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1.
Nat Nanotechnol ; 17(4): 337-346, 2022 04.
Article in English | MEDLINE | ID: covidwho-1783988

ABSTRACT

After over a billion of vaccinations with messenger RNA-lipid nanoparticle (mRNA-LNP) based SARS-CoV-2 vaccines, anaphylaxis and other manifestations of hypersensitivity can be considered as very rare adverse events. Although current recommendations include avoiding a second dose in those with first-dose anaphylaxis, the underlying mechanisms are unknown; therefore, the risk of a future reaction cannot be predicted. Given how important new mRNA constructs will be to address the emergence of new viral variants and viruses, there is an urgent need for clinical approaches that would allow a safe repeated immunization of high-risk individuals and for reliable predictive tools of adverse reactions to mRNA vaccines. In many aspects, anaphylaxis symptoms experienced by the affected vaccine recipients resemble those of infusion reactions to nanomedicines. Here we share lessons learned over a decade of nanomedicine research and discuss the current knowledge about several factors that individually or collectively contribute to infusion reactions to nanomedicines. We aim to use this knowledge to inform the SARS-CoV-2 lipid-nanoparticle-based mRNA vaccine field.


Subject(s)
Anaphylaxis , COVID-19 , Anaphylaxis/etiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Liposomes , Nanomedicine , Nanoparticles , RNA, Messenger/genetics , SARS-CoV-2/genetics , Vaccines, Synthetic
2.
Adv Drug Deliv Rev ; 180: 114079, 2022 01.
Article in English | MEDLINE | ID: covidwho-1620432

ABSTRACT

Polyethylene glycol or PEG has a long history of use in medicine. Many conventional formulations utilize PEG as either an active ingredient or an excipient. PEG found its use in biotechnology therapeutics as a tool to slow down drug clearance and shield protein therapeutics from undesirable immunogenicity. Nanotechnology field applies PEG to create stealth drug carriers with prolonged circulation time and decreased recognition and clearance by the mononuclear phagocyte system (MPS). Most nanomedicines approved for clinical use and experimental nanotherapeutics contain PEG. Among the most recent successful examples are two mRNA-based COVID-19 vaccines that are delivered by PEGylated lipid nanoparticles. The breadth of PEG use in a wide variety of over the counter (OTC) medications as well as in drug products and vaccines stimulated research which uncovered that PEG is not as immunologically inert as it was initially expected. Herein, we review the current understanding of PEG's immunological properties and discuss them in the context of synthesis, biodistribution, safety, efficacy, and characterization of PEGylated nanomedicines. We also review the current knowledge about immunological compatibility of other polymers that are being actively investigated as PEG alternatives.


Subject(s)
Drug Carriers , Nanomedicine , Polyethylene Glycols/chemistry , Animals , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Drug Delivery Systems , Humans
3.
Adv Drug Deliv Rev ; 181: 114081, 2022 02.
Article in English | MEDLINE | ID: covidwho-1568454

ABSTRACT

With numerous recent advances, the field of therapeutic nucleic acid nanotechnology is now poised for clinical translation supported by several examples of FDA-approved nucleic acid nanoformulations including two recent mRNA-based COVID-19 vaccines. Within this rapidly growing field, a new subclass of nucleic acid therapeutics called nucleic acid nanoparticles (NANPs) has emerged in recent years, which offers several unique properties distinguishing it from traditional therapeutic nucleic acids. Key unique aspects of NANPs include their well-defined 3D structure, their tunable multivalent architectures, and their ability to incorporate conditional activations of therapeutic targeting and release functions that enable diagnosis and therapy of cancer, regulation of blood coagulation disorders, as well as the development of novel vaccines, immunotherapies, and gene therapies. However, non-consolidated research developments of this highly interdisciplinary field create crucial barriers that must be overcome in order to impact a broader range of clinical indications. Forming a consortium framework for nucleic acid nanotechnology would prioritize and consolidate translational efforts, offer several unifying solutions to expedite their transition from bench-to-bedside, and potentially decrease the socio-economic burden on patients for a range of conditions. Herein, we review the unique properties of NANPs in the context of therapeutic applications and discuss their associated translational challenges.


Subject(s)
Nanoparticles/chemistry , Nanoparticles/therapeutic use , Nucleic Acids/chemistry , Nucleic Acids/therapeutic use , Animals , COVID-19/drug therapy , COVID-19/immunology , COVID-19 Vaccines/immunology , Drug Delivery Systems/methods , Humans , Immunotherapy/methods , Nanotechnology/methods , SARS-CoV-2/drug effects
4.
Front Immunol ; 12: 642860, 2021.
Article in English | MEDLINE | ID: covidwho-1231336

ABSTRACT

Cytokine storm (CS), an excessive release of proinflammatory cytokines upon overactivation of the innate immune system, came recently to the focus of interest because of its role in the life-threatening consequences of certain immune therapies and viral diseases, including CAR-T cell therapy and Covid-19. Because complement activation with subsequent anaphylatoxin release is in the core of innate immune stimulation, studying the relationship between complement activation and cytokine release in an in vitro CS model holds promise to better understand CS and identify new therapies against it. We used peripheral blood mononuclear cells (PBMCs) cultured in the presence of autologous serum to test the impact of complement activation and inhibition on cytokine release, testing the effects of liposomal amphotericin B (AmBisome), zymosan and bacterial lipopolysaccharide (LPS) as immune activators and heat inactivation of serum, EDTA and mini-factor H (mfH) as complement inhibitors. These activators induced significant rises of complement activation markers C3a, C4a, C5a, Ba, Bb, and sC5b-9 at 45 min of incubation, with or without ~5- to ~2,000-fold rises of IL-1α, IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13 and TNFα at 6 and 18 h later. Inhibition of complement activation by the mentioned three methods had differential inhibition, or even stimulation of certain cytokines, among which effects a limited suppressive effect of mfH on IL-6 secretion and significant stimulation of IL-10 implies anti-CS and anti-inflammatory impacts. These findings suggest the utility of the model for in vitro studies on CS, and the potential clinical use of mfH against CS.


Subject(s)
COVID-19/immunology , Complement Activation , Cytokine Release Syndrome/immunology , Interleukin-10/immunology , Interleukin-6/immunology , Leukocytes, Mononuclear/immunology , Models, Immunological , SARS-CoV-2/immunology , COVID-19/pathology , Complement Factor H/immunology , Cytokine Release Syndrome/pathology , Humans , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology
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