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Camille Locht is Research Director at the French National Institute of Health and Medical Research (Inserm) and was the founding director of the Center for Infection and Immunity of Lille at the Institut Pasteur de Lille (IPL). He has obtained his PhD at the Catholic University of Leuven. After a 3-year post-doctoral stay at the NIH, USA, he joined SmithKline–Beecham in 1989 at IPL, where he was the Scientific Director from 2002 to 2013. His main interest is in bacterial pathogenesis and vaccine development against respiratory disease, including pertussis and tuberculosis.
Allergic diseases, in particular atopic asthma, have been on the rise in most industrialized countries for several decades now. Allergic asthma is characterized by airway narrowing, bronchial hyperresponsiveness, excessive airway mucus production, eosinophil influx in the lungs and an imbalance of the Th1/Th2 responses, including elevated IgE levels. Most available interventions provide only short-term relief from disease symptoms and do not alter the underlying immune imbalance. A number of studies, mostly in mouse models, have shown that Mycobacterium bovis bacillus Calmette-Guérin (BCG) treatment is capable of preventing or reducing an established allergen-driven inflammatory response, by redirecting pathogenic Th2 towards protective Th1 and/or regulatory T cell responses. Dendritic cells stimulated by BCG appear to be a crucial first step in the immunomodulatory effects of BCG. While the protective and therapeutic effects of BCG against allergy and asthma are well documented in animal models, they are less clear in humans, both in observational studies and in randomized controlled trials. The purpose of this article is to provide an up-to-date overview of the available evidence on the anti-allergy, in particular anti-asthma effects of BCG in mice, rats and humans.
Magdalena Kowalewicz-Kulbat; Camille Locht. BCG for the prevention and treatment of allergic asthma. Vaccine 2021, 1 .
AMA StyleMagdalena Kowalewicz-Kulbat, Camille Locht. BCG for the prevention and treatment of allergic asthma. Vaccine. 2021; ():1.
Chicago/Turabian StyleMagdalena Kowalewicz-Kulbat; Camille Locht. 2021. "BCG for the prevention and treatment of allergic asthma." Vaccine , no. : 1.
Camille Locht. Long-lived immunity to genetically detoxified pertussis vaccines. EClinicalMedicine 2021, 37, 101014 .
AMA StyleCamille Locht. Long-lived immunity to genetically detoxified pertussis vaccines. EClinicalMedicine. 2021; 37 ():101014.
Chicago/Turabian StyleCamille Locht. 2021. "Long-lived immunity to genetically detoxified pertussis vaccines." EClinicalMedicine 37, no. : 101014.
Background Current vaccination strategies against pertussis are sub-optimal. Optimal protection against Bordetella pertussis, the causative agent of pertussis, likely requires mucosal immunity. Current pertussis vaccines consist of inactivated whole B. pertussis cells or purified antigens thereof, combined with diphtheria and tetanus toxoids. Although they are highly protective against severe pertussis disease, they fail to elicit mucosal immunity. Compared to natural infection, immune responses following immunization are short-lived and fail to prevent bacterial colonization of the upper respiratory tract. To overcome these shortcomings, efforts have been made for decades, and continue to be made, toward the development of mucosal vaccines against pertussis. Objectives In this review we systematically analyzed published literature on protection conferred by mucosal immunization against pertussis. Immune responses mounted by these vaccines are summarized. Method The PubMed Library database was searched for published studies on mucosal pertussis vaccines. Eligibility criteria included mucosal administration and the evaluation of at least one outcome related to efficacy, immunogenicity and safety. Results While over 349 publications were identified by the search, only 63 studies met the eligibility criteria. All eligible studies are included here. Initial attempts of mucosal whole-cell vaccine administration in humans provided promising results, but were not followed up. More recently, diverse vaccination strategies have been tested, including non-replicating and replicating vaccine candidates given by three different mucosal routes: orally, nasally or rectally. Several adjuvants and particulate formulations were tested to enhance the efficacy of non-replicating vaccines administered mucosally. Most novel vaccine candidates were only tested in animal models, mainly mice. Only one novel mucosal vaccine candidate was tested in baboons and in human trials. Conclusion Three vaccination strategies drew our attention, as they provided protective and durable immunity in the respiratory tract, including the upper respiratory tract: acellular vaccines adjuvanted with lipopeptide LP1569 and c-di-GMP, outer membrane vesicles and the live attenuated BPZE1 vaccine. Among all experimental vaccines, BPZE1 is the only one that has advanced into clinical development.
Violaine Dubois; Camille Locht. Mucosal Immunization Against Pertussis: Lessons From the Past and Perspectives. Frontiers in Immunology 2021, 12, 1 .
AMA StyleViolaine Dubois, Camille Locht. Mucosal Immunization Against Pertussis: Lessons From the Past and Perspectives. Frontiers in Immunology. 2021; 12 ():1.
Chicago/Turabian StyleViolaine Dubois; Camille Locht. 2021. "Mucosal Immunization Against Pertussis: Lessons From the Past and Perspectives." Frontiers in Immunology 12, no. : 1.
Pertussis, mainly caused by Bordetella pertussis, is a severe respiratory disease that can be fatal, especially in young infants. Vaccines, massively implemented since the middle of the last century, have substantially reduced the pertussis incidence, but have not been able to fully control the disease. One of the shortcomings of current pertussis vaccines is their inability to prevent infection by and transmission of B. pertussis, in contrast to immunity following natural infection. We have developed the live attenuated nasal vaccine BPZE1 and have shown that it prevents both disease and B. pertussis infection in preclinical models. This vaccine is now in clinical development. However, the initial clinical studies have suggested that vaccine take is hampered by pre-existing antibodies to pertactin. Here, we have constructed a pertactin-deficient BPZE1 derivative called BPZE1P in order to overcome this limitation. BPZE1P colonized the murine respiratory tract as efficiently as BPZE1 and induced antibodies at levels similar to those elicited by BPZE1. In the presence of pre-existing antibodies induced by acellular pertussis vaccination, BPZE1P colonized the mouse respiratory tract more efficiently than BPZE1. Both vaccines protected equally well the murine lungs and noses from challenge with laboratory and clinical strains of B. pertussis, including pertactin-deficient strains, against which current acellular pertussis vaccines are less efficient. BPZE1P may thus be an interesting alternative to BPZE1 to overcome vaccine take limitations due to pre-existing antibodies to pertactin.
Luis Solans; Anne-Sophie Debrie; Loïc Coutte; Camille Locht. Construction and evaluation of a pertactin-deficient live attenuated pertussis vaccine candidate BPZE1 derivative. Vaccine 2021, 39, 2843 -2849.
AMA StyleLuis Solans, Anne-Sophie Debrie, Loïc Coutte, Camille Locht. Construction and evaluation of a pertactin-deficient live attenuated pertussis vaccine candidate BPZE1 derivative. Vaccine. 2021; 39 (21):2843-2849.
Chicago/Turabian StyleLuis Solans; Anne-Sophie Debrie; Loïc Coutte; Camille Locht. 2021. "Construction and evaluation of a pertactin-deficient live attenuated pertussis vaccine candidate BPZE1 derivative." Vaccine 39, no. 21: 2843-2849.
Introduction: Pertussis, caused by Bordetella pertussis, remains a major public health problem, despite high vaccination coverage. Furthermore, the disease incidence has increased recently, especially in countries that have switched from whole-cell to acellular pertussis vaccines. Areas covered: Here, we provide a state-of-the art summary of the reasons for the pertussis resurgence and discuss potential solutions using current vaccines and challenges for the development of novel vaccines. PubMed was searched for publications with the terms pertussis and vaccines. Many new vaccine candidates are proposed but most have not reached clinical development. Most of them induce strong systemic immune responses and protection in mice. However, since B. pertussis is a mucosal pathogen, albeit with systemic effects, local immunity may be crucial to prevent B. pertussis infection and transmission. Recent efforts have focused on vaccine candidates able to induce immunity in the nasal cavity, and one of them is currently in clinical development. Expert commentary: New pertussis vaccines are needed to durably control the disease and circulation of B. pertussis. A major challenge is to prove efficacy against disease in randomized controlled trials, while it is feasible to provide evidence for prevention of infection, since asymptomatic carriage of B. pertussis is wide spread.
Camille Locht. Is there a potential for novel, nasal pertussis vaccines? Expert Review of Vaccines 2021, 1 -9.
AMA StyleCamille Locht. Is there a potential for novel, nasal pertussis vaccines? Expert Review of Vaccines. 2021; ():1-9.
Chicago/Turabian StyleCamille Locht. 2021. "Is there a potential for novel, nasal pertussis vaccines?" Expert Review of Vaccines , no. : 1-9.
The only currently available anti-tuberculosis vaccine, Bacillus Calmette–Guérin (BCG), has been reported to also protect against unrelated diseases, including inflammatory diseases such as allergic asthma. Recombinant BCG strains that produce IL-18 have been shown to enhance Th1 responses over non-recombinant BCG and to reduce IL-5 production and bronchoalveolar eosinophilia in mice. However, their ability to decrease the immune polarization of human Th2 cells is not known. Here, we show that BCG and recombinant BCG producing human IL-18 (rBCG-hIL-18) induced the maturation of Der p 1-stimulated monocyte-derived dendritic cells (MD-DCs) from healthy controls and from patients allergic to house dust mites. After incubation with mycobacteria and Der p 1, MD-DCs produced significantly more IL-23 and IP-10 but had no effect on IL-12p70 or IL-10 production compared to Der p 1-pulsed MD-DCs in the absence of mycobacteria. In the presence of Der p 1, BCG- and rBCG-hIL-18-pulsed MD-DCs cocultured with naive, but not with memory T cells from allergic patients, resulted in a decrease in IL-5 production compared to non-pulsed MD-DCs cultured in the presence of Der p 1. BCG, and especially rBCG-hIL-18, may thus be potential therapeutic tools to reduce exacerbated Th2 responses in patients with allergic asthma.
Magdalena Kowalewicz-Kulbat; Piotr Szpakowski; Krzysztof Krawczyk; Marek Kowalski; Slawomir Kosinski; Franck Biet; Wieslawa Rudnicka; Camille Locht. Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite. Vaccines 2021, 9, 277 .
AMA StyleMagdalena Kowalewicz-Kulbat, Piotr Szpakowski, Krzysztof Krawczyk, Marek Kowalski, Slawomir Kosinski, Franck Biet, Wieslawa Rudnicka, Camille Locht. Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite. Vaccines. 2021; 9 (3):277.
Chicago/Turabian StyleMagdalena Kowalewicz-Kulbat; Piotr Szpakowski; Krzysztof Krawczyk; Marek Kowalski; Slawomir Kosinski; Franck Biet; Wieslawa Rudnicka; Camille Locht. 2021. "Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite." Vaccines 9, no. 3: 277.
Whooping cough, or pertussis, mostly caused by Bordetella pertussis, is a respiratory disease that affects all age groups, but severe and fatal pertussis occurs almost exclusively in young children. The widespread use of whole-cell and, more recently, of acellular vaccines has substantially reduced the disease incidence. However, it has not been eliminated in any part of the world and has made a worrisome rebound in several areas. Cocoon and maternal immunization have been implemented in several countries but have their intrinsic limitations. To effectively control pertussis, novel vaccines are needed that protect against disease and prevent B. pertussis infection and transmission, which is not the case for current vaccines. Several approaches are contemplated, including alternative administration routes, such as nasal immunization, improvement of acellular vaccines by adding more antigens and T-cell-promoting adjuvants, and the development of novel vaccines, such as outer membrane vesicles and live attenuated vaccines. Among them, only a live attenuated vaccine has so far been assessed for safety and immunogenicity in preclinical models other than mice and is in clinical development. Before any of these vaccines can be used in neonates, extensive safety and immunogenicity assessment in pre-clinical neonatal models and in carefully designed clinical trials is necessary. The aim of this review is to discuss the current pertussis problem, implemented strategies to resolve it, the value of animal models and novel vaccine approaches.
Camille Locht. The Path to New Pediatric Vaccines against Pertussis. Vaccines 2021, 9, 228 .
AMA StyleCamille Locht. The Path to New Pediatric Vaccines against Pertussis. Vaccines. 2021; 9 (3):228.
Chicago/Turabian StyleCamille Locht. 2021. "The Path to New Pediatric Vaccines against Pertussis." Vaccines 9, no. 3: 228.
BPZE1 is a live attenuated vaccine against infection by Bordetella pertussis, the causative agent of whooping cough. It was previously shown that BPZE1 provides heterologous protection in mouse models of disease caused by unrelated pathogens, such as influenza virus and respiratory syncytial virus. Protection was also observed in mouse models of asthma and contact dermatitis. In this study, we demonstrate that BPZE1 also displays protection against an unrelated bacterial pathogen in a mouse model of invasive pneumococcal disease mediated by Streptococcus pneumoniae. While a single administration of BPZE1 provided no protection, two doses of 106 colony-forming units of BPZE1 given in a three-week interval protected against mortality, lung colonization and dissemination in both BALB/c and C57BL/6 mice. Unlike for the previously reported influenza challenge model, protection was short-lived, and waned within days after booster vaccination. Formaldehyde-killed BPZE1 protected only when administered following a live prime, indicating that priming requires live BPZE1 for protection. Protection against mortality was directly linked to substantially decreased bacterial dissemination in the blood and was lost in MyD88 knock-out mice, demonstrating the role of the innate immune system in the mechanism of protection. This is the first report on a heterologous protective effect of the live BPZE1 vaccine candidate against an unrelated bacterial infection.
Thomas Belcher; Hana Kammoun; Loïc Coutte; Anne-Sophie Debrie; Nathalie Mielcarek; Jean-Claude Sirard; Stéphane Cauchi; Camille Locht. Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice. Vaccine 2021, 1 .
AMA StyleThomas Belcher, Hana Kammoun, Loïc Coutte, Anne-Sophie Debrie, Nathalie Mielcarek, Jean-Claude Sirard, Stéphane Cauchi, Camille Locht. Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice. Vaccine. 2021; ():1.
Chicago/Turabian StyleThomas Belcher; Hana Kammoun; Loïc Coutte; Anne-Sophie Debrie; Nathalie Mielcarek; Jean-Claude Sirard; Stéphane Cauchi; Camille Locht. 2021. "Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice." Vaccine , no. : 1.
C. Locht; M. Lerm. Good old BCG – what a century‐old vaccine can contribute to modern medicine. Journal of Internal Medicine 2020, 288, 611 -613.
AMA StyleC. Locht, M. Lerm. Good old BCG – what a century‐old vaccine can contribute to modern medicine. Journal of Internal Medicine. 2020; 288 (6):611-613.
Chicago/Turabian StyleC. Locht; M. Lerm. 2020. "Good old BCG – what a century‐old vaccine can contribute to modern medicine." Journal of Internal Medicine 288, no. 6: 611-613.
Camille Locht. Vaccines against COVID-19. Anaesthesia Critical Care & Pain Medicine 2020, 39, 703 -705.
AMA StyleCamille Locht. Vaccines against COVID-19. Anaesthesia Critical Care & Pain Medicine. 2020; 39 (6):703-705.
Chicago/Turabian StyleCamille Locht. 2020. "Vaccines against COVID-19." Anaesthesia Critical Care & Pain Medicine 39, no. 6: 703-705.
Current pertussis vaccines protect against disease, but not against colonization by and transmission of Bordetella pertussis, whereas natural infection protects against both. The live attenuated vaccine BPZE1 was developed to mimic immunogenicity of natural infection without causing disease, and in preclinical models protected against pertussis disease and B. pertussis colonization after a single nasal administration. Phase 1 clinical studies showed that BPZE1 is safe and immunogenic in humans when administered as a liquid formulation, stored at ≤−70 °C. Although BPZE1 is stable for two years at ≤−70 °C, a lyophilized formulation stored at ≥5 °C is required for commercialization. The development of a BPZE1 drug product, filled and lyophilized directly in vials, showed that post-lyophilization survival of BPZE1 depended on the time of harvest, the lyophilization buffer, the time between harvest and lyophilization, as well as the lyophilization cycle. The animal component-free process, well defined in terms of harvest, processing and lyophilization, resulted in approximately 20% survival post-lyophilization. The resulting lyophilized drug product was stable for at least two years at −20 °C ± 10 °C, 5 °C ± 3 °C and 22.5 °C ± 2.5 °C and maintained its vaccine potency, as evaluated in a murine protection assay. This manufacturing process thus enables further clinical and commercial development of BPZE1.
Marcel Thalen; Anne-Sophie Debrie; Loic Coutte; Dominique Raze; Ken Solovay; Keith Rubin; Nathalie Mielcarek; Camille Locht. Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1. Vaccines 2020, 8, 523 .
AMA StyleMarcel Thalen, Anne-Sophie Debrie, Loic Coutte, Dominique Raze, Ken Solovay, Keith Rubin, Nathalie Mielcarek, Camille Locht. Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1. Vaccines. 2020; 8 (3):523.
Chicago/Turabian StyleMarcel Thalen; Anne-Sophie Debrie; Loic Coutte; Dominique Raze; Ken Solovay; Keith Rubin; Nathalie Mielcarek; Camille Locht. 2020. "Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1." Vaccines 8, no. 3: 523.
The Mycobacterium avium complex includes two closely related species, Mycobacterium avium and Mycobacterium intracellulare. They are opportunistic pathogens in humans and responsible for severe disease in a wide variety of animals. Yet, little is known about factors involved in their pathogenicity. Here, we identified, purified and characterized adhesins belonging to the heparin-binding hemagglutinin (HBHA) and laminin-binding protein (LBP) family from M. intracellulare ATCC13950 and examined clinical isolates from patients with different pathologies associated with M. intracellulare infection for the presence and conservation of HBHA and LBP. Using a recombinant derivative strain of M. intracellulare ATCC13950 producing green fluorescent protein and luciferase, we found that the addition of heparin inhibited mycobacterial adherence to A549 cells, whereas the addition of laminin enhanced adherence. Both HBHA and LBP were purified by heparin-Sepharose chromatography and their methylation profiles were determined by mass spectrometry. Patients with M. intracellulare infection mounted strong antibody responses to both proteins. By using PCR and immunoblot analyses, we found that both proteins were highly conserved among all 17 examined clinical M. intracellulare isolates from patients with diverse disease manifestations, suggesting a conserved role of these adhesins in M. intracellulare virulence in humans and their potential use as a diagnostic tool.
Louise H. Lefrancois; Thierry Cochard; Maxime Branger; Olivia Peuchant; Cyril Conde; Adeline Pastuszka; Camille Locht; Philippe Lanotte; Franck Biet. Feature of Adhesins Produced by Human Clinical Isolates of Mycobacterium intracellulare, Mycobacterium intracellulare subsp. chimaera and Closely Related Species. Microorganisms 2020, 8, 1154 .
AMA StyleLouise H. Lefrancois, Thierry Cochard, Maxime Branger, Olivia Peuchant, Cyril Conde, Adeline Pastuszka, Camille Locht, Philippe Lanotte, Franck Biet. Feature of Adhesins Produced by Human Clinical Isolates of Mycobacterium intracellulare, Mycobacterium intracellulare subsp. chimaera and Closely Related Species. Microorganisms. 2020; 8 (8):1154.
Chicago/Turabian StyleLouise H. Lefrancois; Thierry Cochard; Maxime Branger; Olivia Peuchant; Cyril Conde; Adeline Pastuszka; Camille Locht; Philippe Lanotte; Franck Biet. 2020. "Feature of Adhesins Produced by Human Clinical Isolates of Mycobacterium intracellulare, Mycobacterium intracellulare subsp. chimaera and Closely Related Species." Microorganisms 8, no. 8: 1154.
Bordetella pertussis , the etiological agent of whooping cough, remains a major global health problem. Despite the global usage of whole-cell vaccines since the 1950s and of acellular vaccines in the 1990s, it still is one of the most prevalent vaccine-preventable diseases in industrialized countries. Virulence of B. pertussis is controlled by BvgA/S, a two-component system responsible for upregulation of virulence-activated genes ( vag s) and downregulation of virulence-repressed genes ( vrg s). By transcriptome sequencing (RNAseq) analyses, we identified more than 270 vag s or vrg s, and chromatin immunoprecipitation sequencing (ChIPseq) analyses revealed 148 BvgA-binding sites, 91 within putative promoter regions, 52 within open reading frames, and 5 in noncoding regions. Some vag s, such as dnt and fhaL , do not contain a BvgA-binding site, suggesting indirect regulation. In contrast, several vrg s and some genes not identified by RNAseq analyses under laboratory conditions contain strong BvgA-binding sites, indicating previously unappreciated complexities of BvgA/S biology.
Loïc Coutte; Rudy Antoine; Stephanie Slupek; Luis Solans; Julien Derop; Amelie Bonnefond; David Hot; Camille Locht. Combined RNAseq and ChIPseq Analyses of the BvgA Virulence Regulator of Bordetella pertussis. mSystems 2020, 5, 1 .
AMA StyleLoïc Coutte, Rudy Antoine, Stephanie Slupek, Luis Solans, Julien Derop, Amelie Bonnefond, David Hot, Camille Locht. Combined RNAseq and ChIPseq Analyses of the BvgA Virulence Regulator of Bordetella pertussis. mSystems. 2020; 5 (3):1.
Chicago/Turabian StyleLoïc Coutte; Rudy Antoine; Stephanie Slupek; Luis Solans; Julien Derop; Amelie Bonnefond; David Hot; Camille Locht. 2020. "Combined RNAseq and ChIPseq Analyses of the BvgA Virulence Regulator of Bordetella pertussis." mSystems 5, no. 3: 1.
The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1. We performed multiple assays to dissect the immune responses induced in humans (n=12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n=12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, novel immunogenic B. pertussis antigens were identified. All BPZE1 vaccinees showed robust B. pertussis-specific antibody responses with regard to significant increase in one or more of the parameters IgG, IgA and memory B cells to B. pertussis antigens. BPZE1-specific T cells showed a Th1 phenotype and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccinees showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared to the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated reactive oxygen species (ROS) production in neutrophils and enhanced bactericidal function, which was in line with that antibodies against adenylate cyclase toxin were only elicited by BPZE1. The breadth of the antibodies, the Th1-type cellular response and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission. ClinicalTrials.gov NCT02453048, NCT00870350FUNDING. ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-lung Foundation.
Ang Lin; Danijela Apostolovic; Maja Jahnmatz; Frank Liang; Sebastian Ols; Teghesti Tecleab; Chenyan Wu; Marianne Van Hage; Ken Solovay; Keith Rubin; Camille Locht; Rigmor Thorstensson; Marcel Thalen; Karin Loré. Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans. Journal of Clinical Investigation 2020, 130, 2332 -2346.
AMA StyleAng Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne Van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, Karin Loré. Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans. Journal of Clinical Investigation. 2020; 130 (5):2332-2346.
Chicago/Turabian StyleAng Lin; Danijela Apostolovic; Maja Jahnmatz; Frank Liang; Sebastian Ols; Teghesti Tecleab; Chenyan Wu; Marianne Van Hage; Ken Solovay; Keith Rubin; Camille Locht; Rigmor Thorstensson; Marcel Thalen; Karin Loré. 2020. "Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans." Journal of Clinical Investigation 130, no. 5: 2332-2346.
Pertussis is a severe respiratory disease mainly caused by Bordetella pertussis. Despite wide global vaccination coverage with efficacious pertussis vaccines, it remains one of the least well-controlled vaccine-preventable diseases, illustrating the shortcomings of the current vaccines. We have developed the live attenuated nasal pertussis vaccine BPZE1, currently undergoing clinical evaluation in human phase 2 trials. We have previously shown that in mice, BPZE1 provides strong and long-lasting protection against B. pertussis challenge by inducing potent Ab and T cell responses as well as secretory IgA and IL-17–producing resident memory T lymphocytes in the nasal cavity. In this study, we show that BPZE1 induces protection in mice against B. pertussis within days after vaccination, at a time when Ab and T cell responses were not detectable. Early protection was independent of T and B cell responses, as demonstrated by the use of SCID mice. Instead, it was due to TLR4-dependent signaling through the MyD88-dependent pathway of the innate immune response, as demonstrated in experiments with TLR4-deficient and MyD88-knockout mice. TLR2-dependent signaling did not play a major role in early protection. In addition, this study also shows that even at high doses, BPZE1 is safe in the severely immunocompromised MyD88-deficient mice, whereas virulent B. pertussis caused a severe pathological condition and death in these mice, even at a low dose. Finally, coadministration of virulent B. pertussis with BPZE1 did not cause exacerbated outgrowth of the virulent strain, thereby adding to the safety profile of this live vaccine candidate. Key Points Live pertussis vaccine BPZE1 protects against B. pertussis infection within days. Early protection induced by BPZE1 does not depend on adaptive immune responses. Early protection induced by BPZE1 depends on TLR4-mediated innate immune responses.
Anne-Sophie Debrie; Nathalie Mielcarek; Sophie Lecher; Xavier Roux; Jean-Claude Sirard; Camille Locht. Early Protection against Pertussis Induced by Live AttenuatedBordetella pertussisBPZE1 Depends on TLR4. The Journal of Immunology 2019, 203, 3293 -3300.
AMA StyleAnne-Sophie Debrie, Nathalie Mielcarek, Sophie Lecher, Xavier Roux, Jean-Claude Sirard, Camille Locht. Early Protection against Pertussis Induced by Live AttenuatedBordetella pertussisBPZE1 Depends on TLR4. The Journal of Immunology. 2019; 203 (12):3293-3300.
Chicago/Turabian StyleAnne-Sophie Debrie; Nathalie Mielcarek; Sophie Lecher; Xavier Roux; Jean-Claude Sirard; Camille Locht. 2019. "Early Protection against Pertussis Induced by Live AttenuatedBordetella pertussisBPZE1 Depends on TLR4." The Journal of Immunology 203, no. 12: 3293-3300.
Studies on protein–protein interactions (PPI) can be helpful for the annotation of unknown protein functions and for the understanding of cellular processes, such as specific virulence mechanisms developed by bacterial pathogens. In that context, several methods have been extensively used in recent years for the characterization of Mycobacterium tuberculosis PPI to further decipher tuberculosis (TB) pathogenesis. This review aims at compiling the most striking results based on in vivo methods (yeast and bacterial two-hybrid systems, protein complementation assays) for the specific study of PPI in mycobacteria. Moreover, newly developed methods, such as in-cell native mass resonance and proximity-dependent biotinylation identification, will have a deep impact on future mycobacterial research, as they are able to perform dynamic (transient interactions) and integrative (multiprotein complexes) analyses.
Romain Veyron-Churlet; Camille Locht. In Vivo Methods to Study Protein–Protein Interactions as Key Players in Mycobacterium Tuberculosis Virulence. Pathogens 2019, 8, 173 .
AMA StyleRomain Veyron-Churlet, Camille Locht. In Vivo Methods to Study Protein–Protein Interactions as Key Players in Mycobacterium Tuberculosis Virulence. Pathogens. 2019; 8 (4):173.
Chicago/Turabian StyleRomain Veyron-Churlet; Camille Locht. 2019. "In Vivo Methods to Study Protein–Protein Interactions as Key Players in Mycobacterium Tuberculosis Virulence." Pathogens 8, no. 4: 173.
Pertussis or whooping cough, mainly caused by Bordetella pertussis, is a severe respiratory disease that can affect all age groups but is most severe and can be life-threatening in young children. Vaccines against this disease are widely available since the 1950s. Despite high global vaccination coverage, the disease is not under control in any country, and its incidence is even increasing in several parts of the world. Epidemiological and experimental evidence has shown that the vaccines fail to prevent B. pertussis infection and transmission, although they are very effective in preventing disease. Given the high infection rate of B. pertussis, effective control of the disease likely requires prevention of infection and transmission in addition to protection against disease. With rare exceptions B. pertussis infections are restricted to the airways and do not usually disseminate beyond the respiratory epithelium. Therefore, protection at the level of the respiratory mucosa may be helpful for an improved control of pertussis. Yet, compared to systemic responses, mucosal immune responses have attracted relatively little attention in the context of pertussis vaccine development. In this review we summarize the available literature on the role of mucosal immunity in the prevention of B. pertussis infection. In contrast to vaccination, natural infection in humans and experimental infections in animals induce strong secretory IgA responses in the naso-pharynx and in the lungs. Several studies have shown that secretory IgA may be instrumental in the control of B. pertussis infection. Furthermore, studies in mouse models have revealed that B. pertussis infection, but not immunization with current acellular pertussis vaccines induces resident memory T cells, which may also contribute to protection against colonization by B. pertussis. As these resident memory T cells are long lived, vaccines that are able to induce them should provide long-lasting immunity. As of today, only one vaccine designed to induce potent mucosal immunity is in clinical development. This vaccine is a live attenuated B. pertussis strain delivered nasally in order to mimic the natural route of infection. Due to its ability to induce mucosal immunity it is expected that this approach will contribute to improved control of pertussis.
Luis Solans; Camille Locht. The Role of Mucosal Immunity in Pertussis. Frontiers in Immunology 2019, 9, 3068 .
AMA StyleLuis Solans, Camille Locht. The Role of Mucosal Immunity in Pertussis. Frontiers in Immunology. 2019; 9 ():3068.
Chicago/Turabian StyleLuis Solans; Camille Locht. 2019. "The Role of Mucosal Immunity in Pertussis." Frontiers in Immunology 9, no. : 3068.
Heparin-binding hemagglutinin (HBHA), a surface protein of Mycobacterium tuberculosis, is an attractive vaccine candidate and marker of protective immunity against tuberculosis, although the mechanisms underlying this protective immunity are not fully understood. Comparisons of the immune responses of latently M. tuberculosis–infected (LTBI) subjects to those of patients with active tuberculosis (aTB) may help to identify surrogate markers of protection, as LTBI subjects are most often lifelong protected against the disease. HBHA was shown to induce strong Th1 responses and cytotoxic CD8+ responses in LTBI subjects, but additional mechanisms of control of M. tuberculosis infection remain to be identified. In this study, using HBHA-induced blast formation as a readout of specific T lymphocyte activation, we report the presence in M. tuberculosis–infected subjects of HBHA-induced CD4+ T cell blasts that degranulate, as measured by surface capture of CD107a. This suggests the induction by HBHA of a CD4+ T cell subset with cytolytic function, and as nearly half of these cells also contained IFN-γ, they had both Th1 and cytotoxic characteristics. We further identified a CD4+ T lymphocyte subset producing IFN-γ together with a combination of mediators of cytotoxicity, i.e., perforin, granzymes, and granulysin, and we called them polycytotoxic CD4+ T lymphocytes. Interestingly, whereas purified protein derivative induced such cells in both LTBI subjects and patients with aTB, HBHA-specific polycytotoxic CD4+ T lymphocytes were detected in LTBI subjects and not in patients with pulmonary aTB. To our knowledge, we thus identified a new HBHA-induced CD4+ T cell subset that may contribute to the control of M. tuberculosis infection.
Laetitia Aerts; Elodie Selis; Véronique Corbière; Kaat Smits; Anne Van Praet; Nicolas Dauby; Emmanuelle Petit; Mahavir Singh; Camille Locht; Violette Dirix; Françoise Mascart. HBHA-Induced Polycytotoxic CD4+ T Lymphocytes Are Associated with the Control of Mycobacterium tuberculosis Infection in Humans. The Journal of Immunology 2018, 202, 421 -427.
AMA StyleLaetitia Aerts, Elodie Selis, Véronique Corbière, Kaat Smits, Anne Van Praet, Nicolas Dauby, Emmanuelle Petit, Mahavir Singh, Camille Locht, Violette Dirix, Françoise Mascart. HBHA-Induced Polycytotoxic CD4+ T Lymphocytes Are Associated with the Control of Mycobacterium tuberculosis Infection in Humans. The Journal of Immunology. 2018; 202 (2):421-427.
Chicago/Turabian StyleLaetitia Aerts; Elodie Selis; Véronique Corbière; Kaat Smits; Anne Van Praet; Nicolas Dauby; Emmanuelle Petit; Mahavir Singh; Camille Locht; Violette Dirix; Françoise Mascart. 2018. "HBHA-Induced Polycytotoxic CD4+ T Lymphocytes Are Associated with the Control of Mycobacterium tuberculosis Infection in Humans." The Journal of Immunology 202, no. 2: 421-427.
Bordetella pertussis is the agent of pertussis, also referred to as whooping cough, a disease that remains an important public health issue. Vaccine-induced immunity to pertussis wanes over time. In industrialized countries, high vaccine coverage has not prevented infection and transmission of B. pertussis, leading to periodic outbreaks in people of all ages. The consequence is the formation of a large source for transmission to children, who show the highest susceptibility of developing severe whooping cough and mortality. With the aim of providing protection against both disease and infection, a live attenuated pertussis vaccine, in which three toxins have been genetically inactivated or removed, is now in clinical development. This vaccine, named BPZE1, offers strong protection in mice and non-human primates. It has completed a phase I clinical trial in which safety, transient colonization of the human airway and immunogenicity could be demonstrated. In mice, BPZE1 was also found to protect against inflammation resulting from heterologous airway infections, including those caused by other Bordetella species, influenza virus and respiratory syncytial virus. Furthermore, the heterologous protection conferred by BPZE1 was also observed for non-infectious inflammatory diseases, such as allergic asthma, as well as for inflammatory disorders outside of the respiratory tract, such as contact dermatitis. Current studies focus on the mechanisms underlying the anti-inflammatory effects associated with nasal BPZE1 administration. Given the increasing importance of inflammatory disorders, novel preventive and therapeutic approaches are urgently needed. Therefore, live vaccines, such as BPZE1, may offer attractive solutions. It is now essential to understand the cellular and molecular mechanisms of action before translating these biological findings into new healthcare solutions.
Stéphane Cauchi; Camille Locht. Non-specific Effects of Live Attenuated Pertussis Vaccine Against Heterologous Infectious and Inflammatory Diseases. Frontiers in Immunology 2018, 9, 2872 .
AMA StyleStéphane Cauchi, Camille Locht. Non-specific Effects of Live Attenuated Pertussis Vaccine Against Heterologous Infectious and Inflammatory Diseases. Frontiers in Immunology. 2018; 9 ():2872.
Chicago/Turabian StyleStéphane Cauchi; Camille Locht. 2018. "Non-specific Effects of Live Attenuated Pertussis Vaccine Against Heterologous Infectious and Inflammatory Diseases." Frontiers in Immunology 9, no. : 2872.
The whooping cough agent Bordetella pertussis coordinately regulates the expression of its virulence factors with the two-component system BvgAS. In laboratory conditions, specific chemical modulators are used to trigger phenotypic modulation of B. pertussis from its default virulent Bvg+ phase to avirulent Bvg- or intermediate Bvgi phases, in which no virulence factors or only a subset of them are produced, respectively. Whether phenotypic modulation occurs in the host remains unknown. In this work, recombinant B. pertussis strains harboring BvgS variants were tested in a mouse model of infection and analyzed using transcriptomic approaches. Recombinant BP-BvgΔ65, which is in the Bvgi phase by default and can be up-modulated to the Bvg+ phase in vitro, could colonize the mouse nose but was rapidly cleared from the lungs, while Bvg+-phase strains colonized both organs for up to four weeks. These results indicated that phenotypic modulation, which might have restored the full virulence capability of BP-BvgΔ65, does not occur in mice or is temporally or spatially restricted and has no effect in those conditions. Transcriptomic analyses of this and other recombinant Bvgi and Bvg+-phase strains revealed that two distinct ranges of virulence gene expression allow colonization of the mouse nose and lungs, respectively. We also showed that a recombinant strain expressing moderately lower levels of the virulence genes than its wild type parent was as efficient at colonizing both organs. Altogether, genetic modifications of BvgS generate a range of phenotypic phases, which are useful tools to decipher host-pathogen interactions.
Elodie Lesne; Loic Coutte; Luis Solans; Stephanie Slupek; Anne-Sophie Debrie; Véronique Dhennin; Philippe Froguel; David Hot; Camille Locht; Rudy Antoine; Françoise Jacob-Dubuisson. Distinct virulence ranges for infection of mice by Bordetella pertussis revealed by engineering of the sensor-kinase BvgS. PLOS ONE 2018, 13, e0204861 .
AMA StyleElodie Lesne, Loic Coutte, Luis Solans, Stephanie Slupek, Anne-Sophie Debrie, Véronique Dhennin, Philippe Froguel, David Hot, Camille Locht, Rudy Antoine, Françoise Jacob-Dubuisson. Distinct virulence ranges for infection of mice by Bordetella pertussis revealed by engineering of the sensor-kinase BvgS. PLOS ONE. 2018; 13 (10):e0204861.
Chicago/Turabian StyleElodie Lesne; Loic Coutte; Luis Solans; Stephanie Slupek; Anne-Sophie Debrie; Véronique Dhennin; Philippe Froguel; David Hot; Camille Locht; Rudy Antoine; Françoise Jacob-Dubuisson. 2018. "Distinct virulence ranges for infection of mice by Bordetella pertussis revealed by engineering of the sensor-kinase BvgS." PLOS ONE 13, no. 10: e0204861.