Protective Effect of a Lipid-Based Preparation from <i>Mycobacterium smegmatis</i> in a Murine Model of Progressive Pulmonary Tuberculosis

García, Maria de los Angeles; Borrero, Reinier; Lanio, Maria E.; Tirado, Yanely; Alvarez, Nadine; Puig, Alina; Aguilar, Alicia; Canet, Liem; Mata Espinoza, Dulce; Barrios Payán, Jorge; Sarmiento, María Elena; Hernández-Pando, Rogelio; Norazmi, Mohd-Nor; Acosta, Armando

doi:https://doi.org/10.1155/2014/273129

BioMed Research International

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Research Article | Open Access

Volume 2014 | Article ID 273129 | https://doi.org/10.1155/2014/273129

Protective Effect of a Lipid-Based Preparation from Mycobacterium smegmatis in a Murine Model of Progressive Pulmonary Tuberculosis

Maria de los Angeles García,¹Reinier Borrero,¹Maria E. Lanio,²Yanely Tirado,¹Nadine Alvarez,¹Alina Puig,¹Alicia Aguilar,¹Liem Canet,²Dulce Mata Espinoza,³Jorge Barrios Payán,³María Elena Sarmiento,^1,4and Rogelio Hernández-Pando³ et al.

Academic Editor: Kota V. Ramana

Received21 Jul 2014

Revised11 Sept 2014

Accepted15 Sept 2014

Published07 Dec 2014

Abstract

A more effective vaccine against tuberculosis (TB) is urgently needed. Based on its high genetic homology with Mycobacterium tuberculosis (Mtb), the nonpathogenic mycobacteria, Mycobacterium smegmatis (Ms), could be an attractive source of potential antigens to be included in such a vaccine. We evaluated the capability of lipid-based preparations obtained from Ms to provide a protective response in Balb/c mice after challenge with Mtb H37Rv strain. The intratracheal model of progressive pulmonary TB was used to assess the level of protection in terms of bacterial load as well as the pathological changes in the lungs of immunized Balb/c mice following challenge with Mtb. Mice immunized with the lipid-based preparation from Ms either adjuvanted with Alum (LMs-AL) or nonadjuvanted (LMs) showed significant reductions in bacterial load () compared to the negative control group (animals immunized with phosphate buffered saline (PBS)). Both lipid formulations showed the same level of protection as Bacille Calmette and Guerin (BCG). Regarding the pathologic changes in the lungs, mice immunized with both lipid formulations showed less pneumonic area when compared with the PBS group () and showed similar results compared with the BCG group. These findings suggest the potential of LMs as a promising vaccine candidate against TB.

1. Introduction

Bacille Calmette and Guerin (BCG), the only anti-TB vaccine currently available, seems to be only effective against severe childhood forms of the disease but not against adult pulmonary TB and for the control of the transmission. Therefore, there is an urgent need for new improved vaccines against TB [1, 2].

Lipids are considered important molecules involved in the pathogenesis of TB [3–5]. Many of these molecules are localized at the cell surface and are components of the cell wall of mycobacteria [3–5]. The localization of such molecules as well as the fact that they constitute important virulence factors makes them potential valuable targets for the host immune system [3–5]. Although most subunit TB vaccines (with few exceptions) that are in different phases of evaluation are based primarily on proteins [6], we hypothesize that mycobacterial lipid antigens could also be effective vaccine candidates against Mtb infection. In fact, the protective effect against Mtb of a liposome formulation composed of total lipids of Mtb has been reported in the guinea pig model [7]. Liposomes containing lipid fractions of Mtb have been reported to confer specific humoral and cellular immune responses, as well as protection upon Mtb challenge in guinea pigs [8, 9].

Our group has previously reported on the capability of preparations containing chloroform extractable lipids from Mycobacterium smegmatis (Ms) to induce specific IgG antibodies as well as a cross-reactive response against a mixture of Mtb antigens in Balb/c mice [10, 11]. Additionally, proteoliposomes from Ms and BCG elicited cross reactive responses against antigenic fractions from Mtb, demonstrating the antigenic similarities between the cell wall components of these non-pathogenic mycobacteria and Mtb [12, 13].

In this study, we evaluated whether a lipid-based preparation from Ms could provide protection against the virulent laboratory Mtb H37Rv strain in Balb/c mice by using the intratracheal progressive pulmonary TB infection model.

In fact, the current study shows that lipid extracts obtained from Ms either adjuvanted with Alum (LMs-AL) or nonadjuvanted (LMs) were able to provide similar protection against Mtb compared to that provided by BCG.

2. Materials and Methods

2.1. Bacterial Strains

Ms mc²155 strain was obtained from the collection of the National Reference Laboratory of Tuberculosis, Pedro Kouri Institute, Cuba. BCG (Phipps) was kindly provided by Marcel A. Behr from the McGill General Hospital, Montreal, Canada.

2.2. LMs

Ms was grown in 8% nutrient broth (BIOCEN, Cuba) containing 1% (w/v) yeast extract (Merk, Germany), 0.5% (v/v) glycerol (Riedel de Haen, Germany), and 0.4% (v/v) Tween 80 (Fluka, Germany) for 48 h with continuous agitation (200 rpm) at 37°C. The Mtb H37Rv and BCG Phipps strains were grown to early mid-log phase in Middlebrook 7H9 medium (Difco, Detroit, MI) supplemented with ADC (BBL, Cockeysville, MD) and 0.05% Tween 80 (Sigma Chemical Co., St. Louis, MO) at 37°C with 5% CO₂ and with continuous agitation. Ziehl-Neelsen staining was performed to determine the presence of mycobacteria in the culture [14]. Lipids from Ms were extracted according to the method of Bligh and Dyer [15] and liposome-like particles were prepared by dehydration and rehydration using the method described previously [16].

2.3. Mice

Female Balb/c mice (6–8 weeks) were used for immunization. Mice were maintained in cages fitted with microisolators connected to negative pressure.

2.4. Challenge Study

Four groups of mice ( each) were inoculated subcutaneously (100 μL) with either PBS (PBS), BCG (BCG Phipps, CFU), LMs (1 mg of total lipid preparation from Ms), or LMs-AL (1 mg LMs + 1 mg Alum Alhydrogel, Sigma). The animals received two doses of PBS, LMs, and LMs-AL at 0 and 21 days whereas the group immunized with BCG received a single dose on day 0. Two months after the last immunization, all mice were challenged simultaneously by intratracheal exposure to Mtb H37Rv (2.5 × 10⁵ CFU) as described [17, 18]. All procedures were performed in a laminar flow cabinet in a biosafety level III facility.

2.5. Bacilli Load

Two months after challenge, the mice were euthanized and one lung from each animal was aseptically removed and homogenized with a Polytron in sterile isotonic saline solution containing 0.05% Tween 80 (Sigma). Homogenized lungs were serially diluted and plated in duplicates on 7H10 agar (Difco Lab cod) plates. The plates were incubated for 3 weeks at 37°C and colonies were counted to determine the total CFU in lungs.

2.6. Histopathology and Morphometric Studies

Lung samples (the other lung from each infected Balb/c mouse) were dehydrated and embedded in paraffin. The lung tissues were sectioned at 5 μm thick and stained with haematoxylin and eosin [18]. The areas affected by pneumonia which correspond to alveolar spaces occupied by inflammatory cells were measured and analyzed using Leica Q-win system software (Leica Microsystems Imaging Solutions ltd., Cambridge, UK, 25X). First, the whole area of the lung was measured. Then the areas affected by pneumonia were determined, and the percentage of lung surface affected by pneumonia was calculated in each mouse from the different groups.

2.7. Data Management

Measurements were made blind, and data of log₁₀ CFU and percentage of pneumonic area/lung are expressed as the mean ± SD. One way ANOVA and Multiple Range tests were used for the determination of significant differences between the groups.

All the procedures were carried out according to the guidelines [19] and approved by the Ethical Committee for Experimentation in Animals of the National Institute of Medical Sciences and Nutrition “Salvador Zubirán” (INCMNSZ) of Mexico.

3. Results and Discussion

In the present study, the protective capability against TB in mice of a lipid preparation from Ms (LMs-AL and LMs) using PBS as negative control and BCG as the gold standard was evaluated.

As shown in Figure 1, mice immunized with LMs-AL and LMs had significantly reduced bacterial load in the lungs compared to those immunized with PBS (). LMs-immunized mice, with and without Alum, showed similar levels of lung CFU compared with each other and with BCG-vaccinated animals (Figure 1).

We have previously shown that mice immunized with LMs produced a significantly higher level of specific IgG response compared to animals receiving PBS alone [10]. We also demonstrated that immunization with this formulation elicited a cross-reactive IgG response against a cell wall fraction from Mtb [10]. Animals receiving the same formulation in combination with Alum or Montanide did not show specific or cross-reactive immune responses [10]. A higher reactivity of IgG antibodies against this formulation was detected in patients with pulmonary TB, compared with healthy individuals, which suggests the expression of similar or cross-reactive epitopes during the active infection with Mtb in humans [10]. When the total lipid extract of Ms was formulated in liposomes containing commercial lipids without adjuvants, a similar induction of specific and cross-reactive IgG response against Mtb was obtained [11].

The histologic study showed several patches of pneumonia in the lungs of control nonvaccinated mice, while vaccinated animals with BCG, LMs, or LMs-AL showed smaller pneumonic areas (Figure 2).

(a)

(b)

(c)

(d)

These histological differences were confirmed by automated morphometry. As shown in Figure 3, animals immunized with LMs and LMs-AL have significantly lower percentage of lung pneumonic area compared to animals immunized with PBS () and no differences with the group immunized with BCG. A previous study has shown similar results using lipids from Mtb in the experimental guinea pig model of TB [7].

Mycobacterial lipids are recognized as antigens with the capacity to stimulate specific T cell responses and play a role in protection against TB, mainly mediated by presentation in the context of CD1 molecules [5, 20–24].

The CD1 molecules have a restricted presence in mice, represented only by CD1d. Therefore, the mechanisms of induction of protection mediated by lipids in this species may differ compared to humans [5, 20].

Regarding the mechanisms of protection mediated by CD1d in mice, it has been demonstrated that the recognition of lipid antigens mediated by CD1d is related to a subpopulation of cells defined as NKT cells which has the capacity to recognize different lipids including self-determinants and exogenous lipids from different microorganisms as Streptococcus pneumoniae, Helicobacter pylori, Borrelia burgdorferi, Sphingomonas spp, and Group B Streptococcus [25]. Regarding mycobacteria, the presentation mediated by CD1d in mice and humans of phosphatidylinositol mannoside (PIM) which induce the production of gamma interferon and cell-mediated cytotoxic responses in NKT cells [26] has been described. This kind of response could be involved in the protection induced by our vaccine candidate. In our case, the protective effect induced by the immunization with the lipid formulations at the cellular level could be explained by the presentation of different components via CD1d and other unknown mechanisms.

Taking into consideration the induction of specific IgG antibodies and the elicitation of cross-reactive immune responses against Mtb after immunization with formulations containing lipids of Ms in mice [10, 11], the role of specific antibodies in the protection induced by these formulations cannot be ruled out. The contribution of specific antibodies in protection against TB is a subject of debate, but a growing body of evidence supports the potential role of antibodies in the protection against TB [27–36]. The adjuvant effect of a formulation containing total lipid extracts of Ms has been reported [37, 38]. This formulation demonstrated adjuvant effect after the administration with antigens from Leptospira and showed stimulatory capacity upon the innate and specific immune responses [37, 38].

Other mycobacterial lipid components such as phosphatidylinositol mannosides have demonstrated mucosal adjuvanticity [39]. The cationic adjuvant formulation AF01 composed of DDA as a delivery vehicle and synthetic mycobacterial cord factor as the immunomodulator has been extensively evaluated [40–45]. This formulation induced superior specific cellular and humoral immune response against ovalbumin compared to other currently used adjuvants [40]. The induced response is independent of the stimulation of toll-like receptors (TLR) 2, 3, 4, and 7 [40]. The use of this adjuvant with Mtb antigens induces strong protection against challenge with Mtb in experimental animals [40, 41, 46]. Other combinations of DDA with lipid fractions of BCG demonstrated high adjuvanticity and the induction of strong protection when combined with Mtb antigens [47, 48].

Considering the intrinsic adjuvant effect of the lipid components of mycobacteria, the protective effect produced by the administration of our lipid formulations could be explained by a combination of nonspecific immunostimulatory effects and the specific stimulation of humoral and cellular immune responses targeting lipid antigens.

The potential of mucosal immunization in the development of new generation vaccine candidates against TB has been recognized [49–51] as well as the role of mycobacterial lipidic components as mucosal adjuvants [39]. These antecedents suggest the possibility of evaluating our experimental vaccine candidate administered by the mucosal route in future studies.

The observation that LMs, either with or without Alum, reduced the bacterial burden as well as pathology in the lungs of mice challenged with Mtb shows the potential of lipids from nonpathogenic mycobacteria as candidate vaccines against the disease.

Compared to previous studies (7–9), the advantage of our study is the use of fast-growing, nonpathogenic mycobacteria, which could facilitate the large-scale use of such a preparation in humans.

4. Conclusions

This study is the first to report on the protective efficacy of a preparation based on total lipids extracted from Ms against Mtb infection. LMs and LMs-AL showed better protective efficacy compared to the negative control group and similar protection to the gold standard BCG vaccine in terms of reducing the bacterial load and pneumonic area in the lungs. However, further investigations are necessary to evaluate their eventual potential as improved vaccines against TB.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The authors acknowledge the financial contribution by the Long-Term Research Grant Scheme (203/PSK/6722001), Department of Higher Education, Ministry of Education, Malaysia, Ministry of Science and Technology, Cuba, and the Institute of Science and Technology of Mexico City (PICSA12-173).

References

A. Zumla, M. Raviglione, R. Hafner, and C. F. Von Reyn, “Tuberculosis,” The New England Journal of Medicine, vol. 368, no. 8, pp. 745–755, 2013.
View at: Publisher Site | Google Scholar
S. H. E. Kaufmann, C. Lange, M. Rao et al., “Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review,” The Lancet Respiratory Medicine, vol. 2, no. 4, pp. 301–320, 2014.
View at: Publisher Site | Google Scholar
M. Morandi, M. Sali, R. Manganelli, and G. Delogu, “Exploiting the mycobacterial cell wall to design improved vaccines against tuberculosis,” The Journal of Infection in Developing Countries, vol. 7, no. 3, pp. 169–181, 2013.
View at: Publisher Site | Google Scholar
L. M. Lopez-Marin, “Non protein structures from mycobacteria: emerging actors for tuberculosis control,” Clinical & Developmental Immunology, vol. 2012, Article ID 917860, 9 pages, 2012.
View at: Publisher Site | Google Scholar
A. G. Kasmar, E. Layre, and B. Moody, “Lipid adjuvants and antigens embedded in the mycobacterial cell envelope,” in The Art & Science of Tuberculosis Vaccine Development, M. N. Norazmi, A. Acosta, and M. E. Sarmiento, Eds., pp. 123–149, Oxford University Press, Malaysia, 2nd edition, 2014, http://tbvaccines.usm.my/finlay.
View at: Google Scholar
M. J. Brennan, A. R. Sweeney, J. Woolley, B. Clagett, and L. F. Barker, “New TB vaccines. What is the pipeline?” in The Art & Science of Tuberculosis Vaccine Development, pp. 949–981, Oxford University Press, Malaysia, 2nd edition, 2014, http://tbvaccines.usm.my/finlay/.
View at: Google Scholar
C. C. Dascher, K. Hiromatsu, X. Xiong et al., “Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis,” International Immunology, vol. 15, no. 8, pp. 915–925, 2003.
View at: Publisher Site | Google Scholar
A. P. Singh and G. K. Khuller, “Liposomes as a carrier for mannophosphoinositide antigens of mycobacteria.,” Indian Journal of Biochemistry and Biophysics, vol. 30, no. 3, pp. 160–165, 1993.
View at: Google Scholar
A. P. Singh and G. K. Khuller, “Induction of immunity against experimental tuberculosis with mycobacterial mannophosphoinositides encapsulated in liposomes containing lipid A,” FEMS Immunology and Medical Microbiology, vol. 8, no. 2, pp. 119–126, 1994.
View at: Publisher Site | Google Scholar
M. de los Angeles García, R. Borrero, R. Marrón et al., “Evaluation of specific humoral immune response and cross reactivity against Mycobacterium tuberculosis antigens induced in mice immunized with liposomes composed of total lipids extracted from Mycobacterium smegmatis,” BMC Immunology, vol. 14, supplement 1, article S11, 2013.
View at: Publisher Site | Google Scholar
R. Borrero, M. de los A García, L. Canet et al., “Evaluation of the humoral immune response and cross reactivity against Mycobacterium tuberculosis of mice immunized with liposomes containing glycolipids of Mycobacterium smegmatis,” BMC immunology, vol. 14, supplement 1, article S13, 2013.
View at: Publisher Site | Google Scholar
L. Rodriguez, Y. Tirado, F. Reyes et al., “Proteoliposomes from Mycobacterium smegmatis induce immune cross-reactivity against Mycobacterium tuberculosis antigens in mice,” Vaccine, vol. 29, no. 37, pp. 6236–6241, 2011.
View at: Publisher Site | Google Scholar
F. Reyes, Y. Tirado, A. Puig et al., “Immunogenicity and cross-reactivity against Mycobacterium tuberculosis of proteoliposomes derived from Mycobacterium bovis BCG,” BMC immunology, vol. 14, article S7, 2013.
View at: Publisher Site | Google Scholar
P. J. Bishop and G. Neumann, “The history of the Ziehl-Neelsen stain,” Tubercle, vol. 51, no. 2, pp. 196–206, 1970.
View at: Publisher Site | Google Scholar
E. G. Bligh and W. J. Dyer, “A rapid method of total lipid extraction and purification,” Canadian Journal of Biochemistry and Physiology, vol. 37, no. 8, pp. 911–917, 1959.
View at: Publisher Site | Google Scholar
C. Kirby and G. Gergoriadis, “Dehydration-rehydration vesicles: a simple method for high yield drug entrapment in liposomes,” Nature Biotechnology, vol. 2, no. 11, pp. 979–984, 1984.
View at: Publisher Site | Google Scholar
A. R. Cervantes-Villagrana, R. Hernández-Pando, A. Biragyn et al., “Prime-boost BCG vaccination with DNA vaccines based in β-defensin-2 and mycobacterial antigens ESAT6 or Ag85B improve protection in a tuberculosis experimental model,” Vaccine, vol. 31, no. 4, pp. 676–684, 2013.
View at: Publisher Site | Google Scholar
R. Hernández-Pando, D. Aguilar-Leon, H. Orozco et al., “16α-Bromoepiandrosterone restores T helper cell type 1 activity and accelerates chemotherapy-induced bacterial clearance in a model of progressive pulmonary tuberculosis,” Journal of Infectious Diseases, vol. 191, no. 2, pp. 299–306, 2005.
View at: Publisher Site | Google Scholar
Canadian Council on Animal Care, Guide to the Care and Use of Experimental Animals, Ottawa, Canada, 1984.
P. Arora, E. L. Foster, and S. A. Porcelli, “CD1d and natural killer T cells in immunity to Mycobacterium tuberculosis,” Advances in Experimental Medicine and Biology, vol. 783, pp. 199–223, 2013.
View at: Publisher Site | Google Scholar
C. Seshadri, M. T. Turner, D. M. Lewinsohn, D. B. Moody, and I. van Rhijn, “Lipoproteins are major targets of the polyclonal human T cell response to Mycobacterium tuberculosis,” Journal of Immunology, vol. 190, no. 1, pp. 278–284, 2013.
View at: Publisher Site | Google Scholar
D. J. Montamat-Sicotte, K. A. Millington, C. R. Willcox et al., “A mycolic acid-specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection,” The Journal of Clinical Investigation, vol. 121, no. 6, pp. 2493–2503, 2011.
View at: Publisher Site | Google Scholar
M. M. Venkataswamy, A. Baena, M. F. Goldberg et al., “Incorporation of NKT cell-activating glycolipids enhances immunogenicity and vaccine efficacy of Mycobacterium bovis bacillus Calmette-Guérin,” Journal of Immunology, vol. 183, no. 3, pp. 1644–1656, 2009.
View at: Publisher Site | Google Scholar
J. Guiard, A. Collmann, L. F. Garcia-Alles et al., “Fatty acyl structures of mycobacterium tuberculosis sulfoglycolipid govern T cell response1,” The Journal of Immunology, vol. 182, no. 11, pp. 7030–7037, 2009.
View at: Publisher Site | Google Scholar
E. Girardi and D. M. Zajonc, “Molecular basis of lipid antigen presentation by CD1d and recognition by natural killer T cells,” Immunological Reviews, vol. 250, no. 1, pp. 167–179, 2012.
View at: Publisher Site | Google Scholar
K. Fischer, E. Scotet, M. Niemeyer et al., “Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10685–10690, 2004.
View at: Publisher Site | Google Scholar
N. Olivares, A. León, Y. López et al., “The effect of the administration of human gamma globulins in a model of BCG infection in mice,” Tuberculosis, vol. 86, no. 3-4, pp. 268–272, 2006.
View at: Publisher Site | Google Scholar
N. Olivares, A. Puig, D. Aguilar et al., “Prophylactic effect of administration of human gamma globulins in a mouse model of tuberculosis,” Tuberculosis, vol. 89, no. 3, pp. 218–220, 2009.
View at: Publisher Site | Google Scholar
Y. López, D. Yero, G. Falero-Diaz et al., “Induction of a protective response with an IgA monoclonal antibody against Mycobacterium tuberculosis 16 kDa protein in a model of progressive pulmonary infection,” International Journal of Medical Microbiology, vol. 299, no. 6, pp. 447–452, 2009.
View at: Publisher Site | Google Scholar
A. Acosta, M. N. Norazmi, and M. E. Sarmiento, “Antibody mediated immunity-a missed opportunity in the fight against tuberculosis?” Malaysian Journal of Medical Sciences, vol. 17, no. 2, pp. 66–67, 2010.
View at: Google Scholar
Y. López, G. Falero-Díaz, D. Yero, R. L. Solís, M. E. Sarmiento, and A. Acosta, “Antibodies in the protection against mycobacterial infections: what have we learned?” Procedia in Vaccinology, vol. 2, no. 2, pp. 172–177, 2010.
View at: Publisher Site | Google Scholar
A. Acosta, Y. López, M. N. Norazmi, R. H. Pando, N. Alvarez, and M. E. Sarmiento, “Towards a new challenge in TB control: development of antibody-based protection,” in Mycobacterium Tuberculosis/Book 3, P. Cardona, Ed., 2012.
View at: Google Scholar
N. Alvarez, O. Otero, F. Camacho et al., “Passive administration of purified secretory IgA from human colostrum induces protection against Mycobacterium tuberculosis in a murine model of progressive pulmonary infection,” BMC immunology, vol. 14, supplement 1, article S3, 2013.
View at: Google Scholar
A. Acosta, Y. Lopez, M. N. Norazmi et al., “The role of antibodies in the defense against tuberculosis,” in Current Issues in Diagnosis and Management, B. Mahboub, Ed., 2013.
View at: Google Scholar
A. Glatman-Freedman, “The role of antibodies against TB,” in The Art & Science of Tuberculosis Vaccine Development, M. N. Norazmi, A. Acosta, and M. E. Sarmiento, Eds., pp. 239–273, Oxford University Press, Malaysia, 2nd edition, 2014, http://tbvaccines.usm.my/finlay/.
View at: Google Scholar
E. Roy, E. Stavropoulos, J. Brennan et al., “Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice,” Infection and Immunity, vol. 73, no. 9, pp. 6101–6109, 2005.
View at: Publisher Site | Google Scholar
S. M. Faisal, J.-W. Chen, S. P. McDonough, C.-F. Chang, C.-H. Teng, and Y.-F. Chang, “Immunostimulatory and antigen delivery properties of liposomes made up of total polar lipids from non-pathogenic bacteria leads to efficient induction of both innate and adaptive immune responses,” Vaccine, vol. 29, no. 13, pp. 2381–2391, 2011.
View at: Publisher Site | Google Scholar
S. M. Faisal, W. Yan, S. P. McDonough, H. O. Mohammed, T. J. Divers, and Y.-F. Chang, “Immune response and prophylactic efficacy of smegmosomes in a hamster model of leptospirosis,” Vaccine, vol. 27, no. 44, pp. 6129–6136, 2009.
View at: Publisher Site | Google Scholar
N. A. Parlane, M. Denis, W. B. Severn et al., “Phosphatidylinositol mannosides are efficient mucosal adjuvants,” Immunological Investigations, vol. 37, no. 2, pp. 129–142, 2008.
View at: Publisher Site | Google Scholar
E. M. Agger, I. Rosenkrands, J. Hansen et al., “Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for vaccines with different immunological requirements,” PLoS ONE, vol. 3, no. 9, Article ID e3116, 2008.
View at: Publisher Site | Google Scholar
D. Christensen, E. M. Agger, L. V. Andreasen, D. Kirby, P. Andersen, and Y. Perrie, “Liposome-based cationic adjuvant formulations (CAF): past, present, and future,” Journal of Liposome Research, vol. 19, no. 1, pp. 2–11, 2009.
View at: Publisher Site | Google Scholar
M. Henriksen-Lacey, D. Christensen, V. W. Bramwell et al., “Comparison of the depot effect and immunogenicity of liposomes based on dimethyldioctadecylammonium (DDA), 3β-[N-(N′,N′- dimethylaminoethane)carbomyl] cholesterol (DC-Chol), and 1,2-dioleoyl-3- trimethylammonium propane (DOTAP): prolonged liposome retention mediates stronger Th1 responses,” Molecular Pharmaceutics, vol. 8, no. 1, pp. 153–161, 2011.
View at: Publisher Site | Google Scholar
M. Henriksen-Lacey, A. Devitt, and Y. Perrie, “The vesicle size of DDA: TDB liposomal adjuvants plays a role in the cell-mediated immune response but has no significant effect on antibody production,” Journal of Controlled Release, vol. 154, no. 2, pp. 131–137, 2011.
View at: Publisher Site | Google Scholar
S. E. Mcneil, I. Rosenkrands, E. M. Agger, P. Andersen, and Y. Perrie, “Subunit vaccines: distearoylphosphatidylcholine-based liposomes entrapping antigen offer a neutral alternative to dimethyldioctadecylammonium-based cationic liposomes as an adjuvant delivery system,” Journal of Pharmaceutical Sciences, vol. 100, no. 5, pp. 1856–1865, 2011.
View at: Publisher Site | Google Scholar
J. Davidsen, I. Rosenkrands, D. Christensen et al., “Characterization of cationic liposomes based on dimethyldioctadecylammonium and synthetic cord factor from M. tuberculosis (trehalose 6,6′- dibehenate)—a novel adjuvant inducing both strong CMI and antibody responses,” Biochimica et Biophysica Acta, vol. 1718, no. 1-2, pp. 22–31, 2005.
View at: Publisher Site | Google Scholar
A. T. Kamath, A.-F. Rochat, D. Christensen et al., “A liposome-based mycobacterial vaccine induces potent adult and neonatal multifunctional T cells through the exquisite targeting of dendritic cells,” PLoS ONE, vol. 4, no. 6, Article ID e5771, 2009.
View at: Publisher Site | Google Scholar
C. A. S. Andersen, I. Rosenkrands, A. W. Olsen et al., “Novel generation mycobacterial adjuvant based on liposome-encapsulated monomycoloyl glycerol from Mycobacterium bovis bacillus Calmette-Guérin,” The Journal of Immunology, vol. 183, no. 4, pp. 2294–2302, 2009.
View at: Publisher Site | Google Scholar
P. Nordly, K. S. Korsholm, E. A. Pedersen et al., “Incorporation of a synthetic mycobacterial monomycoloyl glycerol analogue stabilizes dimethyldioctadecylammonium liposomes and potentiates their adjuvant effect in vivo,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 77, no. 1, pp. 89–98, 2011.
View at: Publisher Site | Google Scholar
T. Olafsdottir and A. M. Harandi, “Mucosal immunity and vaccination with special emphasis on respiratory tract,” in The Art & Science of Tuberculosis Vaccine Development, M. N. Norazmi, A. Acosta, and M. E. Sarmiento, Eds., chapter 6, pp. 985–997, Oxford University Press, Malaysia, 2nd edition, 2014, http://tbvaccines.usm.my/finlay.
View at: Google Scholar
D. J. Laddy, A. J. Graves, A. Misra, and D. A. Hokey, “Inhalable vaccines for TB,” in The Art & Science of Tuberculosis Vaccine Development, M. N. Norazmi, A. Acosta, and M. E. Sarmiento, Eds., pp. 1027–1054, Oxford University Press, Malaysia, 2nd edition, 2014, http://tbvaccines.usm.my/finlay.
View at: Google Scholar
Z. Xing, F. Smaill, C. Horvath et al., “Respiratory mucosal immunization against pulmonary TB,” in The Art & Science of Tuberculosis Vaccine Development, M. N. Norazmi, A. Acosta, and M. E. Sarmiento, Eds., pp. 999–1025, Oxford University Press, Malaysia, 2nd edition, 2014, http://tbvaccines.usm.my/finlay.
View at: Google Scholar

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Copyright © 2014 Maria de los Angeles García et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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