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Detoxified pertussis

Geert Leroux-Roels, Maria Lattanzi, Claudia Dovali Solis, Mario Contorni, Marco Costantini, Luca Moraschini, Monia Bardelli, Sylvie Bertholet, Erica Borgogni, Francesca Buricchi, Rocco Cantisani, Elisa Faenzi, Oretta Finco, Rosanna Leuzzi, Mariagrazia Pizza, Domenico Rosa, Francesca Schiavetti, Anja Seubert, Fabiana Spensieri, Gianfranco Volpini, Luisanna Zedda, Giuseppe Del Giudice, Ilaria Galgani
Despite high vaccination coverage worldwide, pertussis has re-emerged in many countries. This randomized, controlled, observer-blind phase I study and extension study in Belgium (March 2012-June 2015) assessed safety and immunogenicity of investigational acellular pertussis vaccines containing genetically detoxified pertussis toxin (PT) (NCT01529645; NCT02382913). 420 healthy adults (average age: 26.8 ± 5.5 years, 60% female) were randomized to 1 of 10 vaccine groups: 3 investigational aP vaccines (containing pertussis antigens PT, filamentous hemagglutinin [FHA] and pertactin [PRN] at different dosages), 6 investigational TdaP (additionally containing tetanus toxoid [TT] and diphtheria toxoid [DT]), and 1 TdaP comparator containing chemically inactivated PT...
January 2, 2018: Human Vaccines & Immunotherapeutics
Michaël Esquerré, Myriam Bouillette-Marussig, Anne Goubier, Marie Momot, Christophe Gonindard, Hélène Keller, Astrid Navarro, Marie-Christine Bissery
BACKGROUND: Prophylactic vaccines are available for women and girls not yet infected with HPV, but women already infected with HPV need a treatment to prevent progression to high-grade cervical lesions and cancer. GTL001 is a bivalent therapeutic vaccine for eradicating HPV-infected cells that contains HPV16 E7 and HPV18 E7 both fused to detoxified adenylate cyclase from Bordetella pertussis, which binds specifically to CD11b+ antigen-presenting cells. This study examined the ability of therapeutic vaccination with GTL001 adjuvanted with topical imiquimod cream to induce functional HPV16 E7- and HPV18 E7-specific CD8+ T cell responses...
2017: PloS One
Marieke E Hoonakker, Lisa M Verhagen, Larissa van der Maas, Arjen Sloots, Coenraad F M Hendriksen
Detoxified pertussis toxin (pertussis toxoid) is a major antigen in acellular pertussis vaccines. Testing these vaccines on the presence of residual pertussis toxin (PTx) and reversion to toxicity is performed by the regulatory required in vivo Histamine Sensitization test (HIST). Lack of mechanistic understanding of the HIST, technical handicaps and animal welfare concerns, have promoted the development of alternative methods. As the majority of the cellular effects of PTx depend on its ability to activate intracellular pathways involving cAMP, the in vitro cAMP-PTx assay was developed...
February 22, 2017: Vaccine
Chukiat Sirivichayakul, Pornthep Chanthavanich, Kriengsak Limkittikul, Claire-Anne Siegrist, Wassana Wijagkanalan, Pailinrut Chinwangso, Jean Petre, Pham Hong Thai, Mukesh Chauhan, Simonetta Viviani
BACKGROUND: An acellular Pertussis (aP) vaccine containing recombinant genetically detoxified Pertussis Toxin (PTgen), Filamentous Hemagglutinin (FHA) and Pertactin (PRN) has been developed by BioNet-Asia (BioNet). We present here the results of the first clinical study of this recombinant aP vaccine formulated alone or in combination with tetanus and diphtheria toxoids (TdaP). METHODS: A phase I/II, observer-blind, randomized controlled trial was conducted at Mahidol University in Bangkok, Thailand in healthy adult volunteers aged 18-35 y...
January 2, 2017: Human Vaccines & Immunotherapeutics
Chun-Ting Yuen, Catpagavalli Asokanathan, Sarah Cook, Naomi Lin, Dorothy Xing
Pertussis toxin (PTx) is a major virulence factor produced by Bordetella pertussis and its detoxified form is one of the major protective antigens in vaccines against whooping cough. Ideally, PTx in the vaccine should be completely detoxified while still preserving immunogenicity. However, this may not always be the case. Due to multilevel reaction mechanisms of chemical detoxification that act on different molecular sites and with different production processes, it is difficult to define a molecular characteristic of a pertussis toxoid...
April 19, 2016: Vaccine
Nicholas H Carbonetti
Pertussis toxin (PT) is a multisubunit protein toxin secreted by Bordetella pertussis, the bacterial agent of the disease pertussis or whooping cough. PT in detoxified form is a component of all licensed acellular pertussis vaccines, since it is considered to be an important virulence factor for this pathogen. PT inhibits G protein-coupled receptor signaling through Gi proteins in mammalian cells, an activity that has led to its widespread use as a cell biology tool. But how does this activity of PT contribute to pertussis, including the severe respiratory symptoms of this disease? In this minireview, the contribution of PT to the pathogenesis of pertussis disease will be considered based on evidence from both human infections and animal model studies...
November 2015: Pathogens and Disease
Valentina Agnolon, Cristina Bruno, Rosanna Leuzzi, Bruno Galletti, Ugo D'Oro, Mariagrazia Pizza, Anja Seubert, Derek T O'Hagan, Barbara C Baudner
The successful approach of combining diphtheria, tetanus and pertussis antigens into a single vaccine has become a cornerstone of immunization programs. Yet, even if vaccination coverage is high, a resurgence of pertussis has been reported in many countries suggesting current vaccines may not provide adequate protection. To induce better tailored and more durable immune responses against pertussis vaccines different approaches have been proposed, including the use of novel adjuvants. Licensed aP vaccines contain aluminum salts, which mainly stimulate humoral immune responses and might not be ideal for protecting against Bordetella pertussis infection...
August 15, 2015: International Journal of Pharmaceutics
Beatris Mastelic Gavillet, Lucie Mondoulet, Véronique Dhelft, Christiane Sigrid Eberhardt, Floriane Auderset, Hong Thai Pham, Jean Petre, Paul-Henri Lambert, Pierre-Henri Benhamou, Claire-Anne Siegrist
The limited durability of pertussis vaccine-induced protection requires novel approaches to reactivate immunity and limit pertussis resurgence in older children and adults. We propose that periodic boosters could be delivered using a novel epicutaneous delivery system (Viaskin) to deliver optimized pertussis antigens such as genetically-detoxified pertussis toxin (rPT). To best mimic the human situation in which vaccine-induced memory cells persist, whereas antibodies wane, we developed a novel adoptive transfer murine model of pertussis immunity...
July 9, 2015: Vaccine
Anja Seubert, Ugo D'Oro, Maria Scarselli, Mariagrazia Pizza
Pertussis toxin (PT) is one of the major virulence factors of Bordetella pertussis and the primary component of all pertussis vaccines available to date. Because of its various noxious effects the toxin needs to be detoxified. In all currently available vaccines, detoxification is achieved by treatment with high quantity of chemical agents such as formaldehyde, glutaraldehyde or hydrogen peroxide. Although effective in detoxification, this chemical treatment alters dramatically the immunological properties of the toxin...
October 2014: Expert Review of Vaccines
Gilles Dadaglio, Catherine Fayolle, Xiaoming Zhang, Bernard Ryffel, Marine Oberkampf, Tristan Felix, Sandra Hervas-Stubbs, Radim Osicka, Peter Sebo, Daniel Ladant, Claude Leclerc
Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant...
August 15, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Nicole Guiso
Pertussis or whooping cough is a respiratory disease caused by Bordetella pertussis or Bordetella parapertussis that are only known to infect humans. This severe and acute respiratory disease presents epidemic cycles and became a vaccine-preventable disease in the 1940s/1950s when developed countries introduced vaccination. The first type of vaccine developed against this disease was a whole-cell pertussis (wP) vaccine containing inactivated B. pertussis bacteria. Most developed countries produced their own vaccine and given the pediatric nature of the disease at the time of licensure, infants and toddlers were the primary targets and were thus massively vaccinated...
October 2014: Expert Review of Vaccines
Clara Maria Ausiello, Antonio Cassone
The resurgence of pertussis (whooping cough) in countries with high vaccination coverage is alarming and invites reconsideration of the use of current acellular pertussis (aP) vaccines, which have largely replaced the old, reactogenic, whole-cell pertussis (wP) vaccine. Some drawbacks of these vaccines in terms of limited antigenic composition and early waning of antibody levels could be anticipated by the results of in-trial or postlicensure human investigations of B- and T-cell responses in aP versus wP vaccine recipients or unvaccinated, infected children...
June 10, 2014: MBio
Rigmor Thorstensson, Birger Trollfors, Nabil Al-Tawil, Maja Jahnmatz, Jakob Bergström, Margaretha Ljungman, Anna Törner, Lena Wehlin, Annie Van Broekhoven, Fons Bosman, Anne-Sophie Debrie, Nathalie Mielcarek, Camille Locht
BACKGROUND: Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. METHODS: We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract...
2014: PloS One
Dorothy Xing, Rose Gaines Das, Alex Douglas-Bardsley, Catpagavalli Asokanathan, Michael Corbel
Speculation that the Japanese modified intra-cerebral challenge assay, which is used in several countries for control of acellular pertussis vaccines, depends on the presence of small amounts of active pertussis toxin led to an assumption that it may not be appropriate for highly toxoided or genetically detoxified vaccines. Consequently, at the recommendation of a World Health Organisation AD Hoc Working Group on mouse protection models for testing and control of acellular pertussis vaccine, the effect of pertussis toxin on the modified intra-cerebral challenge assay (modified Kendrick, MICA) was evaluated in an international collaborative study...
March 2014: Biologicals: Journal of the International Association of Biological Standardization
Corinna Schnoeller, Xavier Roux, Devika Sawant, Dominique Raze, Wieslawa Olszewska, Camille Locht, Peter J Openshaw
RATIONALE: We attenuated virulent Bordetella pertussis by genetically eliminating or detoxifying three major toxins. This strain, named BPZE1, is being developed as a possible live nasal vaccine for the prevention of whooping cough. It is immunogenic and safe when given intranasally in adult volunteers. OBJECTIVES: Before testing in human infants, we wished to examine the potential effect of BPZE1 on a common pediatric infection (respiratory syncytial virus [RSV]) in a preclinical model...
January 15, 2014: American Journal of Respiratory and Critical Care Medicine
S F C Vaessen, S Verkoeijen, R J Vandebriel, M W P Bruysters, J L A Pennings, R Bos, C A M Krul, A M Akkermans
In this study we aimed to identify genes that are responsive to pertussis toxin (PTx) and might eventually be used as biological markers in a testing strategy to detect residual PTx in vaccines. By microarray analysis we screened six human cell types (bronchial epithelial cell line BEAS-2B, fetal lung fibroblast cell line MRC-5, primary cardiac microvascular endothelial cells, primary pulmonary artery smooth muscle cells, hybrid cell line EA.Hy926 of umbilical vein endothelial cells and epithelial cell line A549 and immature monocyte-derived dendritic cells) for differential gene expression induced by PTx...
October 25, 2013: Vaccine
Hokyung Oh, Byoung-Guk Kim, Kyung-Tak Nam, Seung-Hwa Hong, Dong-Ho Ahn, Gi-Sub Choi, Hyungjin Kim, Jin-Tae Hong, Byung-Yoon Ahn
Pertussis toxin (PTx) is an essential component of the acellular pertussis (aP) vaccine. However, because PTx in its native form is considered too toxic for human vaccine use, it must be inactivated into a stable, nontoxic form by treatment with chemical detoxifying agents or by genetic modification. Therefore, testing for the residual PTx in the aP vaccine is a major quality control step for vaccine manufacturers and regulatory authorities. The histamine sensitization test is currently the standard safety test method for all aP vaccines, regardless of the vaccine formula or the detoxification process, except for those with genetically modified PTx...
June 24, 2013: Vaccine
Robert J Mitkus, Maureen A Hess, Sorell L Schwartz
Formaldehyde is a one-carbon, highly water-soluble aldehyde that is used in certain vaccines to inactivate viruses and to detoxify bacterial toxins. As part of the manufacturing process, some residual formaldehyde can remain behind in vaccines at levels less than or equal to 0.02%. Environmental and occupational exposure, principally by inhalation, is a continuing risk assessment focus for formaldehyde. However, exposure to formaldehyde via vaccine administration is qualitatively and quantitatively different from environmental or occupational settings and calls for a different perspective and approach to risk assessment...
June 7, 2013: Vaccine
Yajun Tan, Roland A Fleck, Catpagavalli Asokanathan, Chun-Ting Yuen, Dorothy Xing, Shumin Zhang, Junzhi Wang
Pertussis toxin in its detoxified form is a major component of all current acellular pertussis vaccines. Here we report the membrane translocation and internalization activities of pertussis toxin and various pertussis toxoids using Chinese hamster ovary cells and confocal microscopy based on indirect immunofluorescence labeling. Chemically detoxified pertussis toxoids were able to translocate/internalize into cells at the concentration about 1,000 times higher than the native toxin. Pertussis toxoids detoxified with different procedures (glutaraldehyde, glutaraldehyde plus formaldehyde, hydrogen peroxide or genetic mutation) showed differences in fluorescence intensity under the same condition, indicating toxoids from different detoxification methods may have different translocation/internalization activities on cells...
February 2013: Human Vaccines & Immunotherapeutics
Jamie N Sutherland, Christine Chang, Sandra M Yoder, Michael T Rock, Jennifer A Maynard
Despite more than 50 years of vaccination, disease caused by the bacterium Bordetella pertussis persists, with rates increasing in industrialized countries over the past decade. This rise may be attributed to several factors, including increased surveillance, emergence of vaccine escape variants, waning immunity in adults, and the introduction of acellular subunit vaccines, which include chemically detoxified pertussis toxin (PTd). Two potently protective epitopes on pertussis toxin (PTx) are recognized by the monoclonal antibodies 1B7 and 11E6, which inhibit catalytic and cell-binding activities, respectively...
June 2011: Clinical and Vaccine Immunology: CVI
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