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.

Stimulator of interferon genes (STING)-activating nanoparticles can be employed as a tool for controlled immune activation

Advances in materials and chemistry have helped stimulator of interferon genes (STING) agonists deliver nanomedicine, and drug delivery scientists have generated a spate of STING-activating nanocarriers capable of bypassing biological barriers for targeted innate and adaptive immune activation. Using STING-activating nanoparticles in antiviral vaccination has yielded several promising results in preclinical studies, and the strong antiviral humoral and cellular immunity elicited by these particulate adjuvants against HIV, influenza, and coronaviruses justifies the continued development of the platforms against the global infectious threat. STING-activating nanoparticles can be employed in virology and immunology research as a tool for controlled immune activation, as many processes underpinning STING-mediated immunological potency in viral infections are yet unclear. Because many of the nanoparticle platforms used to deliver STING agonists may also be utilized with various molecular adjuvants, these systems may be utilized to examine how diverse innate immune signals impact adaptive immunity production. Combinatorial nanoparticles mixing STING agonists with other molecular adjuvants may further increase antiviral protectivity by synergistically increasing immunological potential. Despite the promise of nanoparticulate vaccines, these synthetic nanoparticles are strikingly absent from COVID-19 vaccine research worldwide talks. Many elements, such as formulation safety, manufacturing scalability, storage, and deployment logistics, must be considered to achieve the enormous potential of the nanoparticulate STING agonists. Reduced synthetic methods and formulation lyophilization are important factors in platform designs to make antiviral vaccines accessible and affordable to poor nations. Nevertheless, the platform's great efficiency and wide use provide promise advances in both fundamental and translational research, opening the way to a deeper knowledge of viral containment and superior approaches.

Nucleic Acid-Based Approaches for Tumor Therapy

Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients’ anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.

Clinical Pathology, Immunopathology and Advanced Vaccine Technology in Bovine Theileriosis: A Review

Theileriosis is a blood piroplasmic disease that adversely affects the livestock industry, especially in tropical and sub-tropical countries. It is caused by haemoprotozoan of the Theileria genus, transmitted by hard ticks and which possesses a complex life cycle. The clinical course of the disease ranges from benign to lethal, but subclinical infections can occur depending on the infecting Theileria species. The main clinical and clinicopathological manifestations of acute disease include fever, lymphadenopathy, anorexia and severe loss of condition, conjunctivitis, and pale mucous membranes that are associated with Theileria-induced immune-mediated haemolytic anaemia and/or non-regenerative anaemia. Additionally, jaundice, increases in hepatic enzymes, and variable leukocyte count changes are seen. Theileria annulata and Theileria parva induce an incomplete transformation of lymphoid and myeloid cell lineages, and these cells possess certain phenotypes of cancer cells. Pathogenic genotypes of Theileria orientalis have been recently associated with severe production losses in Southeast Asia and some parts of Europe. The infection and treatment method (ITM) is currently used in the control and prevention of T. parva infection, and recombinant vaccines are still under evaluation. The use of gene gun immunization against T. parva infection has been recently evaluated. This review, therefore, provides an overview of the clinicopathological and immunopathological profiles of Theileria-infected cattle and focus on DNA vaccines consisting of plasmid DNA with genes of interest, molecular adjuvants, and chitosan as the most promising next-generation vaccine against bovine theileriosis.

Designed DNA-Encoded IL-36 Gamma Acts as a Potent Molecular Adjuvant Enhancing Zika Synthetic DNA Vaccine-Induced Immunity and Protection in a Lethal Challenge Model

Identification of novel molecular adjuvants which can boost and enhance vaccine-mediated immunity and provide dose-sparing potential against complex infectious diseases and for immunotherapy in cancer is likely to play a critical role in the next generation of vaccines. Given the number of challenging targets for which no or only partial vaccine options exist, adjuvants that can address some of these concerns are in high demand. Here, we report that a designed truncated Interleukin-36 gamma (IL-36 gamma) encoded plasmid can act as a potent adjuvant for several DNA-encoded vaccine targets including human immunodeficiency virus (HIV), influenza, and Zika in immunization models. We further show that the truncated IL-36 gamma (opt-36γt) plasmid provides improved dose sparing as it boosts immunity to a suboptimal dose of a Zika DNA vaccine, resulting in potent protection against a lethal Zika challenge.