharmaceuticals, Butantan Institute, Sao Paulo 05503-900, Brazil.; Interunits Graduate Program in Biotechnology, University of Sao Paulo, Sao Paulo 05508-270, Brazil., Oliveira ASA; Laboratory of Biopharmaceuticals, Butantan Institute, Sao Paulo 05503-900, Brazil., de Souza MM; CENTD-Centre of Excellence in New Target Discovery, Butantan Institute, São Paulo 05503-900, Brazil., Manieri TM; Laboratory of Biopharmaceuticals, Butantan Institute, Sao Paulo 05503-900, Brazil.; CeRDI-Center for Research and Development in Immunobiologicals, Butantan Institute, São Paulo 05503-900, Brazil., Moro AM; Laboratory of Biopharmaceuticals, Butantan Institute, Sao Paulo 05503-900, Brazil.; CeRDI-Center for Research and Development in Immunobiologicals, Butantan Institute, São Paulo 05503-900, Brazil.

المصدر: International journal of molecular sciences [Int J Mol Sci] 2024 May 26; Vol. 25 (11). Date of Electronic Publication: 2024 May 26.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

مواضيع طبية MeSH: Neurons*/metabolism , Antibodies, Monoclonal*/immunology , Endocytosis* , Tetanus Toxin*/immunology , Tetanus Toxin*/metabolism , Molecular Docking Simulation*, Animals ; Rats ; Humans ; Tetanus/prevention & control ; Tetanus/immunology ; Epitopes/immunology ; Gangliosides/immunology ; Gangliosides/metabolism ; Cells, Cultured ; Computer Simulation ; Metalloendopeptidases

مستخلص: Tetanus disease, caused by C. tetani , starts with wounds or mucous layer contact. Prevented by vaccination, the lack of booster shots throughout life requires prophylactic treatment in case of accidents. The incidence of tetanus is high in underdeveloped countries, requiring the administration of antitetanus antibodies, usually derived from immunized horses or humans. Heterologous sera represent risks such as serum sickness. Human sera can carry unknown viruses. In the search for human monoclonal antibodies (mAbs) against TeNT (Tetanus Neurotoxin), we previously identified a panel of mAbs derived from B-cell sorting, selecting two nonrelated ones that binded to the C-terminal domain of TeNT (HCR/T), inhibiting its interaction with the cellular receptor ganglioside GT1b. Here, we present the results of cellular assays and molecular docking tools. TeNT internalization in neurons is prevented by more than 50% in neonatal rat spinal cord cells, determined by quantitative analysis of immunofluorescence punctate staining of Alexa Fluor 647 conjugated to TeNT. We also confirmed the mediator role of the Synaptic Vesicle Glycoprotein II (SV2) in TeNT endocytosis. The molecular docking assays to predict potential TeNT epitopes showed the binding of both antibodies to the HCR/T domain. A higher incidence was found between N1153 and W1297 when evaluating candidate residues for conformational epitope.

المؤلفون: Li BL; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China., Wang JR; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China., Liu XY; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China.; Pharmaceutical College, Henan University, Kaifeng, 475001, China., Lu JS; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China., Wang R; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China., Du P; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China., Yu S; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China., Pang XB; Pharmaceutical College, Henan University, Kaifeng, 475001, China. pxb0411@163.com., Yu YZ; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China. yunzhouyu@163.com., Yang ZX; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, 20 Dongdajie Street, Beijing, 100071, China. yy_xiao@126.com.

المصدر: Applied microbiology and biotechnology [Appl Microbiol Biotechnol] 2023 Dec; Vol. 107 (23), pp. 7197-7211. Date of Electronic Publication: 2023 Sep 23.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Springer International Country of Publication: Germany NLM ID: 8406612 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0614 (Electronic) Linking ISSN: 01757598 NLM ISO Abbreviation: Appl Microbiol Biotechnol Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus Toxin*/genetics , Tetanus Toxin*/metabolism , Botulinum Toxins, Type A*/genetics , Botulinum Toxins, Type A*/metabolism, Animals ; Protein Binding ; Antibodies, Neutralizing ; Vaccines, Subunit/genetics

مستخلص: Tetanus toxin (TeNT) and botulinum neurotoxins (BoNTs) are neuroprotein toxins, with the latter being the most toxic known protein. They are structurally similar and contain three functional domains: an N-terminal catalytic domain (light chain), an internal heavy-chain translocation domain (HN domain), and a C-terminal heavy chain receptor binding domain (Hc domain or RBD). In this study, fusion functional domain molecules consisting of the TeNT RBD (THc) and the BoNT/A RBD (AHc) (i.e., THc-Linker-AHc and AHc-Linker-THc) were designed, prepared, and identified. The interaction of each Hc domain and the ganglioside receptor (GT1b) or the receptor synaptic vesicle glycoprotein 2 (SV2) was explored in vitro. Their immune response characteristics and protective efficacy were investigated in animal models. The recombinant THc-linker-AHc and AHc-linker-THc proteins with the binding activity had the correct size and structure, thus representing novel subunit vaccines. THc-linker-AHc and AHc-linker-THc induced high levels of specific neutralizing antibodies, and showed strong immune protective efficacy against both toxins. The high antibody titers against the two novel fusion domain molecules and against individual THc and AHc suggested that the THc and AHc domains, as antigens in the fusion functional domain molecules, do not interact with each other and retain their full key epitopes responsible for inducing neutralizing antibodies. Thus, the recombinant THc-linker-AHc and AHc-linker-THc molecules are strong and effective bivalent biotoxin vaccines, protecting against two biotoxins simultaneously. Our experimental design will be valuable to develop recombinant double-RBD fusion molecules as potent bivalent subunit vaccines against bio-toxins. KEY POINTS: • Double-RBD fusion molecules from two toxins had the correct structure and activity. • THc-linker-AHc and AHc-linker-THc efficiently protected against both biotoxins. • Such bivalent biotoxin vaccines based on the RBD are a valuable experimental design.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

المؤلفون: Liu XY; Pharmaceutical College, Henan University, Kaifeng 475001, China; Beijing Institute of Biotechnology, Beijing 100071, China., Wei DK; Pharmaceutical College, Henan University, Kaifeng 475001, China; Beijing Institute of Biotechnology, Beijing 100071, China., Li ZY; Pharmaceutical College, Henan University, Kaifeng 475001, China; Beijing Institute of Biotechnology, Beijing 100071, China., Lu JS; Beijing Institute of Biotechnology, Beijing 100071, China., Xie XM; Pharmaceutical College, Henan University, Kaifeng 475001, China. Electronic address: xxm@vip.henu.edu.cn., Yu YZ; Beijing Institute of Biotechnology, Beijing 100071, China. Electronic address: yunzhouyu@163.com., Pang XB; Pharmaceutical College, Henan University, Kaifeng 475001, China. Electronic address: pxb0411@163.com.

المصدر: Vaccine [Vaccine] 2023 Nov 02; Vol. 41 (46), pp. 6834-6841. Date of Electronic Publication: 2023 Oct 08.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 8406899 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2518 (Electronic) Linking ISSN: 0264410X NLM ISO Abbreviation: Vaccine Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus Toxin*/immunology , Antibodies, Neutralizing*/immunology , Antibodies, Bacterial*/immunology , Antibodies, Bacterial*/blood , Tetanus*/prevention & control , Tetanus*/immunology, Animals ; Mice ; Female ; Mice, Inbred BALB C ; Peptide Fragments/immunology

مستخلص: Tetanus toxin (TeNT) is a protein toxin produced by Clostridium tetani bacteria, which causes hyperreflexia and rhabdomyolysis by spastic paralysis. Like botulinum neurotoxin, TeNT comprises a heavy chain (HC) and a light chain (LC) linked via an interchain disulfide bond, which include the following three functional domains: a receptor-binding domain (Hc), a translocation domain (HN), and a catalytic domain (LC). Herein, we produced and characterized three functional domains of TeNT and three types of TeNT-derived L-HN fragments (TL-HN, TL-GS-HN and TL-2A-HN), which contained L and HN domains but lacked the Hc domain. The immunological effects of these different functional domains or fragments of TeNT were explored in an animal model. Our investigations showed the TL-HN functional fragment provided the best immunoprotection among all the TeNT functional domains. The TL-HN fragment, as a protective antigen, induced the highest levels of neutralizing antibodies, indicating that it might contain some crucial epitopes. Further experiments revealed that the protective effect of TL-HN was superior to that of the THc, TL, or THN fragments, either individually or in combination. Therefore, the TL-HN fragment exerts an important function in immune protection against tetanus toxin, providing a good basis for the development of TeNT vaccines or antibodies, and could serve as a promising subunit vaccine to replace THc or tetanus toxoid (TT).
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)

المؤلفون: Cheng K; Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Lu J; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Guo J; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Wang R; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Chen L; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Wang X; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Jiang Y; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Li Y; Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Xu C; Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Kang Q; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Qiaerxie G; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Du P; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Gao C; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Yu Y; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Yang Z; Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China., Wang W; Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.

المصدر: Human vaccines & immunotherapeutics [Hum Vaccin Immunother] 2024 Dec 31; Vol. 20 (1), pp. 2366641. Date of Electronic Publication: 2024 Jun 27.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101572652 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2164-554X (Electronic) Linking ISSN: 21645515 NLM ISO Abbreviation: Hum Vaccin Immunother Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus Toxin*/immunology , Tetanus*/prevention & control , Tetanus*/immunology , Antibodies, Neutralizing*/immunology , Single-Domain Antibodies*/immunology , Immunoglobulin Heavy Chains*/immunology, Animals ; Mice ; Female ; Camelus/immunology ; Humans ; Antibodies, Bacterial/immunology ; Mice, Inbred BALB C

مستخلص: Tetanus toxin (TeNT) is one of the most toxic proteins. Neutralizing antibodies against TeNT are effective in prevention and treatment. In this study, 14 anti-tetanus nanobodies were obtained from a phage display nanobody library by immunizing a camel with the C-terminal receptor-binding domain of TeNT (TeNT-Hc) as the antigen. After fusion with the human Fc fragment, 11 chimeric heavy-chain antibodies demonstrated nanomolar binding toward TeNT-Hc. The results of toxin neutralization experiments showed that T83-7, T83-8, and T83-13 completely protected mice against 20 × the median lethal dose (LD 50 ) at a low concentration. The neutralizing potency of T83-7, T83-8, and T83-13 against TeNT is 0.4 IU/mg, 0.4 IU/mg and 0.2 IU/mg, respectively. In the prophylactic setting, we found that 5 mg/kg of T83-13 provided the mice with full protection from tetanus, even when they were injected 14 days before exposure to 20 × LD 50 TeNT. T83-7 and T83-8 were less effective, being fully protective only when challenged 7 or 10 days before exposure, respectively. In the therapeutic setting, 12 h after exposure to TeNT, 1 ~ 5 mg/kg of T83-7, and T83-8 could provide complete protection for mice against 5 × LD 50 TeNT, while 1 mg/kg T83-13 could provide complete protection 24 h after exposure to 5 × LD 50 TeNT. Our results suggested that these antibodies represent prophylactic and therapeutic activities against TeNT in a mouse model. The T83-7, T83-8, and T83-13 could form the basis for the subsequent development of drugs to treat TeNT toxicity.

المؤلفون: Mohammadi M; Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.; Department of Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran., Zangooei M; Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Abbasi E; Department of Bacterial Vaccines, Razi Vaccine and Serum Research Institute, Karaj, Iran., Ebrahimi Fana S; Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Aminian M; Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.; Recombinant Vaccine Research Center, Tehran University of Medical Sciences, Tehran, Iran.

المصدر: Journal of immunoassay & immunochemistry [J Immunoassay Immunochem] 2023 May 04; Vol. 44 (3), pp. 283-295. Date of Electronic Publication: 2022 Oct 27.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Taylor & Francis Country of Publication: England NLM ID: 100963688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-4230 (Electronic) Linking ISSN: 15321819 NLM ISO Abbreviation: J Immunoassay Immunochem Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus Toxin*/pharmacology , Immunoglobulins*, Humans ; Animals ; Horses ; Disease Models, Animal ; Electrophoresis, Polyacrylamide Gel

مستخلص: Tetanus is an acute and often fatal infectious disease caused by Clostridium tetani . Tetanus toxin (TT) is responsible for spastic paralysis observed in tetanus. Anti-tetanus antibodies obtained from horses and humans are the most antitoxins used for tetanus treatment, although some clinical side effects and disadvantages have been reported in their application. The aim of this study is the production of anti-TT IgY and evaluation of its protective effects in a mouse model. Anti-TT IgY was purified from the egg yolk using PEG6000 precipitation and water dilution methods, and its purity was verified by SDS-PAGE. Finally, the potency of purified anti-TT IgY in neutralizing the lethal effects of TT was studied in vivo using a mouse model. PEG6000 precipitation method had better results. Animal studies showed that the purified IgY neutralized the toxic effects of 100 MLD of TT and multiple intravenous-dose injections of anti-TT IgY also had a continuous effect of TT neutralization. The purified anti-TT IgY was effective in neutralizing the lethal activity of TT in a mouse model. Our results suggested that IgY could be an alternative therapeutic source for the management of tetanus in the future. Abbreviations Anti-TT, Anti-tetanus toxin; ELISA, Enzyme-linked immunosorbent assay; IgY, Immunoglobulin Y; MLD, Minimum lethal dose; PBS, Phosphate buffer solution; PEG, Polyethylene glycol; SDS-PAGE, Sodium dodecyl sulfate polyacrylamide gel electrophoresis; TIG, Tetanus immune globulin; TT, Tetanus toxin; WD, Water dilution; RT, Room temperature.

المؤلفون: Iwaki M; Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo, Japan; Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan. Electronic address: miwaki@niid.go.jp., Kenri T; Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo, Japan. Electronic address: kenri@niid.go.jp., Senoh M; Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo, Japan. Electronic address: senoh@niid.go.jp.

المصدر: Biologicals : journal of the International Association of Biological Standardization [Biologicals] 2023 May; Vol. 82, pp. 101681. Date of Electronic Publication: 2023 Apr 30.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Academic Press Country of Publication: England NLM ID: 9004494 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-8320 (Electronic) Linking ISSN: 10451056 NLM ISO Abbreviation: Biologicals Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus Toxoid* , Tetanus Toxin*, Mice ; Animals ; Neutralization Tests/methods ; Enzyme-Linked Immunosorbent Assay/methods ; Animal Welfare

مستخلص: For a long time, a widely used method for tetanus toxoid (Ttd) potency has been the challenge test, in which animals are immunized and then challenged with tetanus toxin in lethal or non-lethal way. In the context of animal welfare, an alternative is desired because the method causes unsustainable distress to animals. We aimed to replace the system for describing test results, in which scores are assigned to symptoms exhibited by challenged animals, with scores assigned to antibody ELISA titers in immunized mouse sera. The potency values and confidence intervals calculated by the absorbance score system were equivalent to those calculated by the symptom score system. We also attempted to utilize the raw ELISA absorbance instead of the assigned absorbance score and obtained similar results. ELISA may serve as an alternative to the lethal challenge for Ttd potency tests, not only in Japan but also in other countries in which mouse challenge tests are employed.
Competing Interests: Declaration of competing interest None.
(Copyright © 2023 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

المؤلفون: Li Y; Academy of Military Medical Sciences, Beijing 100080, China., Chen Y; College of Pharmacy, Harbin University of Commerce, Harbin 1500076, China., Cui J; Academy of Military Medical Sciences, Beijing 100080, China., Liu D; College of Pharmacy, Harbin University of Commerce, Harbin 1500076, China., Zhang W; Academy of Military Medical Sciences, Beijing 100080, China., Xue C; Academy of Military Medical Sciences, Beijing 100080, China., Xiong X; Academy of Military Medical Sciences, Beijing 100080, China. Electronic address: xiongxianghua@sina.com., Liu G; Academy of Military Medical Sciences, Beijing 100080, China. Electronic address: jueliu@sohu.com., Chen H; Academy of Military Medical Sciences, Beijing 100080, China. Electronic address: huipengchen@yeah.net.

المصدر: Journal of immunological methods [J Immunol Methods] 2023 Feb; Vol. 513, pp. 113427. Date of Electronic Publication: 2023 Jan 15.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 1305440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7905 (Electronic) Linking ISSN: 00221759 NLM ISO Abbreviation: J Immunol Methods Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus Toxin*/metabolism , Tetanus*/prevention & control, Humans ; Mice ; Animals ; Antibodies, Neutralizing ; Ascites ; Antibodies, Monoclonal ; Epitopes ; Mice, Inbred BALB C

مستخلص: After Clostridium tetani infects the human body, it propagates under anaerobic conditions and produces tetanus neurotoxin (TeNT). TeNT can affect the central nervous system, inhibit the release of neurotransmitters, and result in respiratory failure, which are the root causes of death in tetanus patients. Identifying monoclonal antibodies (mAbs) targeting TeNT with neutralizing activity is urgently needed for the prevention and treatment of tetanus infection. In this study, through immunizing BALB/c mice with tetanus toxoid (TT), we obtained six positive hybridoma cell lines (1A7, 2C7, 3A7, 3H4, 4C1, and 4E12). Antibody isotyping showed that the antibodies are all of the IgG1/κ subclass. Ascites fluid was prepared by allogeneic ascites induction and the antibodies were purified through protein G affinity chromatography columns. Purities of the produced murine mAbs were all greater than 95%. All six antibodies bound to linear epitopes, among which 3A7 bound to the TeNT/L domain and the other five antibodies bound to the TeNT/Hc domain. Moreover, the affinity constants of these six antibodies against the antigen were all in the nanomolar range, and the affinity of 4E12 antibody reached the picomolar range. Results from toxin-neutralization assays in mice showed that 2C7 antibody delayed animal death, while 1A7, 3A7, 3H4, and 4E12 antibodies conferred partial protection. Additionally, 4C1 antibody offered complete protection, as 200 μg of 4C1 antibody fully protected against toxin challenge with 10 LD 50 of TeNT and had a window period of 1 h. Antibody epitope grouping results revealed that the binding epitopes of 4C1 antibody were different from those of the other five antibodies. When 4C1 antibody was used in combination with another antibody, the neutralizing activities of antibodies were all evidently enhanced. Specifically, 4C1 combined with 3A7 antibody led to the greatest improvement in neutralizing activities, and 20 μg antibodies total (10 + 10 μg) fully protected against toxin challenge with 10 LD 50 . When 4E12, 3A7, and 4C1 antibodies were used in combination, 18 μg antibodies total (6 + 6 + 6 μg) completely neutralized 10 LD 50 toxin. The present study derived murine mAbs with neutralizing activities and laid the foundation for follow-up therapeutic drug development for TeNT poisoning as well as establishment of TeNT detection methods.
Competing Interests: Declaration of Competing Interest No potential conflicts of interest were disclosed.
(Copyright © 2023. Published by Elsevier B.V.)

المؤلفون: Nakano T; Professor, Department of Pediatrics, Kawasaki Medical School, Japan., Hasegawa M; Mitsubishi Tanabe Pharma Corporation, Japan., Endo M; Mitsubishi Tanabe Pharma Corporation, Japan., Matsuda K; Clinical Development Department, Clinical Development Section, The Research Foundation for Microbial Diseases of Osaka University, Japan. Electronic address: clinicaldevelopment@mail.biken.or.jp., Tamai H; Clinical Development Department, Clinical Development Section, The Research Foundation for Microbial Diseases of Osaka University, Japan.

المصدر: Vaccine [Vaccine] 2024 Apr 30; Vol. 42 (12), pp. 3134-3143. Date of Electronic Publication: 2024 Apr 06.

نوع المنشور: Randomized Controlled Trial; Multicenter Study; Clinical Trial, Phase III; Journal Article

بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 8406899 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2518 (Electronic) Linking ISSN: 0264410X NLM ISO Abbreviation: Vaccine Subsets: MEDLINE

مواضيع طبية MeSH: Haemophilus influenzae type b* , Tetanus*/prevention & control , Diphtheria*/prevention & control , Whooping Cough*/prevention & control , Poliomyelitis*/prevention & control , Haemophilus Vaccines*, Infant ; Humans ; Japan ; Tetanus Toxin ; Diphtheria Toxin ; Poliovirus Vaccine, Inactivated ; Immunization Schedule ; Antibodies, Bacterial ; Diphtheria-Tetanus-Pertussis Vaccine ; Vaccines, Combined ; Vaccines, Conjugate

مستخلص: Objective: This study investigated the immunogenicity and safety of a pentavalent vaccine Gobik (DPT-IPV-Haemophilus influenzae type b [Hib]) in healthy Japanese infants aged ≥ 2 and < 43 months using a concomitant vaccination with ActHIB® (Hib) and Tetrabik (DPT-IPV) as a comparator.
Methods: This study was conducted as a phase 3, multicenter, active controlled, assessor-blinded, randomized, parallel-group study. Participants received a total of 4 subcutaneous doses (3 primary immunization doses and a booster dose) of either the experimental drug (DPT-IPV-Hib) or the active comparator (Hib + DPT-IPV). The primary endpoints were the anti-PRP antibody prevalence rate with ≥ 1 μg/mL, and the antibody prevalence rates against pertussis, diphtheria toxin, tetanus toxin, and attenuated poliovirus after the primary immunization.
Results: In 267 randomized participants (133 in the DPT-IPV-Hib group and 134 in the Hib + DPT-IPV group), the antibody prevalence rates after the primary immunization in both groups were 100.0 % and 88.7 % for anti-PRP antibody with ≥ 1 μg/mL, 99.2 % and 98.5 % against diphtheria toxin, and 100.0 % and 99.2 % against tetanus toxin, respectively. The antibody prevalence rates against pertussis and attenuated poliovirus were 100.0 % in both groups. The non-inferiority of the DPT-IPV-Hib group to the Hib + DPT-IPV group was verified for all measured antibodies. In both groups, all the GMTs of antibodies after the primary immunization were higher than those before the first dose, and those after the booster dose were higher than those after the primary immunization. No safety issues were identified.
Conclusion: A single-agent Gobik, the first DPT-IPV-Hib pentavalent vaccine approved in Japan, was confirmed to simultaneously provide primary and booster immunizations against Hib infection, pertussis, diphtheria, tetanus, and poliomyelitis and to have a preventive effect and safety comparable to concomitant vaccination with Hib (ActHIB®) and DPT-IPV quadrivalent vaccine (Tetrabik).
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [As for the conflict of interest in the presentation of this study, the author, Dr. Takashi Nakano, was involved in this study as a medical expert. As the co-authors, Masumi Hasegawa and Mai Endo are employees of Mitsubishi Tanabe Pharma Corporation, and Keiko Matsuda and Hoshio Tamai are employees of the Research Foundation for Microbial Diseases of Osaka University. Dr. Takashi Nakano did not receive any payment from either company other than a lecturer honorarium, a manuscript writing fee, and a supervision fee.].
(Copyright © 2024 The Author(s). Published by Elsevier India Pvt Ltd. All rights reserved.)

المؤلفون: Srivastava V; Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, 305817, India., Godara P; Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, 305817, India., Jena SP; Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, 305817, India., Naik B; Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, 305817, India., Singh S; Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, 305817, India., Prajapati VK; Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi 110021, India., Prusty D; Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, 305817, India. Electronic address: dhaneswarprusty@curaj.ac.in.

المصدر: International journal of biological macromolecules [Int J Biol Macromol] 2024 Mar; Vol. 260 (Pt 2), pp. 129562. Date of Electronic Publication: 2024 Jan 20.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE

مواضيع طبية MeSH: Dengue Virus* , Dengue*/therapy , Dengue*/diagnosis , Severe Dengue*, Humans ; Ligands ; Tetanus Toxin ; Peptides ; Immunotherapy ; Oximes ; Viral Nonstructural Proteins ; Antibodies, Viral

مستخلص: Dengue virus infection has significantly increased, with reported cases soaring from 505,430 in 2000 to 2,809,818 in 2022, emphasizing the need for effective treatments. Among the eleven structural and non-structural proteins of DENV, Non-structural protein 1 (NS1) has emerged as a promising target due to its diverse role in modulating the immune response, inducing vascular leakage, and facilitating viral replication and assembly. Monoclonal antibodies are the sole therapeutics to target NS1, but concerns about their cross-reactivity persist. Given these concerns, our study focuses on designing a novel Peptide Ligand Conjugate (PLC) as a potential alternative immunotherapeutic agent against NS1. This PLC aims to mediate the immune elimination of soluble NS1 and NS1-presenting DENV-infected host cells by pre-existing vaccine-induced immunity. By employing the High Throughput Virtual Screening (HTVS) method, QikProp analysis, and Molecular Dynamics studies, we identified three hits from Asinex Biodesigned Ligands out of 220,177 compounds that show strong binding affinity towards the monoclonal binding site of NS1 protein. After a rigorous analysis of physicochemical characteristics, antigenicity, allergenicity, and toxicity using various servers, we selected two peptides: the minimum epitopic region of the Diphtheria and Tetanus toxins as the peptide components of the PLCs. A non-cleavable, non-reactive oxime linker connected the ligand with the peptide through oxime and amide bonds. DPT vaccine is widely used in dengue-endemic countries, and it has been reported that antibodies titer against MER of Diphtheria toxin and Tetanus toxins persist lifelong in DPT-vaccinated people. Therefore, once the rationally designed PLCs bind to NS1 through the ligands, the peptide will induce an immune response against NS1 by triggering pre-existing DPT antibodies and activating memory cells. This orchestrated immune response will destroy soluble NS1 and NS1-expressing DENV-infected cells, thereby reducing the illness of severe dengue hemorrhagic fever and the DENV infection, respectively. Given the increasing demand for new therapeutics for DENV treatment, further investigation into this novel immune-therapeutic strategy may offer a new avenue for treating mild and severe dengue infections.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)

المؤلفون: Chang MJ; Fina Biosolutions LLC, 9430 Key West Ave, Suite 200, Rockville, MD 20850, United States., Ollivault-Shiflett M; Fina Biosolutions LLC, 9430 Key West Ave, Suite 200, Rockville, MD 20850, United States., Schuman R; Antibody and Immunoassay Consultants, 9430 Key West Ave, Suite 201, Rockville, MD 20850, United States., Ngoc Nguyen S; University of Massachusetts, 240 Thatcher Way, Life Science Laboratories N369, Amherst, MA 01003, United States., Kaltashov IA; University of Massachusetts, 240 Thatcher Way, Life Science Laboratories N369, Amherst, MA 01003, United States., Bobst C; University of Massachusetts, 240 Thatcher Way, Life Science Laboratories N369, Amherst, MA 01003, United States., Rajagopal SP; National Institute for Biological Standards and Control, Medicines and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar EN6 3QG, UK., Przedpelski A; Medical College of Wisconsin, 8701 Watertown Plank Rd., Microbiology and Immunology BSB-2830, Milwaukee, WI 53226, United States., Barbieri JT; Medical College of Wisconsin, 8701 Watertown Plank Rd., Microbiology and Immunology BSB-2830, Milwaukee, WI 53226, United States., Lees A; Fina Biosolutions LLC, 9430 Key West Ave, Suite 200, Rockville, MD 20850, United States.

المصدر: Vaccine [Vaccine] 2022 Aug 19; Vol. 40 (35), pp. 5103-5113. Date of Electronic Publication: 2022 Jul 22.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural

بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 8406899 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2518 (Electronic) Linking ISSN: 0264410X NLM ISO Abbreviation: Vaccine Subsets: MEDLINE

مواضيع طبية MeSH: Tetanus*/prevention & control , Tetanus Toxin*/adverse effects , Tetanus Toxin*/genetics, Animals ; Antibodies, Bacterial ; Carrier Proteins ; Escherichia coli/metabolism ; Mice ; Tetanus Toxoid/adverse effects ; Tetanus Toxoid/genetics ; Vaccines, Conjugate

مستخلص: Tetanus toxoid (TTxd), developed over 100 years ago, is a clinically effective, legacy vaccine against tetanus. Due to the extreme potency of native tetanus toxin, manufacturing and regulatory efforts often focus on TTxd production, standardization, and safety, rather than product modernization. Recently, a genetically detoxified, full-length tetanus toxin protein (8MTT) was reported as a tetanus vaccine alternative to TTxd (Przedpelski et al. mBio, 2020). Here we describe the production of 8MTT in Gor/Met ^TM E. coli, a strain engineered to have an oxidative cytoplasm, allowing for the expression of soluble, disulfide-bonded proteins. The strain was also designed to efficiently cleave N-terminal methionine, the obligatory start amino acid for E. coli expressed proteins. 8MTT was purified as a soluble protein from the cytoplasm in a two-column protocol to > 99 % purity, yielding 0.5 g of purified 8MTT/liter of fermentation broth with low endotoxin contamination, and antigenic purity of 3500 Lf/mg protein nitrogen. Mouse immunizations showed 8MTT to be an immunogenic vaccine and effective as a carrier protein for peptide and polysaccharide conjugates. These studies validate 8MTT as commercially viable and, unlike the heterogenous tetanus toxoid, a uniform carrier protein for conjugate vaccines. The development of a recombinant, genetically detoxified toxin produced in E. coli aligns the tetanus vaccine with modern manufacturing, regulatory, standardization, and safety requirements.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)