Interferon-α as Antiviral and Antitumor Vaccine Adjuvants: Mechanisms of Action and Response Signature

ABSTRACT Previous studies have shown that the synthetic peptide GK1, derived from Taenia crassiceps cysticerci, enhances the immunogenicity of the commercial inactivated influenza vaccine Fluzone in both young and aged mice. In particular, antibody responses were much improved. Since GK1 is a peptide and is rapidly cleared from the body, it offers the possibility to improve vaccine performance without undesirable effects. This study was therefore designed to understand the mechanisms of action involved in the adjuvant properties of GK1. For this, transgenic mice expressing a T-cell receptor specific for an epitope from the influenza virus hemagglutinin (HA) protein were employed. The GK1 peptide significantly increased the in vivo proliferative response of HA-specific CD4+ T cells when it was coimmunized with the HA epitope. Dendritic cells treated in vitro with GK1 were capable of enhancing T-cell activation. Furthermore, in synergy with lipopolysaccharide, GK1 enhanced the expression of major histocompatibility complex class II and costimulatory molecules of dendritic cells and promoted the secretion of proinflammatory cytokines and chemokines upon antigen-driven T-cell interaction. These data provide important insights into the mechanism that underlies the GK1 adjuvant capacity observed previously and underline the feasibility of using the transgenic mouse model described herein as a tool for investigation of the modes of action of different influenza vaccine adjuvants.

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Author Correction: Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action

Nature Reviews Chemistry ◽

10.1038/s41570-021-00273-6 ◽

2021 ◽

Author(s):

Carlo Pifferi ◽

Roberto Fuentes ◽

Alberto Fernández-Tejada

Keyword(s):

Mechanisms Of Action ◽

Vaccine Adjuvants ◽

Synthetic Carbohydrate ◽

Natural And Synthetic

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Toll-Like Receptor 4 Activation in Cancer Progression and Therapy

Clinical and Developmental Immunology ◽

10.1155/2011/609579 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 87

Author(s):

Alja Oblak ◽

Roman Jerala

Keyword(s):

Cancer Progression ◽

Antitumor Immunity ◽

Vaccine Adjuvants ◽

Toll Like Receptor ◽

Cancer Treatments ◽

Toll Like Receptor 4 ◽

Antitumor Vaccine ◽

Tlr4 Activation ◽

Opposing Effects ◽

Intense Research

Cancer immunotherapy has been the focus of intense research since the late 19th century when Coley observed that bacterial components can contribute to cancer regression by eliciting an antitumor immune response. Successful activation and maturation of tumor-specific immune cells is now known to be mediated by bacterial endotoxin, which activates Toll-like receptor 4 (TLR4). TLR4 is expressed on a variety of immune as well as tumor cells, but its activation can have opposing effects. While TLR4 activation can promote antitumor immunity, it can also result in increased tumor growth and immunosuppression. Nevertheless, TLR4 engagement by endotoxin as well as by endogenous ligands represents notable contribution to the outcome of different cancer treatments, such as radiation or chemotherapy. Further research of the role and mechanisms of TLR4 activation in cancer may provide novel antitumor vaccine adjuvants as well as TLR4 inhibitors that could prevent inflammation-induced carcinogenesis.

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General characteristics of adjuvants and their mechanisms of action (part 2)

BIOpreparations Prevention Diagnosis Treatment ◽

10.30895/2221-996x-2021-21-1-20-30 ◽

2021 ◽

Vol 21 (1) ◽

pp. 20-30

Author(s):

N. А. Alpatova ◽

Zh. I. Avdeeva ◽

S. L. Lysikova ◽

O. V. Golovinskaya ◽

L. A. Gayderova ◽

...

Keyword(s):

Vaccine Development ◽

Mechanisms Of Action ◽

Vaccine Adjuvants ◽

Efficacy And Safety ◽

Subunit Vaccines ◽

Public Health Challenges ◽

Efficient Induction ◽

Is Development ◽

Effective Use ◽

New Vaccines

One of the major public health challenges today is development of new vaccines and technologies to optimize the vaccination process. There is a growing scientific interest in vaccine adjuvants that enhance vaccine immunogenicity. At present, numerous studies are underway to develop COVID-19 vaccines, including inactivated and subunit vaccines which contain adjuvants for efficient induction of immune response and solid immunity. The aim of the study was to systematise literature related to the analysis of the structure, mechanisms of action and stimulating properties of vaccine adjuvants (synthetic oligodeoxynucleotides, virosomes, polyoxidonium, sovidone), as well as to summarise data on the effects of adjuvants used in SARS-CoV, MERS-CoV, and SARS-CoV-2 vaccine development studies. The paper analyses the prospects for enhancing the stimulating effect of the adjuvants when used in combination with compounds having a different mechanism of action. It also analyses the results of studies of adjuvanted vaccines against SARS-CoV and MERS-CoV, which may be useful when selecting adjuvants with optimal efficacy and safety profiles to be used in SARS-CoV-2 vaccines under development. It was concluded that understanding of the mechanisms of action of adjuvants that mediate their stimulating effect on the body’s immune system will contribute to safe and effective use of adjuvants to enhance the immunogenicity of both authorised and new vaccines.

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The Use of Interferon-α in Behçet’s Disease — Review of the Literature and Possible Mechanisms of Action

Advances in Experimental Medicine and Biology - Adamantiades-Behçet’s Disease ◽

10.1007/0-306-48382-3_102 ◽

2006 ◽

pp. 503-509 ◽

Cited By ~ 7

Author(s):

Ina Kötter ◽

Ilhan GÜnaydin ◽

Michaela Treusch ◽

Manfred Zierhut ◽

Lothar Kanz ◽

...

Keyword(s):

Behçet’S Disease ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Mechanisms Of Action ◽

Interferon Α ◽

Review Of The Literature ◽

Behcet's Disease

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Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns

Blood ◽

10.1182/blood-2003-04-1216 ◽

2004 ◽

Vol 103 (3) ◽

pp. 1030-1032 ◽

Cited By ~ 134

Author(s):

Dominique De Wit ◽

Véronique Olislagers ◽

Stanislas Goriely ◽

Françoise Vermeulen ◽

Hermann Wagner ◽

...

Keyword(s):

Cord Blood ◽

Plasmacytoid Dendritic Cell ◽

Interferon Α ◽

Mrna Levels ◽

Vaccine Adjuvants ◽

Bacterial Dna ◽

Cpg Oligodeoxynucleotides ◽

Cell Responses ◽

Hla Dr ◽

Increased Susceptibility

Abstract Plasmacytoid dendritic cells (pDCs) respond to unmethylated cytosine-phosphate-guanosine (CpG) motifs present in bacterial DNA or unmethylated synthetic oligodeoxynucleotides (CpG). In order to assess the function of pDCs in human newborns, interferon-α (IFN-α) production induced by CpG 2216 and phenotypic maturation of pDCs in response to CpG 2006 were compared in cord blood and adult blood. We first observed that neonatal pDCs displayed decreased up-regulation of CD80, CD83, CD86, and CD40, whereas HLA-DR and CD54 up-regulation did not differ significantly between adults and neonates. We then found that the production of IFN-α in response to CpG was dramatically impaired in cord blood. This neonatal defect was detected both at protein and mRNA levels and was still present in blood of 4-day-old babies. Further experiments on enriched pDCs confirmed that these cells are intrinsically deficient in CpG-induced IFN-α production at birth. These findings might be relevant to the increased susceptibility of human newborns to infections as well as to the use of CpG oligodeoxynucleotides as vaccine adjuvants in the neonatal period. (Blood. 2004;103:1030-1032)

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Type I Interferons and Cancer: An Evolving Story Demanding Novel Clinical Applications

Cancers ◽

10.3390/cancers11121943 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1943 ◽

Cited By ~ 5

Author(s):

Eleonora Aricò ◽

Luciano Castiello ◽

Imerio Capone ◽

Lucia Gabriele ◽

Filippo Belardelli

Keyword(s):

Ex Vivo ◽

Biological Activities ◽

Mechanisms Of Action ◽

Added Value ◽

Type I Interferons ◽

Interferon Α ◽

Type I ◽

Clinical Use ◽

Antitumor Effects

The first report on the antitumor effects of interferon α/β (IFN-I) in mice was published 50 years ago. IFN-α were the first immunotherapeutic drugs approved by the FDA for clinical use in cancer. However, their clinical use occurred at a time when most of their mechanisms of action were still unknown. These cytokines were being used as either conventional cytostatic drugs or non-specific biological response modifiers. Specific biological activities subsequently ascribed to IFN-I were poorly considered for their clinical use. Notably, a lot of the data in humans and mice underlines the importance of endogenous IFN-I, produced by both immune and tumor cells, in the control of tumor growth and in the response to antitumor therapies. While many oncologists consider IFN-I as “dead drugs”, recent studies reveal new mechanisms of action with potential implications in cancer control and immunotherapy response or resistance, suggesting novel rationales for their usage in target and personalized anti-cancer treatments. In this Perspectives Article, we focus on the following aspects: (1) the added value of IFN-I for enhancing the antitumor impact of standard anticancer treatments (chemotherapy and radiotherapy) and new therapeutic approaches, such as check point inhibitors and epigenetic drugs; (2) the role of IFN-I in the control of cancer stem cells growth and its possible implications for the development of novel antitumor therapies; and (3) the role of IFN-I in the development of cancer vaccines and the intriguing therapeutic possibilities offered by in situ delivery of ex vivo IFN-stimulated dendritic cells.

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