Killed Bacillus subtilis spores as a mucosal adjuvant for an H5N1 vaccine

Song, Manki; Hong, Huynh A.; Huang, Jen-Min; Colenutt, Claire; Kháng, Đinh Duy; Nguyen, Vananh T.; Park, Sung-Moo; Shim, Byoung-Shik; Song, Ho Hyun; Cheon, In Su; Jang, Ji Eun; Choi, Jung-ah; Choi, Young Ki; Stadler, Konrad; Cutting, Simon M.

doi:10.1016/j.vaccine.2012.03.016

Cited by 79 publications

(93 citation statements)

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“…In general, B. subtilis spores have been used as a vaccine adjuvant for other infectious agents, such as highly pathogenic influenza virus, in a formulation for mucosal delivery (26). These studies reported that spores from the PY79 strain of B. subtilis induced high levels of IL-2, IL-1, and IL-6 in spleen cell cultures from immunized mice and a significant increase in antigen-specific antibodies, similar to results obtained with the current study although the strain used here was PA3.…”

Section: Discussionmentioning

confidence: 99%

“…Other investigators have shown that IgA may play a role in modulating infection (36), and thus mucosal administration of the B. subtilis vaccines may warrant further investigation. Killed spores have been shown to induce IgG2a (Th1 type antibody) when administered intranasally (26), but when given orally they induced IgG subclasses that were IgG1 and IgG2b, indicative of a Th2 type of immune response (37). MPL, when inoculated intracutaneously, resulted in IgG1, IgG2a, IgG2b, and IgG3 antibodies being produced (38).…”

Section: Discussionmentioning

confidence: 99%

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Comparative Analysis of Bacillus subtilis Spores and Monophosphoryl Lipid A as Adjuvants of Protein-Based Mycobacterium tuberculosis-Based Vaccines: Partial Requirement for Interleukin-17A for Induction of Protective Immunity

Esparza‐González

Troy

Izzo

2014

Clin Vaccine Immunol

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The development of adjuvants for vaccines has become an important area of research as the number of protein-based vaccines against infectious pathogens increases. Currently, there are a number of adjuvant-based Mycobacterium tuberculosis vaccines in clinical trials that have shown efficacy in animal models. Despite these novel adjuvants, there is still a need to design new and more versatile adjuvants that have minimal adverse side effects but produce robust long-lasting adaptive immune responses. To this end, we hypothesized that Bacillus subtilis spores may provide the appropriate innate signals that are required to generate such vaccine-mediated responses, which would be sufficient to reduce the mycobacterial burden after infection with M. tuberculosis. In addition, we compared the response generated by B. subtilis spores to that generated by monophosphoryl lipid A (MPL), which has been used extensively to test tuberculosis vaccines. The well-characterized, 6-kDa early secretory antigenic target of M. tuberculosis (ESAT-6; Rv3875) was used as a test antigen to determine the T cell activation potential of each adjuvant. Inoculated into mice, B. subtilis spores induced a strong proinflammatory response and Th1 immunity, similar to MPL; however, unlike MPL formulated with dimethyldioctadecylammonium (DDA) bromide, it failed to induce significant levels of interleukin-17A (IL-17A) and was unable to significantly reduce the mycobacterial burden after pulmonary infection with M. tuberculosis. Further analysis of the activity of MPL-DDA suggested that IL-17A was required for protective immunity. Taken together, the data emphasize the requirement for a network of cytokines that are essential for protective immunity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Bacillus subtilis Spores and Monophosphoryl Lipid A as Adjuvants of Protein-Based Mycobacterium tuberculosis-Based Vaccines: Partial Requirement for Interleukin-17A for Induction of Protective Immunity

Esparza‐González

Troy

Izzo

2014

Clin Vaccine Immunol

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“…Presumably, spores facilitate entry of the M. tuberculosis antigens into the major histocompatibility complex class I and II presentation pathways, and their fate parallels the fate of other microparticulate carriers, such as immune-stimulating complexes (ISCOMs), virus-like particles (VLPs), and biodegradable microspheres (28)(29)(30)(31). In other work, we have shown that spores can prime the innate immune system by (i) promoting maturation of dendritic cells, (ii) recruiting NK cells into the lungs, and (iii) activating the NK-B pathway, most probably through interaction of specific spore ligands with one or more Toll-like receptors (6). We predict, then, that these responses may also play a role in protection against M. tuberculosis, for which the importance of innate immunity is now becoming apparent (32).…”

Section: Discussionmentioning

confidence: 99%

“…In the case of influenza virus, killed spores adsorbed with inactivated H5N1 were able to fully protect mice against challenge with live H5N2 when administered by the intranasal (i.n.) route (6). A defining feature of the use of spores as a vaccine delivery system is their ability to generate mucosal immune responses, i.e., secretory IgA (sIgA), coupled with their intrinsic adjuvant properties (5).…”

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confidence: 99%

Mucosal Vaccination against Tuberculosis Using Inert Bioparticles

et al. 2013

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c Needle-free, mucosal immunization is a highly desirable strategy for vaccination against many pathogens, especially those entering through the respiratory mucosa, such as Mycobacterium tuberculosis. Unfortunately, mucosal vaccination against tuberculosis (TB) is impeded by a lack of suitable adjuvants and/or delivery platforms that could induce a protective immune response in humans. Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract. Our data showed that mice immunized nasally with coated spores developed humoral and cellular immune responses and multifunctional T cells and, most importantly, presented significantly reduced bacterial loads in their lungs and spleens following pathogenic challenge. We conclude that this new vaccine delivery platform merits further development as a mucosal vaccine for TB and possibly also other respiratory pathogens. Athird of the world's population is estimated to be infected with Mycobacterium tuberculosis, the causative pathogen of tuberculosis (TB). Although the incidence of TB has been slowly decreasing from year to year, this disease still accounts for over a million deaths per annum, mostly in the developing world. TB, however, is also beginning to have an impact on the more developed nations, for example, because of the increased levels of people movement and international travel, which only serve to disseminate TB. Controlling TB relies on a number of strategies, including vaccination, drug therapy, and improved living standards. However, only improved living standards have been shown to have any real impact, and both the current TB drugs and vaccination strategies carry a number of inherent flaws. With drug therapy, multiresistant strains of M. tuberculosis and, more recently, extensively drug-resistant (XDR) M. tuberculosis variants have emerged, showing that drug development may, at most, produce only a short-term impact. The current vaccine against TB, M. bovis BCG, is generally considered unsatisfactory because of its variable efficacy (in different parts of the world) and the shortlived protection that it confers, especially against the reactivated pulmonary form of the disease. For these reasons, BCG is no longer routinely used in some countries.Bearing in mind these concerns, a better vaccine is now a priority. It should be noted that the results of the first-ever efficacy trial (phase 2b) of a new TB vaccine (MVA85A) that could boost the efficacy of BCG was concluded in early 2013 but with disappointing results (1). Although other trials are planned or are in progress for at least nine other TB vaccines, it is clear that the tasks ahead will be challenging. There are some important issues regarding the design of TB vaccines that might now be reconsidered, for example, the general assumption that cellular responses are of paramount imp...

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“…PY79 has been found to be nontoxic to vertebrates, lacks potentially hazardous virulence traits, and is very closely related to a Bacillus subtilis strain marketed in Italy as a human probiotic (16)(17)(18)(19)(20). PY79 has been studied as an agent to prevent disease caused by food-borne pathogens, as a vehicle for vaccines, and as a mucosal adjuvant (21)(22)(23)(24)(25)(26)(27).…”

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confidence: 99%

Bacillus subtilis Strain Engineered for Treatment of Soil-Transmitted Helminth Diseases

Miller

Derman

et al. 2013

Appl Environ Microbiol

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c Soil-transmitted helminths (hookworms, whipworms, and large roundworms) are agents of intestinal roundworm diseases of poverty that infect upwards of 2 billion people worldwide. A great challenge in treating these diseases is the development of anthelmintic therapeutics that are inexpensive, can be produced in great quantity, and are capable of delivery under varied and adverse environmental conditions. A potential solution to this challenge is the use of live bacteria that are acceptable for human consumption, e.g., Bacillus subtilis, and that can be engineered with therapeutic properties. In this study, we expressed the Bacillus thuringiensis anthelmintic protein Cry5B in a bacterial strain that has been used as a model for live bacterial therapy, Bacillus subtilis PY79. PY79 transformed with a Cry5B expression plasmid (PY79-Cry5B) is able to express Cry5B from the endogenous B. thuringiensis cry5B promoter. During sporulation of PY79-Cry5B, Cry5B is packaged as a crystal. Furthermore, Cry5B produced in PY79 is bioactive, with a 50% lethal concentration (LC 50 ) of 4.3 g/ml against the roundworm Caenorhabditis elegans. PY79-Cry5B was a significantly effective therapeutic in experimental Ancylostoma ceylanicum hookworm infections of hamsters. A single 10-mg/kg (0.071 mol/kg of body weight) dose of Cry5B administered as a Cry5B-PY79 spore crystal lysate achieved a 93% reduction in hookworm burdens, which is superior on a molar level to reductions seen with clinically used anthelmintics. Given that a bacterial strain such as this one can be produced cheaply in massive quantities, our results demonstrate that the engineering and delivery of live bacterial strains have great potential to treat a significant contributor to poverty worldwide, namely, hookworm disease and other soil-transmitted helminthiasis.

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Killed Bacillus subtilis spores as a mucosal adjuvant for an H5N1 vaccine

Cited by 79 publications

References 51 publications

Comparative Analysis of Bacillus subtilis Spores and Monophosphoryl Lipid A as Adjuvants of Protein-Based Mycobacterium tuberculosis-Based Vaccines: Partial Requirement for Interleukin-17A for Induction of Protective Immunity

Comparative Analysis of Bacillus subtilis Spores and Monophosphoryl Lipid A as Adjuvants of Protein-Based Mycobacterium tuberculosis-Based Vaccines: Partial Requirement for Interleukin-17A for Induction of Protective Immunity

Mucosal Vaccination against Tuberculosis Using Inert Bioparticles

Bacillus subtilis Strain Engineered for Treatment of Soil-Transmitted Helminth Diseases

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