scholarly journals High antibody titres induced by protein subunit vaccines using Mycobacterium ulcerans antigens Hsp18 and MUL_3720 with a TLR-2 agonist fail to protect against Buruli ulcer in mice

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9659
Author(s):  
Kirstie M. Mangas ◽  
Nicholas J. Tobias ◽  
Estelle Marion ◽  
Jérémie Babonneau ◽  
Laurent Marsollier ◽  
...  
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Significant Difference ◽  
Vaccine Antigens ◽  
Antibody Titres ◽  
Vaccine Potential ◽  
Time To Onset

Background Mycobacterium ulcerans is the causative agent of a debilitating skin and soft tissue infection known as Buruli ulcer (BU). There is no vaccine against BU. The purpose of this study was to investigate the vaccine potential of two previously described immunogenic M. ulcerans proteins, MUL_3720 and Hsp18, using a mouse tail infection model of BU. Methods Recombinant versions of the two proteins were each electrostatically coupled with a previously described lipopeptide adjuvant. Seven C57BL/6 and seven BALB/c mice were vaccinated and boosted with each of the formulations. Vaccinated mice were then challenged with M. ulcerans via subcutaneous tail inoculation. Vaccine performance was assessed by time-to-ulceration compared to unvaccinated mice. Results The MUL_3720 and Hsp18 vaccines induced high titres of antigen-specific antibodies that were predominately subtype IgG1. However, all mice developed ulcers by day-40 post-M. ulcerans challenge. No significant difference was observed in the time-to-onset of ulceration between the experimental vaccine groups and unvaccinated animals. Conclusions These data align with previous vaccine experiments using Hsp18 and MUL_3720 that indicated these proteins may not be appropriate vaccine antigens. This work highlights the need to explore alternative vaccine targets and different approaches to understand the role antibodies might play in controlling BU.

scholarly journals High antibody titres induced by protein subunit vaccines against Buruli ulcer using Mycobacterium ulcerans antigens Hsp18 and MUL_3720

2020 ◽  
Author(s):  
Kirstie M. Mangas ◽  
Nicholas Tobias ◽  
Estelle Marion ◽  
Jérémie Babonneau ◽  
Laurent Marsollier ◽  
...  
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Significant Difference ◽  
Vaccine Antigens ◽  
Antibody Titres ◽  
Vaccine Potential ◽  
Time To Onset

AbstractBackgroundMycobacterium ulcerans is the causative agent of a debilitating skin and soft tissue infection known as Buruli ulcer (BU). There is no vaccine against BU. The purpose of this study was to investigate the vaccine potential of two previously described immunogenic M. ulcerans proteins, MUL_3720 and Hsp18, using a mouse tail infection model of BU.MethodsRecombinant versions of the two proteins were each electrostatically coupled with a previously described lipopeptide adjuvant. Seven C57BL/6 and seven BALB/c mice were vaccinated and boosted with each of the formulations. Vaccinated mice were then challenged with M. ulcerans via subcutaneous tail inoculation. Vaccine performance was assessed by time-to-ulceration compared to unvaccinated mice.ResultsThe MUL_3720 and Hsp18 vaccines induced high titres of antigen-specific antibodies that were predominately subtype IgG1. However, all mice developed ulcers by day-40 post-M. ulcerans challenge. No significant difference was observed in the time-to-onset of ulceration between the experimental vaccine groups and unvaccinated animals.ConclusionsThese data align with previous vaccine experiments using Hsp18 and MUL_3720 that indicated these proteins may not be appropriate vaccine antigens. This work highlights the need to explore alternative vaccine targets and different approaches to understand the role antibodies might play in controlling BU.

scholarly journals Chemotherapy-Associated Changes of Histopathological Features of Mycobacterium ulcerans Lesions in a Buruli Ulcer Mouse Model

2011 ◽  
Vol 56 (2) ◽  
pp. 687-696 ◽  
Author(s):  
Marie-Thérèse Ruf ◽  
Daniela Schütte ◽  
Aurélie Chauffour ◽  
Vincent Jarlier ◽  
Baohong Ji ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Histopathological Study ◽  
Content Type ◽  
Histopathological Features ◽  
Treatment Regimens ◽  
Mouse Infection Model ◽  
New Treatment

ABSTRACTCombination chemotherapy with rifampin and streptomycin (RIF-STR) for 8 weeks is currently recommended by the WHO as the first-line treatment forMycobacterium ulceransinfection (Buruli ulcer). To gain better insight into the mode of action of these antibiotics against establishedM. ulceransinfection foci and to characterize recovery of local immune responses during chemotherapy, we conducted a detailed histopathological study ofM. ulcerans-infected and RIF-STR-treated mice. Mice were inoculated withM. ulceransin the footpad and 11 weeks later treated with RIF-STR. Development of lesions during the first 11 weeks after infection and subsequent differences in disease progression between RIF-STR-treated and untreated mice were studied. Changes in histopathological features, footpad swelling, and number of CFU were analyzed. After inoculation withM. ulcerans, massive infiltrates dominated by polymorphonuclear leukocytes developed at the inoculation site but did not prevent bacterial multiplication. Huge clusters of extracellular bacteria located in large necrotic areas and surrounded by dead leukocytes developed in the untreated mice. Chemotherapy with RIF-STR led to a rapid drop in CFU associated with loss of solid Ziehl-Neelsen staining of acid-fast bacilli. Development of B-lymphocyte clusters and of macrophage accumulations surrounding the mycobacteria demonstrated the resolution of local immune suppression. Results demonstrate that the experimentalM. ulceransmouse infection model will be a valuable tool to investigate efficacy of new treatment regimens and of candidate vaccines.

scholarly journals Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Paul J. Converse ◽  
Deepak V. Almeida ◽  
Sandeep Tyagi ◽  
Jian Xu ◽  
Eric L. Nuermberger
Keyword(s):  
Buruli Ulcer ◽  
Oxidase Inhibitor ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Synergistic Activity ◽  
Content Type ◽  
Drug Regimens ◽  
Long Acting ◽  
Synthase Inhibitor

ABSTRACT Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc1:aa3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis. Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidase-deficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 μg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.

scholarly journals Dimerization of Dengue Virus E Subunits Impacts Antibody Function and Domain Focus

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
Ashlie Thomas ◽  
Devina J. Thiono ◽  
Stephan T. Kudlacek ◽  
John Forsberg ◽  
Lakshmanane Premkumar ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Quaternary Structure ◽  
Protein Structures ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
E Protein ◽  
Vaccine Antigens ◽  
Viral Surface

ABSTRACT Dengue virus (DENV) is responsible for the most prevalent and significant arthropod-borne viral infection of humans. The leading DENV vaccines are based on tetravalent live-attenuated virus platforms. In practice, it has been challenging to induce balanced and effective responses to each of the four DENV serotypes because of differences in the replication efficiency and immunogenicity of individual vaccine components. Unlike live vaccines, tetravalent DENV envelope (E) protein subunit vaccines are likely to stimulate balanced immune responses, because immunogenicity is replication independent. However, E protein subunit vaccines have historically performed poorly, in part because the antigens utilized were mainly monomers that did not display quaternary-structure epitopes found on E dimers and higher-order structures that form the viral envelope. In this study, we compared the immunogenicity of DENV2 E homodimers and DENV2 E monomers. The stabilized DENV2 homodimers, but not monomers, were efficiently recognized by virus-specific and flavivirus cross-reactive potently neutralizing antibodies that have been mapped to quaternary-structure epitopes displayed on the viral surface. In mice, the dimers stimulated 3-fold-higher levels of virus-specific neutralizing IgG that recognized epitopes different from those recognized by lower-level neutralizing antibodies induced by monomers. The dimer induced a stronger E domain I (EDI)- and EDII-targeted response, while the monomer antigens stimulated an EDIII epitope response and induced fusion loop epitope antibodies that are known to facilitate antibody-dependent enhancement (ADE). This study shows that DENV E subunit antigens that have been designed to mimic the structural organization of the viral surface are better vaccine antigens than E protein monomers. IMPORTANCE Dengue virus vaccine development is particularly challenging because vaccines have to provide protection against four different dengue virus stereotypes. The leading dengue virus vaccine candidates in clinical testing are all based on live-virus vaccine platforms and struggle to induce balanced immunity. Envelope subunit antigens have the potential to overcome these limitations but have historically performed poorly as vaccine antigens, because the versions tested previously were presented as monomers and not in their natural dimer configuration. This study shows that the authentic presentation of DENV2 E-based subunits has a strong impact on antibody responses, underscoring the importance of mimicking the complex protein structures that are found on DENV particle surfaces when designing subunit vaccines.

scholarly journals CoVaccine HT™ adjuvant potentiates robust immune responses to recombinant SARS-CoV-2 Spike S1 immunisation

2020 ◽  
Author(s):  
Brien K. Haun ◽  
Chih-Yun Lai ◽  
Caitlin A. Williams ◽  
Teri Ann Wong ◽  
Michael M. Lieberman ◽  
...  
Keyword(s):  
Immune Responses ◽  
Respiratory Virus ◽  
Protective Efficacy ◽  
Affinity Maturation ◽  
Cell Mediated Immunity ◽  
Antigen Binding ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Contagious Nature ◽  
Antibody Titres

ABSTRACTThe current COVID-19 pandemic has claimed hundreds of thousands of lives and its causative agent, SARS-CoV-2, has infected millions, globally. The highly contagious nature of this respiratory virus has spurred massive global efforts to develop vaccines at record speeds. In addition to enhanced immunogen delivery, adjuvants may greatly impact protective efficacy of a SARS-CoV-2 vaccine. To investigate adjuvant suitability, we formulated protein subunit vaccines consisting of the recombinant S1 domain of SARS-CoV-2 Spike protein alone or in combination with either CoVaccine HT™ or Alhydrogel. CoVaccine HT™ induced high titres of antigen-binding IgG after a single dose, facilitated affinity maturation and class switching to a greater extent than Alhydrogel and elicited potent cell-mediated immunity as well as virus neutralising antibody titres. Data presented here suggests that adjuvantation with CoVaccine HT™ can rapidly induce a comprehensive and protective immune response to SARS-CoV-2.

scholarly journals Vaccine-specific immune responses against Mycobacterium ulcerans infection in a low-dose murine challenge model

2019 ◽  
Author(s):  
Kirstie M. Mangas ◽  
Andrew H. Buultjens ◽  
Jessica L. Porter ◽  
Sarah L. Baines ◽  
Estelle Marion ◽  
...  
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
Subcutaneous Tissue ◽  
Buruli Ulcer ◽  
Experimental Period ◽  
Mycobacterium Ulcerans ◽  
Prognostic Models ◽  
Infection Model ◽  
Multivariate Statistical ◽  
Immune Parameters

AbstractThe neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective BU vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl-reductase (ER) domain of the M. ulcerans mycolactone polyketide synthases electrostatically coupled with a previously described TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of an engineered bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis Bacille Calmette-Guérin (BCG) were equally well protected, with both groups faring significantly better than non-vaccinated animals (p<0.05). A suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were then used to interrogate the immune response data to develop disease-prognostic models. High levels of IL-2 and low IFN-γ produced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression then revealed vaccine-specific profiles of protection. High titres of ER-specific IgG serum antibodies together with IL-2 and IL-4 in the draining lymph node (DLN) were associated with protection induced by the experimental ER vaccine. In contrast, high titres of IL-6, TNF-α, IFN-γ and IL-10 in the DLN and low IFNγ titres in the spleen were associated with protection following BCG vaccination. This study suggests an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.

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