Immunogenicity & reactogenicity of a recombinant HPV6 fusion protein vaccine adjuvanted with monophosphoryl lipid A

Tuberculosis (TB) remains a major and global problem of public health. An effective TB subunit vaccine is urgently needed. Proper selection of the delivery system for the vaccine is crucial for inducing an appropriate immune response tailored to control the target pathogen. In this study, we compared the immunogenicity and protective efficacy of CMFO subunit vaccines against primary progressive TB in two different adjuvant systems: the MTO oil-in-water (O/W) emulsion composed of monophosphoryl lipid A (MPL), trehalose-6,60-dibehenate (TDB), and oil in water emulsion MF59 and the DMT liposome containing dimethyldioctadecylammonium bromide (DDA), monophosphoryl lipid A (MPL), and trehalose-6,60-dibehenate (TDB). Our results demonstrated that the DMT-adjuvanted CMFO could confer more significant protection against M. tuberculosis infection than the CMFO/MTO did in mice. In particular, the adjuvant DMT showed a stronger ability than the O/W emulsion to adjuvant CMFO subunit vaccine and enhanced protection, attributed to elicit Th1-biased responses, strong Th1/Th17 cytokine responses, and IFN-γ+ or IL-2+ T cell responses. Therefore, our findings demonstrate that the liposome delivery system shows more effectiveness to adjuvant TB subunit vaccine than O/W emulsion and highlight the importance of adjuvant formulation for the better efficacy of a protein vaccine.

Download Full-text

A Fusion Protein Consisting of the Vaccine Adjuvant Monophosphoryl Lipid A and the Allergen Ovalbumin Boosts Allergen-Specific Th1, Th2, and Th17 ResponsesIn Vitro

Journal of Immunology Research ◽

10.1155/2016/4156456 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Stefan Schülke ◽

Lothar Vogel ◽

Ann-Christine Junker ◽

Kay-Martin Hanschmann ◽

Adam Flaczyk ◽

...

Keyword(s):

Fusion Protein ◽

Lipid A ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Strong Stimulation ◽

Tlr Agonist ◽

Allergy Treatment ◽

Tlr4 Ligand ◽

Th17 Cytokine ◽

Stimulation Of

Background. The detoxified TLR4-ligand Monophosphoryl Lipid A (MPLA) is the first approved TLR-agonist used as adjuvant in licensed vaccines but has not yet been explored as part of conjugated vaccines.Objective. To investigate the immune-modulating properties of a fusion protein consisting of MPLA and Ovalbumin (MPLA : Ova).Results. MPLA and Ova were chemically coupled by stable carbamate linkage. MPLA : Ova was highly pure without detectable product-related impurities by either noncoupled MPLA or Ova. Light scattering analysis revealed MPLA : Ova to be aggregated. Stimulation of mDC and mDC : DO11.10 CD4+TC cocultures showed a stronger activation of both mDC and Ova-specific DO11.10 CD4+TC by MPLA : Ova compared to the mixture of both components. MPLA : Ova induced both strong proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10) cytokine responses from mDCs while also boosting allergen-specific Th1, Th2, and Th17 cytokine secretion.Conclusion. Conjugation of MPLA and antigen enhanced the immune response compared to the mixture of both components. Due to the nonbiased boost of Ova-specific Th2 and Th17 responses while also inducing Th1 responses, this fusion protein may not be a suitable vaccine candidate for allergy treatment but may hold potential for the treatment of other diseases that require a strong stimulation of the host’s immune system (e.g., cancer).

Download Full-text

Faculty Opinions recommendation of The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1087287.540302 ◽

2007 ◽

Author(s):

Rino Rappuoli

Keyword(s):

Lipid A ◽

Vaccine Adjuvant ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Biased Agonist

Download Full-text

Monophosphoryl lipid A: an effective adjuvant for potentiating mucosal immune responses

Journal of Endotoxin Research ◽

10.1177/09680519990050030305 ◽

1999 ◽

Vol 5 (3) ◽

pp. 181-182 ◽

Cited By ~ 3

Author(s):

Suzanne M. Michalek ◽

Noel K. Childers ◽

Terry Greenway ◽

George Hajishengallis ◽

J. Terry Ulrich

Keyword(s):

Immune Responses ◽

Lipid A ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Mucosal Immune Responses

Download Full-text

Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00064.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. F103-F115 ◽

Cited By ~ 10

Author(s):

Bruns A. Watts ◽

Thampi George ◽

Edward R. Sherwood ◽

David W. Good

Keyword(s):

Bacterial Infections ◽

Lipid A ◽

Thick Ascending Limb ◽

Akt Inhibitor ◽

Erk Activation ◽

Akt Phosphorylation ◽

Medullary Thick Ascending Limb ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4−/−or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)−/−mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.

Download Full-text