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Signal Transduction and Targeted Therapy Jul 2023Adjuvants are indispensable components of vaccines. Despite being widely used in vaccines, their action mechanisms are not yet clear. With a greater understanding of the... (Review)
Review
Adjuvants are indispensable components of vaccines. Despite being widely used in vaccines, their action mechanisms are not yet clear. With a greater understanding of the mechanisms by which the innate immune response controls the antigen-specific response, the adjuvants' action mechanisms are beginning to be elucidated. Adjuvants can be categorized as immunostimulants and delivery systems. Immunostimulants are danger signal molecules that lead to the maturation and activation of antigen-presenting cells (APCs) by targeting Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) to promote the production of antigen signals and co-stimulatory signals, which in turn enhance the adaptive immune responses. On the other hand, delivery systems are carrier materials that facilitate antigen presentation by prolonging the bioavailability of the loaded antigens, as well as targeting antigens to lymph nodes or APCs. The adjuvants' action mechanisms are systematically summarized at the beginning of this review. This is followed by an introduction of the mechanisms, properties, and progress of classical vaccine adjuvants. Furthermore, since some of the adjuvants under investigation exhibit greater immune activation potency than classical adjuvants, which could compensate for the deficiencies of classical adjuvants, a summary of the adjuvant platforms under investigation is subsequently presented. Notably, we highlight the different action mechanisms and immunological properties of these adjuvant platforms, which will provide a wide range of options for the rational design of different vaccines. On this basis, this review points out the development prospects of vaccine adjuvants and the problems that should be paid attention to in the future.
Topics: Adjuvants, Vaccine; Vaccines; Adjuvants, Immunologic; Immunity, Innate; Toll-Like Receptors
PubMed: 37468460
DOI: 10.1038/s41392-023-01557-7 -
Biomolecules Aug 2020There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis,... (Review)
Review
There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.
Topics: Adjuvants, Pharmaceutic; Animals; Anti-Inflammatory Agents; Antioxidants; COVID-19; Coronavirus Infections; Homeostasis; Humans; Melatonin; Pandemics; Pneumonia, Viral
PubMed: 32825327
DOI: 10.3390/biom10091211 -
Frontiers in Immunology 2022Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced... (Review)
Review
Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced humoral and T cell-mediated immunity is paramount to defend against diseases caused by complex intracellular pathogens, such as tuberculosis, malaria, and AIDS. However, currently used vaccines elicit strong antibody responses, but poorly stimulate CD8 cytotoxic T lymphocyte (CTL) responses. To elicit potent CTL memory, vaccines need to engage the cross-presentation pathway, and this requirement has been a crucial bottleneck in the development of subunit vaccines that engender effective T cell immunity. In this review, we focus on recent insights into DC cross-presentation and the extent to which clinically relevant vaccine adjuvants, such as aluminum-based nanoparticles, water-in oil emulsion (MF59) adjuvants, saponin-based adjuvants, and Toll-like receptor (TLR) ligands modulate DC cross-presentation efficiency. Further, we discuss the feasibility of using carbomer-based adjuvants as next generation of adjuvant platforms to elicit balanced antibody- and T-cell based immunity. Understanding of the molecular mechanism of DC cross-presentation and the mode of action of adjuvants will pave the way for rational design of vaccines for infectious diseases and cancer that require balanced antibody- and T cell-based immunity.
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Cross-Priming; T-Lymphocytes, Cytotoxic; Vaccines, Subunit
PubMed: 35979365
DOI: 10.3389/fimmu.2022.940047 -
Theranostics 2021Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing... (Review)
Review
Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing efforts to identify new drugs or alternatives to antibiotics, no new classes of antibiotic or their alternatives have been clinically approved in the last three decades. A combination of antibiotics and non-antibiotic compounds that could inhibit bacterial resistance determinants or enhance antibiotic activity offers a sustainable and effective strategy to confront multidrug-resistant bacteria. In this review, we provide a brief overview of the co-evolution of antibiotic discovery and the development of bacterial resistance. We summarize drug-drug interactions and uncover the art of repurposing non-antibiotic drugs as potential antibiotic adjuvants, including discussing classification and mechanisms of action, as well as reporting novel screening platforms. A pathogen-by-pathogen approach is then proposed to highlight the critical value of drug repurposing and its therapeutic potential. Finally, general advantages, challenges and development trends of drug combination strategy are discussed.
Topics: Adjuvants, Pharmaceutic; Anti-Bacterial Agents; Bacterial Infections; Drug Interactions; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans
PubMed: 33754035
DOI: 10.7150/thno.56205 -
Cell Research Nov 2020CD8 T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent...
CD8 T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8 T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8 T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8 T cells. Mechanically, Mn promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8 T cell differentiation, activation and NK cell activation, and increased memory CD8 T cells. Combining Mn with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.
Topics: Adjuvants, Pharmaceutic; Adult; Aged; Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Carcinogenesis; Dendritic Cells; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Immunity; Immunotherapy; Interferon Type I; Killer Cells, Natural; Lung; Lymphocyte Activation; Male; Manganese; Melanoma, Experimental; Membrane Proteins; Mice, Inbred C57BL; Middle Aged; Neoplasms; Nucleotidyltransferases; Organ Size; Signal Transduction; Treatment Outcome; Tumor Burden
PubMed: 32839553
DOI: 10.1038/s41422-020-00395-4 -
Frontiers in Immunology 2023In the present scenario, immunization is of utmost importance as it keeps us safe and protects us from infectious agents. Despite the great success in the field of... (Review)
Review
In the present scenario, immunization is of utmost importance as it keeps us safe and protects us from infectious agents. Despite the great success in the field of vaccinology, there is a need to not only develop safe and ideal vaccines to fight deadly infections but also improve the quality of existing vaccines in terms of partial or inconsistent protection. Generally, subunit vaccines are known to be safe in nature, but they are mostly found to be incapable of generating the optimum immune response. Hence, there is a great possibility of improving the potential of a vaccine in formulation with novel adjuvants, which can effectively impart superior immunity. The vaccine(s) in formulation with novel adjuvants may also be helpful in fighting pathogens of high antigenic diversity. However, due to the limitations of safety and toxicity, very few human-compatible adjuvants have been approved. In this review, we mainly focus on the need for new and improved vaccines; the definition of and the need for adjuvants; the characteristics and mechanisms of human-compatible adjuvants; the current status of vaccine adjuvants, mucosal vaccine adjuvants, and adjuvants in clinical development; and future directions.
Topics: Humans; Adjuvants, Vaccine; Vaccines; Immunization; Vaccination; Adjuvants, Immunologic
PubMed: 36911719
DOI: 10.3389/fimmu.2023.1043109 -
Cells Aug 2023In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and... (Review)
Review
In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body's natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal is to achieve a complete clinical response, where all measurable cancer cells are either eliminated or greatly reduced in size. With their potential to revolutionize cancer treatment, these therapies represent a promising avenue for researchers and clinicians alike. Despite over 100 years of research, the success of therapeutic cancer vaccines has been variable, particularly in advanced cancer patients, with various limitations, including the heterogeneity of the tumor microenvironment, the presence of immunosuppressive cells, and the potential for tumor escape mechanisms. Additionally, the effectiveness of these therapies may be limited by the variability of the patient's immune system response and the difficulty in identifying appropriate antigens for each patient. Despite these challenges, tumor microenvironment-targeted vaccine cancer therapies have shown promising results in preclinical and clinical studies and have the potential to become a valuable addition to current cancer treatment and "curative" options. While chemotherapeutic and monoclonal antibody treatments remain popular, ongoing research is needed to optimize the design and delivery of these therapies and to identify biomarkers that can predict response and guide patient selection. This comprehensive review explores the mechanisms of cancer vaccines, various delivery methods, and the role of adjuvants in improving treatment outcomes. It also discusses the historical background of cancer vaccine research and examines the current state of major cancer vaccination immunotherapies. Furthermore, the limitations and effectiveness of each vaccine type are analyzed, providing insights into the future of cancer vaccine development.
Topics: Humans; Cancer Vaccines; Immunotherapy; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Antibodies, Monoclonal; Neoplasms
PubMed: 37681891
DOI: 10.3390/cells12172159 -
The New England Journal of Medicine Jun 2022Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine.
METHODS
In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases.
RESULTS
A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%).
CONCLUSIONS
The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Adult; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Double-Blind Method; Humans; Injections, Intramuscular; SARS-CoV-2; Vaccination
PubMed: 35507508
DOI: 10.1056/NEJMoa2201300 -
Science (New York, N.Y.) Mar 2023The Chilean soapbark tree () produces soap-like molecules called QS saponins that are important vaccine adjuvants. These highly valuable compounds are sourced by...
The Chilean soapbark tree () produces soap-like molecules called QS saponins that are important vaccine adjuvants. These highly valuable compounds are sourced by extraction from the bark, and their biosynthetic pathway is unknown. Here, we sequenced the genome. Through genome mining and combinatorial expression in tobacco, we identified 16 pathway enzymes that together enable the production of advanced QS pathway intermediates that represent a bridgehead for adjuvant bioengineering. We further identified the enzymes needed to make QS-7, a saponin with excellent therapeutic properties and low toxicity that is present in low abundance in bark extract. Our results enable the production of vaccine adjuvants in tobacco and open the way for new routes to access and engineer natural and new-to-nature immunostimulants.
Topics: Adjuvants, Vaccine; Quillaja; Saponins; Sequence Analysis, DNA; Genome, Plant; Biosynthetic Pathways; Nicotiana; Plant Proteins
PubMed: 36952412
DOI: 10.1126/science.adf3727 -
Expert Review of Vaccines May 2021The importance of vaccine thermostability has been discussed in the literature. Nevertheless, the challenge of developing thermostable vaccine adjuvants has sometimes... (Review)
Review
INTRODUCTION
The importance of vaccine thermostability has been discussed in the literature. Nevertheless, the challenge of developing thermostable vaccine adjuvants has sometimes not received appropriate emphasis. Adjuvants comprise an expansive range of particulate and molecular compositions, requiring innovative thermostable formulation and process development approaches.
AREAS COVERED
Reports on efforts to develop thermostable adjuvant-containing vaccines have increased in recent years, and substantial progress has been made in enhancing the stability of the major classes of adjuvants. This narrative review summarizes the current status of thermostable vaccine adjuvant development and looks forward to the next potential developments in the field.
EXPERT OPINION
As adjuvant-containing vaccines become more widely used, the unique challenges associated with developing thermostable adjuvant formulations merit increased attention. In particular, more focused efforts are needed to translate promising proof-of-concept technologies and formulations into clinical products.
Topics: Adjuvants, Immunologic; Adjuvants, Vaccine; Humans; Vaccines
PubMed: 33724133
DOI: 10.1080/14760584.2021.1902314