Parenterally Administered Norovirus GII.4 Virus-Like Particle Vaccine Formulated with Aluminum Hydroxide or Monophosphoryl Lipid A Adjuvants Induces Systemic but Not Mucosal Immune Responses in Mice

Norovirus (NoV) is a main cause of acute gastroenteritis across all ages worldwide. NoV vaccine candidates currently in clinical trials are based on noninfectious highly immunogenic virus-like particles (VLPs) delivered intramuscularly (IM). Since NoV is an enteric pathogen, it is likely that mucosal immunity has a significant role in protection from infection in the intestine. Due to the fact that IM delivery of NoV VLPs does not generate mucosal immunity, we investigated whether NoV genotype GII.4 VLPs coadministered with aluminum hydroxide (Al(OH)3) or monophosphoryl lipid A (MPLA) would induce mucosal antibodies in mice. Systemic as well as mucosal IgG and IgA antibodies in serum and intestinal and nasal secretions were measured. As expected, strong serum IgG, IgG1, and IgG2a antibodies as well as a dose sparing effect were induced by both Al(OH)3and MPLA, but no mucosal IgA antibodies were detected. In contrast, IN immunization with GII.4 VLPs without an adjuvant induced systemic as well as mucosal IgA antibody response. These results indicate that mucosal delivery of NoV VLPs is needed for induction of mucosal responses.

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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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Immunogenicity of HPV and HBV vaccines: adjuvanticity of synthetic analogs of monophosphoryl lipid A combined with aluminum hydroxide

Apmis ◽

10.1111/apm.12927 ◽

2019 ◽

Vol 127 (3) ◽

pp. 150-157 ◽

Cited By ~ 2

Author(s):

Nastaran Taleghani ◽

Ali Bozorg ◽

Amin Azimi ◽

Homa Zamani

Keyword(s):

Aluminum Hydroxide ◽

Lipid A ◽

Synthetic Analogs ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

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Enhanced Immunogenicity and Protective Efficacy of aCampylobacter jejuniConjugate Vaccine Coadministered with Liposomes Containing Monophosphoryl Lipid A and QS-21

mSphere ◽

10.1128/msphere.00101-19 ◽

2019 ◽

Vol 4 (3) ◽

Cited By ~ 2

Author(s):

Amritha Ramakrishnan ◽

Nina M. Schumack ◽

Christina L. Gariepy ◽

Heather Eggleston ◽

Gladys Nunez ◽

...

Keyword(s):

Campylobacter Jejuni ◽

Conjugate Vaccine ◽

Aluminum Hydroxide ◽

Nonhuman Primates ◽

Lipid A ◽

Diarrheal Disease ◽

Protective Efficacy ◽

Content Type ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

ABSTRACTCampylobacter jejuniis among the most common causes of diarrheal disease worldwide and efforts to develop protective measures against the pathogen are ongoing. One of the few defined virulence factors targeted for vaccine development is the capsule polysaccharide (CPS). We have developed a capsule conjugate vaccine againstC. jejunistrain 81-176 (CPS-CRM) that is immunogenic in mice and nonhuman primates (NHPs) but only moderately immunogenic in humans when delivered alone or with aluminum hydroxide. To enhance immunogenicity, two novel liposome-based adjuvant systems, the Army Liposome Formulation (ALF), containing synthetic monophosphoryl lipid A, and ALF plus QS-21 (ALFQ), were evaluated with CPS-CRM in this study. In mice, ALF and ALFQ induced similar amounts of CPS-specific IgG that was significantly higher than levels induced by CPS-CRM alone. Qualitative differences in antibody responses were observed where CPS-CRM alone induced Th2-biased IgG1, whereas ALF and ALFQ enhanced Th1-mediated anti-CPS IgG2b and IgG2c and generated functional bactericidal antibody titers. CPS-CRM + ALFQ was superior to vaccine alone or CPS-CRM + ALF in augmenting antigen-specific Th1, Th2, and Th17 cytokine responses and a significantly higher proportion of CD4+IFN-γ+IL-2+TNF-α+and CD4+IL-4+IL-10+T cells. ALFQ also significantly enhanced anti-CPS responses in NHPs when delivered with CPS-CRM compared to alum- or ALF-adjuvanted groups and showed the highest protective efficacy against diarrhea following orogastric challenge withC. jejuni. This study provides evidence that the ALF adjuvants may provide enhanced immunogenicity of this and other novelC. jejunicapsule conjugate vaccines in humans.IMPORTANCECampylobacter jejuniis a leading cause of diarrheal disease worldwide, and currently no preventative interventions are available.C. jejuniis an invasive mucosal pathogen that has a variety of polysaccharide structures on its surface, including a capsule. In phase 1 studies, aC. jejunicapsule conjugate vaccine was safe but poorly immunogenic when delivered alone or with aluminum hydroxide. Here, we report enhanced immunogenicity of the conjugate vaccine delivered with liposome adjuvants containing monophosphoryl lipid A without or with QS-21, known as ALF and ALFQ, respectively, in preclinical studies. Both liposome adjuvants significantly enhanced immunity in mice and nonhuman primates and improved protective efficacy of the vaccine compared to alum in a nonhuman primateC. jejunidiarrhea model, providing promising evidence that these potent adjuvant formulations may enhance immunogenicity in upcoming human studies with thisC. jejuniconjugate and other malaria and HIV vaccine platforms.

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Roles of Aluminum Hydroxide and Monophosphoryl Lipid A Adjuvants in Overcoming CD4+ T Cell Deficiency To Induce Isotype-Switched IgG Antibody Responses and Protection by T-Dependent Influenza Vaccine

The Journal of Immunology ◽

10.4049/jimmunol.1600173 ◽

2016 ◽

Vol 198 (1) ◽

pp. 279-291 ◽

Cited By ~ 18

Author(s):

Eun-Ju Ko ◽

Young-Tae Lee ◽

Ki-Hye Kim ◽

Youri Lee ◽

Yu-Jin Jung ◽

...

Keyword(s):

T Cell ◽

Influenza Vaccine ◽

Aluminum Hydroxide ◽

Lipid A ◽

Antibody Responses ◽

Cd4 T Cell ◽

Igg Antibody ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

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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

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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

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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.

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