Synthetic and Natural TLR4 Agonists as Safe and Effective Vaccine Adjuvants

Author(s):  
Christopher B. Fox ◽  
Martin Friede ◽  
Steven G. Reed ◽  
Gregory C. Ireton
2021 ◽  
Vol 22 (5) ◽  
pp. 2671
Author(s):  
Galina M. Viryasova ◽  
Ekaterina A. Golenkina ◽  
Tibor Hianik ◽  
Nataliya V. Soshnikova ◽  
Nina G. Dolinnaya ◽  
...  

Neutrophil-mediated innate host defense mechanisms include pathogen elimination through bacterial phagocytosis, which activates the 5-lipoxygenase (5-LOX) product synthesis. Here, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs), which mimic the receptor-recognized sites of bacterial (CpG-ODNs) and genomic (G-rich ODNs) DNAs released from the inflammatory area, on the neutrophil functions after cell stimulation with Salmonella typhimurium. A possible mechanism for ODN recognition by Toll-like receptor 9 (TLR9) and RAGE receptor has been proposed. We found for the first time that the combination of the magic peptide LRR11 from the leucine-rich repeat (LRR) of TLR9 with the CpG-ODNs modulates the uptake and signaling from ODNs, in particular, dramatically stimulates 5-LOX pathway. Using thickness shear mode acoustic method, we confirmed the specific binding of CpG-ODNs, but not G-rich ODN, to LRR11. The RAGE receptor has been shown to play an important role in promoting ODN uptake. Thus, FPS-ZM1, a high-affinity RAGE inhibitor, suppresses the synthesis of 5-LOX products and reduces the uptake of ODNs by neutrophils; the inhibitor effect being abolished by the addition of LRR11. The results obtained revealed that the studied peptide-ODN complexes possess high biological activity and can be promising for the development of effective vaccine adjuvants and antimicrobial therapeutics.


Vaccinology ◽  
2012 ◽  
pp. 13-28
Author(s):  
Heather L. Wilson ◽  
Scott Napper ◽  
George K. Mutwiri ◽  
Sylvia van Drunen Littel-van den Hurk ◽  
Hugh Townsend ◽  
...  

2008 ◽  
Vol 14 (5) ◽  
pp. 536-541 ◽  
Author(s):  
James B McLachlan ◽  
Christopher P Shelburne ◽  
Justin P Hart ◽  
Salvatore V Pizzo ◽  
Rajen Goyal ◽  
...  

2005 ◽  
Vol 73 (11) ◽  
pp. 7687-7696 ◽  
Author(s):  
Khaleda Rahman Qazi ◽  
Mousumi Rahman Qazi ◽  
Esther Julián ◽  
Mahavir Singh ◽  
Manuchehr Abedi-Valugerdi ◽  
...  

ABSTRACT During stress conditions, such as infection, the synthesis of heat shock proteins (HSPs) in microorganisms is upregulated. Since a high degree of homology exists within each HSP family, we postulated that exposure to microorganisms could prime the immune system for evolutionarily diverse HSPs. We tested this hypothesis by priming mice with three microorganisms, namely, Mycobacterium bovis BCG, Mycobacterium vaccae, and Chlamydia pneumoniae. After this, mice received a dose of the various HSPs. We found that BCG and M. vaccae but not C. pneumoniae primed the immune system for the induction of secondary immunoglobulin G (IgG) responses to most of the HSPs tested. Analysis of the IgG1 and IgG2a profile and gamma interferon production induced against the HSPs revealed the induction of a mixture of responses. We also observed that sera from mice treated with M. vaccae and HSP70 were cross-reactive, but no antibody complexes were observed in their kidneys, which frequently are targets for autoantibody reactions. Our findings add further support for the use of HSPs as effective vaccine adjuvants.


2021 ◽  
Author(s):  
Hsin-Hung Lin ◽  
Chih-Yen Wang ◽  
Feng-Jen Hsieh ◽  
Fang-Zhen Liao ◽  
Yu-Kai Su ◽  
...  

Abstract Background Vaccination is an effective tool to elicit immunological responses that mediate the protection from infection or disease. Composed of mineral oil and mycobacteria pathogens, complete Freund’s adjuvant (CFA) is one of the most commonly employed adjuvants for antibody production and vaccination due to its high efficiency. However, the dead mycobacteria in CFA can cause many allergic reactions. To avoid these adverse effects, we propose here a new formulation based on the use of nanodiamonds (NDs) as biocompatible non-allergic additives in incomplete Freund’s adjuvant (IFA) instead. ResultsTested with chicken egg ovalbumin (OVA) in mouse models, the new formulation with 100-nm NDs was found to serve well as a safe and potent vaccine adjuvant that significantly enhanced the immune responses and reduced the consumption of antigens in producing the antibodies of interest. Additionally, the composites showed distinct therapeutic activities, as proven by the OVA/ND/IFA treatment which effectively inhibited the tumor progression of OVA-expressing E.G7 cells inoculated in mice and allowed the animals to survive up to 35 days post tumor-cell challenges. ConclusionsThe dual functionality of ND/IFA makes it useful as adjuvants not only to increase antibody production but also to create single-dose vaccines.


2019 ◽  
Vol 24 (6) ◽  
pp. 628-640
Author(s):  
Hae Woong Choi ◽  
Cliburn Chan ◽  
Ivo D. Shterev ◽  
Heather E. Lynch ◽  
Taylor J. Robinette ◽  
...  

Mast cells (MCs) are known to regulate innate and adaptive immunity. MC activators have recently been described as safe and effective vaccine adjuvants. Many currently known MC activators are inadequate for in vivo applications, however, and research on identifying novel MC activators is limited. In this study, we identified novel MC activators by using high-throughput screening (HTS) assays using approximately 55,000 small molecules. Data sets obtained by the primary HTS assays were statistically evaluated using quality control rules and the B-score calculation, and compounds with B-scores of >3.0 were chosen as mast cell activators (hits). These hits were re-evaluated with secondary and tertiary HTS assays, followed by further statistical analysis. From these hits, we selected 15 compounds that caused degranulation in murine and human MCs, with potential for flexible chemical modification for further study. Among these 15 compounds, ST101036, ST029248, and ST026567 exhibited higher degranulation potency than other hit compounds in both human and mouse MCs. In addition, the 15 compounds identified promote de novo synthesis of cytokines and induce the release of eicosanoids from human and mouse MCs. HTS enabled us to identify small-molecule MC activators with unique properties that may be useful as vaccine adjuvants.


2011 ◽  
Vol 208 (1) ◽  
pp. 149-165 ◽  
Author(s):  
Lina E. Tze ◽  
Keisuke Horikawa ◽  
Heather Domaschenz ◽  
Debbie R. Howard ◽  
Carla M. Roots ◽  
...  

Effective vaccine adjuvants must induce expression of major histocompatability (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea–induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10–driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.


2020 ◽  
Vol 11 (3) ◽  
pp. 213-226
Author(s):  
N. Mojgani ◽  
Y. Shahali ◽  
M. Dadar

Vaccination is one of the most important prevention tools providing protection against infectious diseases especially in children below the age of five. According to estimates, more than 5 million lives are saved annually by the implementation of six standard vaccines, including diphtheria, hepatitis B, Haemophilus influenza type b, polio, tetanus and yellow fever. Despite these efforts, we are faced with challenges in developing countries where increasing population and increasing disease burden and difficulties in vaccine coverage and delivery cause significant morbidity and mortality. Additionally, the high cost of these vaccines is also one of the causes for inappropriate and inadequate vaccinations in these regions. Thus, developing cost-effective vaccine strategies that could provide a stronger immune response with reduced vaccination schedules and maximum coverage is of critical importance. In last decade, different approaches have been investigated; among which live bacterial vaccines have been the focus of attention. In this regard, probiotic lactic acid bacteria have been extensively studied as safe and effective vaccine candidates. These microorganisms represent the largest group of probiotic bacteria in the intestine and are generally recognised as safe (GRAS) bacteria. They have also attracted attention due to their immunomodulatory actions and their effective role as novel vaccine adjuvants. A significant property of these bacteria is their ability to mimic natural infections, while intrinsically possessing mucosal adjuvant properties. Additionally, as live bacterial vaccines are administered orally or nasally, they have higher acceptance and better safety, but also avoid the risk of contamination due to needles and syringes. In this review, we emphasise the role of probiotic Lactobacillus strains as putative oral vaccine carriers and novel vaccine adjuvants.


2015 ◽  
Vol 204 ◽  
pp. 51-59 ◽  
Author(s):  
Fangjia Lu ◽  
Alejandra Mencia ◽  
Lin Bi ◽  
Aaron Taylor ◽  
Yuan Yao ◽  
...  

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