Mechanisms of vaccine adjuvant activity: initiation and regulation of immune responses by vaccine adjuvants

Toll-like receptor (TLR) ligands are being developed for use as vaccine adjuvants and as immunomodulators because of their ability to stimulate innate and adaptive immune responses. Flagellin, a TLR5 ligand, was reported to show potent mucosal vaccine adjuvant activity. To identify ligands that potentiate the adjuvant activity of flagellin, we screened a plant library using HEK293T cells transiently cotransfected with phTLR5 and pNF-κB-SEAP plasmids. The 90% EtOH extract fromCroton tigliumshowed significant NF-κB transactivation in a TLR5-independent manner along with the increase of a flagellin activity. We have studied to characterize an active component fromCroton tigliumand to elucidate the action mechanisms. Phorbol 12-myristate 13-acetate (PMA) was isolated as an active component ofCroton tigliumby activity-guided fractionation, column chromatography, HPLC, NMR, and MS. PMA at a range of nM induced PKC-dependent NF-κB activation and IL-8 production in both TLR5− and TLR5+ assay systems. In in vivo mouse vaccination model, PMA induced antigen-specific IgG and IgA antibody responses and increased IL-12 production corresponding to T cell responses in spleen lymphocytes. These results suggest that PMA would serve as an efficacious mucosal vaccine adjuvant.

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Cytokines: The Future of Intranasal Vaccine Adjuvants

Clinical and Developmental Immunology ◽

10.1155/2011/289597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-17 ◽

Cited By ~ 38

Author(s):

Afton L. Thompson ◽

Herman F. Staats

Keyword(s):

Animal Models ◽

Immune Responses ◽

Clinical Studies ◽

Vaccine Adjuvants ◽

Adjuvant Activity ◽

Subunit Vaccines ◽

E Coli ◽

Nasal Vaccine ◽

Intranasal Vaccine ◽

Nasal Immunization

Due to its potential as an effective, needle-free route of immunization for use with subunit vaccines, nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental vaccine adjuvants, such as cholera toxin andE. coliheat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as nasal vaccine adjuvants.

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Catechol-Driven Self-Assembly to Fabricate Highly Ordered and SERS-Active Glycoadjuvant Patterns

Journal of Materials Chemistry B ◽

10.1039/d1tb00833a ◽

2021 ◽

Author(s):

Shuyi Shen ◽

yan Huang ◽

yue Sun ◽

Weidong Zhang

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Self Assembly ◽

Critical Role ◽

Vaccine Adjuvant ◽

Vaccine Adjuvants

Vaccine adjuvants play a critical role in innate immunity and tumor-specific immune responses. Engineering and detection of vaccine (adjuvant and antigen) is crucial for the fundamental studies of immunotherapy. In...

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Development of N-Acetylated Dipalmitoyl-S-Glyceryl Cysteine Analogs as Efficient TLR2/TLR6 Agonists

Molecules ◽

10.3390/molecules24193512 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3512 ◽

Cited By ~ 1

Author(s):

Yang Zhou ◽

Abid H. Banday ◽

Victor J. Hruby ◽

Minying Cai

Keyword(s):

Immune Responses ◽

Cancer Vaccines ◽

Docking Studies ◽

Infection Process ◽

Vaccine Adjuvant ◽

Vaccine Adjuvants ◽

Toll Like Receptor ◽

Ideal Candidate ◽

Toll Like Receptor 2

Cancer vaccine is a promising immunotherapeutic approach to train the immune system with vaccines to recognize and eliminate tumors. Adjuvants are compounds that are necessary in cancer vaccines to mimic an infection process and amplify immune responses. The Toll-like receptor 2 and 6 (TLR2/TLR6) agonist dipalmitoyl-S-glyceryl cysteine (Pam2Cys) was demonstrated as an ideal candidate for synthetic vaccine adjuvants. However, the synthesis of Pam2Cys requires expensive N-protected cysteine as a key reactant, which greatly limits its application as a synthetic vaccine adjuvant in large-scaled studies. Here, we report the development of N-acetylated Pam2Cys analogs as TLR2/TLR6 agonists. Instead of N-protected cysteine, the synthesis utilizes N-acetylcysteine to bring down the synthetic costs. The N-acetylated Pam2Cys analogs were demonstrated to activate TLR2/TLR6 in vitro. Moreover, molecular docking studies were performed to provide insights into the molecular mechanism of how N-acetylated Pam2Cys analogs bind to TLR2/TLR6. Together, these results suggest N-acetylated Pam2Cys analogs as inexpensive and promising synthetic vaccine adjuvants to accelerate the development of cancer vaccines in the future.

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Facile fabrication of varisized calcium carbonate microspheres as vaccine adjuvants

Journal of Materials Chemistry B ◽

10.1039/c6tb02845d ◽

2017 ◽

Vol 5 (8) ◽

pp. 1611-1623 ◽

Cited By ~ 17

Author(s):

Jilei Jia ◽

Qi Liu ◽

Tingyuan Yang ◽

Lianyan Wang ◽

Guanghui Ma

Keyword(s):

Calcium Carbonate ◽

Immune Responses ◽

Vaccine Adjuvant ◽

Vaccine Adjuvants ◽

Facile Fabrication

HBsAg loaded CaCO3 microspheres with various diameters were fabricated via different mixing strategies and 1 μm particles has the strongest immune responses as vaccine adjuvant.

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A De-O-acylated Lipooligosaccharide-Based Adjuvant System Promotes Antibody and Th1-Type Immune Responses to H1N1 Pandemic Influenza Vaccine in Mice

BioMed Research International ◽

10.1155/2016/3713656 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Ji In Ryu ◽

Shin Ae Park ◽

Seo Ri Wui ◽

Ara Ko ◽

Ji Eun Han ◽

...

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Pandemic Influenza ◽

Inflammatory Responses ◽

Protective Efficacy ◽

Vaccine Dose ◽

H1n1 Pandemic ◽

Vaccine Adjuvants ◽

Adjuvant Activity ◽

Adjuvant System

Vaccine adjuvants are agents that are used to promote immune responses to vaccine antigens and thereby to enhance the protective efficacy of the vaccines. In this study, we investigated the adjuvant activity of CIA06, an adjuvant system that is composed of a toll-like receptor 4 agonist de-O-acylated lipooligosaccharide (dLOS) and aluminum hydroxide, on the H1N1 pandemic influenza vaccine Greenflu-S® in mice. CIA06 significantly enhanced influenza-specific serum IgG, hemagglutination-inhibition, and virus-neutralizing antibody titers, which eliminated vaccine dose-dependency in the antibody response. Mice immunized with the CIA06-adjuvanted Greenflu-S showed Th1-type-predominant cytokine profiles, and both CD4+and CD8+T cell responses were induced. Immunization of mice with the CIA06-adjuvanted vaccine reduced the mortality and morbidity of mice upon lethal challenges with influenza virus, and no excessive inflammatory responses were observed in the lung tissues of the immunized mice after viral infection. These data suggest that the dLOS-based adjuvant system CIA06 can be used to promote the immune responses to influenza vaccine or to spare antigen dose without causing harmful inflammatory responses.

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Polyphosphazenes as Adjuvants for Animal Vaccines and Other Medical Applications

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.625482 ◽

2021 ◽

Vol 9 ◽

Author(s):

Dylan J. Chand ◽

Royford B. Magiri ◽

Heather L. Wilson ◽

George K. Mutwiri

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Animal Species ◽

Mechanisms Of Action ◽

Present Review ◽

Medical Applications ◽

Large Animal ◽

Vaccine Adjuvants ◽

Adjuvant Activity ◽

Laboratory Rodents

Polyphosphazenes are a class of experimental adjuvants that have shown great versatility as vaccine adjuvants in many animal species ranging from laboratory rodents to large animal species. Their adjuvant activity has shown promising results with numerous viral and bacterial antigens, as well as with crude and purified antigens. Vaccines adjuvanted with polyphosphazenes can be delivered via systemic and mucosal administration including respiratory, oral, rectal, and intravaginal routes. Polyphosphazenes can be used in combination with other adjuvants, further enhancing immune responses to antigens. The mechanisms of action of polyphosphazenes have not fully been defined, but several systematic studies have suggested that they act primarily by activating innate immunity. In the present review, we will highlight progress in the development of polyphosphazenes as adjuvants in animals and their other medical applications.

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Heat-inactivated modified vaccinia virus Ankara boosts Th1-biased cellular and humoral immune responses as a vaccine adjuvant by activating the STING-mediated cytosolic DNA-sensing pathway

10.1101/2021.07.24.453449 ◽

2021 ◽

Author(s):

Ning Yang ◽

Aitor Garzia ◽

Cindy Meyer ◽

Thomas Tuschl ◽

Taha Merghoub ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Adjuvant ◽

Effective Vaccine ◽

Therapeutic Vaccination ◽

Vaccine Adjuvants ◽

Subunit Vaccines ◽

Cross Presentation ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Sting Pathway

Background: Protein or peptide-based subunit vaccines are promising platforms for combating human cancers and infectious diseases. However, one primary concern regarding subunit vaccines is the relatively weak immune responses induced by proteins or peptides. Therefore, developing novel and effective vaccine adjuvants is critical for the success of subunit vaccines. Modified vaccinia virus (MVA) is a safe and effective vaccine against smallpox and monkeypox. In this study, we explored the potential of heat-inactivated MVA (heat-iMVA) as a novel vaccine adjuvant. Methods: We co-administered heat-iMVA with a model antigen, chicken ovalbumin (OVA), either intramuscularly or subcutaneously twice, two weeks apart, and analyzed anti-OVA specific CD8+ and CD4+ T cells in the spleens and skin draining lymph nodes (dLNs) and serum anti-OVA IgG1 and IgG2c antibodies. We also compared the adjuvant effects of heat-iMVA with several known vaccine adjuvants. In addition, we tested whether co-administration of heat-iMVA plus tumor neoantigen peptides or irradiated tumor cells improves antitumor efficacy in a B16-F10 murine melanoma therapeutic vaccination model. Using Stimulator of Interferon Genes (STING) or Batf3-deficient mice, we evaluated the contribution of the STING pathway and Batf3-dependent CD103+/CD8alpha DCs in heat-iMVA-induced immunity. Results: Co-administration of protein- or peptide-based immunogens with heat-iMVA dramatically enhances Th1-biased cellular and humoral immune responses. This adjuvant effect of heat-iMVA is dependent on the STING-mediated cytosolic DNA-sensing pathway, and the antigen-specific CD8+ T cell response requires Batf3-dependent CD103+/CD8alpha dendritic cells (DCs). Heat-iMVA infection of bone marrow-derived DCs (BMDCs) promoted antigen cross-presentation, whereas live MVA infection did not. RNA-seq analyses revealed that heat-iMVA is a more potent activator of the STING pathway than live MVA. Additionally, combining tumor neoantigen peptides or irradiated tumor cells with heat-iMVA delayed tumor growth and extended the median survival in B16-F10 therapeutic vaccination models. Conclusions: Heat-iMVA induces type I interferon (IFN) production and antigen cross-presentation via a STING-dependent mechanism in DCs. Co-administration of heat-iMVA with peptide antigen generates strong Th1-biased cellular and humoral immunity. Collectively, our results demonstrate that heat-iMVA is a safe and potent vaccine adjuvant.

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