The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development

Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence. The finding that CDNs can trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signalling pathway has prompted the extensive research and development of CDNs as potential immunostimulators and novel molecular adjuvants for induction of systemic and mucosal innate and adaptive immune responses. In this review, we summarize the chemical structure, biosynthesis regulation, and the role of CDNs in enhancing the crosstalk between host innate and adaptive immune responses. We also discuss the strategies to improve the efficient delivery of CDNs and the recent advance and future challenges in the development of CDNs as potential adjuvants in prophylactic vaccines against infectious diseases and in therapeutic vaccines against cancers.

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Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Cells ◽

10.3390/cells9092109 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2109

Author(s):

Samuel T. Pasco ◽

Juan Anguita

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Vaccine Development ◽

Vaccine Design ◽

Innate Immune ◽

Bacillus Calmette Guerin ◽

Adaptive Immune Responses ◽

Trained Immunity ◽

Adaptive Immune ◽

Potential Methods

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

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Integrated time-serial transcriptome networks reveal common innate and tissue-specific adaptive immune responses to PRRSV infection

Veterinary Research ◽

10.1186/s13567-020-00850-5 ◽

2020 ◽

Vol 51 (1) ◽

Author(s):

Byeonghwi Lim ◽

Sangwook Kim ◽

Kyu-Sang Lim ◽

Chang-Gi Jeong ◽

Seung-Chai Kim ◽

...

Keyword(s):

Immune Responses ◽

Influenza A ◽

Vaccine Development ◽

Expression Patterns ◽

Economic Losses ◽

Respiratory Syndrome Virus ◽

Specific Group ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Gene Expression Control

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) infection is the most important viral disease causing severe economic losses in the swine industry. However, mechanisms underlying gene expression control in immunity-responsible tissues at different time points during PRRSV infection are poorly understood. We constructed an integrated gene co-expression network and identified tissue- and time-dependent biological mechanisms of PRRSV infection through bioinformatics analysis using three tissues (lungs, bronchial lymph nodes [BLNs], and tonsils) via RNA-Seq. Three groups with specific expression patterns (i.e., the 3-dpi, lung, and BLN groups) were discovered. The 3 dpi-specific group showed antiviral and innate-immune signalling similar to the case for influenza A infection. Moreover, we observed adaptive immune responses in the lung-specific group based on various cytokines, while the BLN-specific group showed down-regulated AMPK signalling related to viral replication. Our study may provide comprehensive insights into PRRSV infection, as well as useful information for vaccine development.

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Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

Microorganisms ◽

10.3390/microorganisms7100402 ◽

2019 ◽

Vol 7 (10) ◽

pp. 402

Author(s):

Titus Abiola Olukitibi ◽

Zhujun Ao ◽

Mona Mahmoudi ◽

Gary A. Kobinger ◽

Xiaojian Yao

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Ebola Virus ◽

Vaccine Development ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Immunological Approach ◽

Vaccine Approach ◽

Acquired Immune Responses ◽

Diverse Virus

In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.

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Novel Concepts for HIV Vaccine Vector Design

mSphere ◽

10.1128/msphere.00415-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 8

Author(s):

Quazim A. Alayo ◽

Nicholas M. Provine ◽

Pablo Penaloza-MacMaster

Keyword(s):

Immune Responses ◽

Viral Vectors ◽

Vaccine Development ◽

Viral Vector ◽

Intracellular Pathogens ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Recent Advances ◽

Robust Adaptive ◽

Selection Of

ABSTRACT The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best-characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce.

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Adaptive Immune Responses to Infection and Opportunities for Vaccine Development (Rickettsiaceae)

Intracellular Pathogens II: Rickettsiales ◽

10.1128/9781555817336.ch10 ◽

2014 ◽

pp. 304-329

Author(s):

Gustavo Valbuena

Keyword(s):

Immune Responses ◽

Vaccine Development ◽

Adaptive Immune Responses ◽

Adaptive Immune

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Influenza Virus Hemagglutinin Glycoproteins with Different N-Glycan Patterns Activate Dendritic CellsIn Vitro

Journal of Virology ◽

10.1128/jvi.00452-16 ◽

2016 ◽

Vol 90 (13) ◽

pp. 6085-6096 ◽

Cited By ~ 18

Author(s):

Wen-Chun Liu ◽

Yu-Li Lin ◽

Maureen Spearman ◽

Pei-Yun Cheng ◽

Michael Butler ◽

...

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Vaccine Development ◽

Influenza Viruses ◽

Viral Escape ◽

Complex Type ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Influenza Virus Hemagglutinin ◽

High Mannose

ABSTRACTInfluenza virus hemagglutinin (HA) N-glycans play important regulatory roles in the control of virus virulence, antigenicity, receptor-binding specificity, and viral escape from the immune response. Considered essential for controlling innate and adaptive immune responses against influenza virus infections, dendritic cells (DCs) trigger proinflammatory and adaptive immune responses in hosts. In this study, we engineered Chinese hamster ovary (CHO) cell lines expressing recombinant HA from pandemic H1, H5, and H7 influenza viruses. rH1HA, rH5HA, and rH7HA were obtained as wild-type proteins or in the presence of kifunensine (KIF) or further with endo-β-N-acetylglucosaminidase-treated KIF (KIF+E) to generate single-N-acetylglucosamine (GlcNAc) N-glycans consisting of (i) terminally sialylated complex-type N-glycans, (ii) high-mannose-type N-glycans, and (iii) single-GlcNAc-type N-glycans. Our results show that high-mannose-type and single-GlcNAc-type N-glycans, but not complex-type N-glycans, are capable of inducing more active hIL12 p40, hIL12 p70, and hIL-10 production in human DCs. Significantly higher HLA-DR, CD40, CD83, and CD86 expression levels, as well reduced endocytotic capacity in human DCs, were noted in the high-mannose-type rH1HA and single-GlcNAc-type rH1HA groups than in the complex-type N-glycan rH1HA group. Our data indicate that native avian rHA proteins (H5N1 and H7N9) are more immunostimulatory than human rHA protein (pH1N1). The high-mannose-type or single-GlcNAc-type N-glycans of both avian and human HA types are more stimulatory than the complex-type N-glycans. HA-stimulated DC activation was accomplished partially through a mannose receptor(s). These results provide more understanding of the contribution of glycosylation of viral proteins to the immune responses and may have implications for vaccine development.IMPORTANCEInfluenza viruses trigger seasonal epidemics or pandemics with mild-to-severe consequences for human and poultry populations. DCs are the most potent professional antigen-presenting cells, which play a crucial role in the link between innate and adaptive immunity. In this study, we obtained stable-expression CHO cells to produce rH1HA, rH5HA, and rH7HA proteins containing distinct N-glycan patterns. These rHA proteins, each with a distinct N-glycan pattern, were used to investigate interactions with mouse and human DCs. Our data indicate that native avian rHA proteins (H5N1 and H7N9) are more immunostimulatory than human rHA protein (pH1N1). High-mannose-type and single-GlcNAc-type N-glycans were more effective than complex-type N-glycans in triggering mouse and human DC activation and maturation. We believe these results provide some useful information for influenza vaccine development regarding how influenza virus HA proteins with different types of N-glycans activate DCs.

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