Monophosphoryl lipid A behaves as a T-cell-independent type 1 carrier for hapten-specific antibody responses in mice.

ABSTRACTDespite several attempts to develop an effective prophylactic vaccine for HSV-2, all have failed to show efficacy in the clinic. The most recent of these failures was the GlaxoSmithKline (GSK) subunit vaccine based on the glycoprotein gD with the adjuvant monophosphoryl lipid A (MPL). In a phase 3 clinical trial, this vaccine failed to protect from HSV-2 disease, even though good neutralizing antibody responses were elicited. We aimed to develop a superior, novel HSV-2 vaccine containing either gD or gB alone or in combination, together with the potent adjuvant CpG oligodeoxynucleotides (CPG). The immunogenic properties of these vaccines were compared in mice. We show that gB/CPG/alum elicited a neutralizing antibody response similar to that elicited by gD/CPG/alum vaccine but a significantly greater gamma interferon (IFN-γ) T cell response. Furthermore, the combined gB-gD/CPG/alum vaccine elicited significantly greater neutralizing antibody and T cell responses than gD/MPL/alum. The efficacies of these candidate vaccines were compared in the mouse and guinea pig disease models, including a novel male guinea pig genital disease model. These studies demonstrated that increased immune response did not correlate to improved protection. First, despite a lower IFN-γ T cell response, the gD/CPG/alum vaccine was more effective than gB/CPG/alum in mice. Furthermore, the gB-gD/CPG/alum vaccine was no more effective than gD/MPL/alum in mice or male guinea pigs. We conclude that difficulties in correlating immune responses to efficacy in animal models will act as a deterrent to researchers attempting to develop effective HSV vaccines.

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TLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation

The Journal of Immunology ◽

10.4049/jimmunol.1302569 ◽

2014 ◽

Vol 192 (9) ◽

pp. 4221-4232 ◽

Cited By ~ 34

Author(s):

Weiguo Cui ◽

Nikhil S. Joshi ◽

Ying Liu ◽

Hailong Meng ◽

Steven H. Kleinstein ◽

...

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Lipid A ◽

Cd8 T Cell ◽

T Cell Differentiation ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Memory Cd8 T Cell

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The Immunogenicity of Capsid-Like Particle Vaccines in Combination with Different Adjuvants Using Different Routes of Administration

Vaccines ◽

10.3390/vaccines9020131 ◽

2021 ◽

Vol 9 (2) ◽

pp. 131

Author(s):

Christoph M. Janitzek ◽

Philip H. R. Carlsen ◽

Susan Thrane ◽

Vijansh M. Khanna ◽

Virginie Jakob ◽

...

Keyword(s):

Aluminum Hydroxide ◽

Lipid A ◽

Antibody Responses ◽

Bacterial Protein ◽

Adjuvant Effect ◽

Water Emulsion ◽

Routes Of Administration ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Vaccine Antigens

Capsid-like particle (CLP) displays can be used to enhance the immunogenicity of vaccine antigens, but a better understanding of how CLP vaccines are best formulated and delivered is needed. This study compared the humoral immune responses in mice elicited against two different vaccine antigens (a bacterial protein and a viral peptide) delivered on an AP205 CLP platform using six different adjuvant formulations. In comparison to antibody responses obtained after immunization with the unadjuvanted CLP vaccine, three of the adjuvant systems (neutral liposomes/monophosphoryl lipid A/quillaja saponaria 21, squalene-in-water emulsion, and monophosphoryl lipid A) caused significantly increased antibody levels, whereas formulation with the three other adjuvants (aluminum hydroxide, cationic liposomes, and cationic microparticles) resulted in similar or even decreased antibody responses. When delivering the soluble bacterial protein in a squalene-in-water emulsion, 4-log lower IgG levels were obtained compared to when the protein was delivered on CLPs without the adjuvant. The AP205 CLP platform promoted induction of both IgG1 and IgG2 subclasses, which could be skewed towards a higher production of IgG1 (aluminum hydroxide). Compared to other routes, intramuscular administration elicited the highest IgG levels. These results indicate that the effect of the external adjuvant does not always synergize with the adjuvant effect of the CLP display, which underscores the need for empirical testing of different extrinsic adjuvants.

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Inactivation of suppressor T-cell activity by nontoxic monophosphoryl lipid A.

Infection and Immunity ◽

10.1128/iai.56.5.1076-1083.1988 ◽

1988 ◽

Vol 56 (5) ◽

pp. 1076-1083 ◽

Cited By ~ 30

Author(s):

P J Baker ◽

J R Hiernaux ◽

M B Fauntleroy ◽

B Prescott ◽

J L Cantrell ◽

...

Keyword(s):

T Cell ◽

Lipid A ◽

Cell Activity ◽

Suppressor T Cell ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

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Monophosphoryl Lipid A Based Cationic Liposome Facilitates Vaccine Induced Expansion of Polyfunctional T Cell Immune Responses against Visceral Leishmaniasis

ACS Applied Bio Materials ◽

10.1021/acsabm.8b00184 ◽

2018 ◽

Vol 1 (4) ◽

pp. 999-1018 ◽

Cited By ~ 1

Author(s):

Amrita Das ◽

Mohammad Asad ◽

Abdus Sabur ◽

Nicky Didwania ◽

Nahid Ali

Keyword(s):

T Cell ◽

Visceral Leishmaniasis ◽

Immune Responses ◽

Lipid A ◽

Cationic Liposome ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

T Cell Immune Responses

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Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines

Clinical and Vaccine Immunology ◽

10.1128/cvi.00370-08 ◽

2009 ◽

Vol 16 (5) ◽

pp. 699-705 ◽

Cited By ~ 16

Author(s):

David I. Bernstein ◽

Rhonda D. Cardin ◽

Fernando J. Bravo ◽

Jane E. Strasser ◽

Nicholas Farley ◽

...

Keyword(s):

Genital Herpes ◽

Lipid A ◽

Cationic Liposome ◽

Antibody Responses ◽

Dna Complexes ◽

Adjuvant Activity ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Simplex Virus

ABSTRACT Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further.

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A Novel LNP-based Chlamydia subunit vaccine formulation that induces Th1 responses without upregulating IL-17 provides equivalent protection in mice as formulations that induced IL-17 and Th1 cytokines

10.21203/rs.2.16752/v1 ◽

2019 ◽

Author(s):

Melissa Ann Boddicker ◽

Robin M. Kaufhold ◽

Kara S. Cox ◽

Bob J. Lucas ◽

Jinfu Xie ◽

...

Keyword(s):

T Cell ◽

Membrane Protein ◽

Lipid A ◽

T Cell Responses ◽

Control Group ◽

Cell Responses ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Antibody Titers ◽

Dimethyldioctadecylammonium Bromide

Abstract Sexually transmitted Chlamydia infections can lead to the development of debilitating diseases such as chronic pelvic pain, ectopic pregnancy, pelvic inflammatory disease, and infertility. It has been proposed that immunity against Chlamydia infection and disease may be determined by a balance of IL-17 signaling. We sought to evaluate novel formulations for a candidate Chlamydia vaccine, consisting of Chlamydia major outer membrane protein (MOMP) alone or in combination with polymorphic membrane protein D (PmpD) and polymorphic membrane protein G (PmpG) as target immunogens. Native MOMP (nMOMP) isolated from C. muridarum elementary bodies (EBs) and recombinant PmpD and PmpG proteins were adjuvanted with Monophosphoryl lipid A (MPLA), in one of two formulations containing either lipid nanoparticles (LNPs) or the cationic lipid dimethyldioctadecylammonium bromide (DDA). Antibody titers to C. muridarum, nMOMP, and EBs were evaluated by ELISA, and T-cell responses by intracellular cytokine staining (ICS). Protection from challenge was determined by qPCR and gross pathology. All mice immunized with the new vaccine formulations showed significantly higher antibody titers to nMOMP (P<0.001) and C. muridarum EBs (P<0.001), when compared to the negative control group (adjuvant alone). Antibody titers in vaccine groups with Monophosphoryl lipid A (MPLA)+LNP were higher as compared to the MPLA+DDA group (P<0.001) except for groups 6 (Cm nMOMP+PmpG+PmpD p73+PmpD p82+MPLA+DDA) vs 7 (Cm nMOMP+PmpG+PmpD p73+PmpD p82+MPLA+LNP) for both C. muridarum EBs and PmpG; the groups were not statistically significant. ICS analysis showed more robust CD4+ T-cell responses (IFN-γ/IL-2/TNF-α) in the dimethyldioctadecylammonium bromide (DDA) and LNP groups compared to the adjuvant alone group. The combination of DDA and MPLA gave robust Th17 responses in comparison to MPLA and LNP group. Immunized groups also showed protection from challenge with C. muridarum , as evidenced by a reduction in bacterial shedding from the vagina for all groups (P<0.003) compared to shedding from the adjuvant control, Group 1. Both vaccine formulations generated robust immunological responses and both vaccine formulations were protective by reducing bacterial shedding after challenge. This data indicates equal protection can be achieved without the induction of Th17 responses.

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