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In the early nineties, pioneering steps were taken in the use of mRNA as a therapeutic tool for vaccination. In the following decades, an improved understanding of the mRNA pharmacology, together with novel insights in immunology have positioned mRNA-based technologies as next-generation vaccines. This review outlines the history and current state-of-the-art in mRNA vaccination, while presenting an immunological view on mRNA vaccine development. As such, we highlight the challenges in vaccine design, testing and administration, key considerations in the design of mRNA-based vaccines and new opportunities that arise when packaging mRNA in nanoparticulate vaccines. Finally, we discuss the mRNA self-adjuvant effect as a critical, but dichotomous parameter that determines the safety, efficacy and strength of the evoked immune response.
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... It was often suggested that the main advantage of mRNA-based vaccines, compared to the more conventional approaches is the possibility of their rapid development and largescale deployment [6,7], which are both desirable properties in pandemic situations. The statement that vaccine mRNAs do not pose a risk for genome integration, e.g., [6,[8][9][10][11][12], and consequently, that there is no insertional mutagenesis risk, is another commonly listed advantage of mRNA-based vaccines, especially when contrasted with the safety profile of DNA-based therapeutics [10,12,13]. This claim prompted me to look more carefully into the mRNA vaccine literature to find a rationale for it. ...
... However, it remains puzzling why and how the mRNA vaccinology field neglected the retroposition biology of L1 retroelements and its theoretical links to possible vaccine mRNA retroposition, especially when one considers the volume, visibility and significance of the L1 [44,45,60,[83][84][85]117,131] and retroposition research [36][37][38][39][40][41]45,46,49,60,66,68,77,80]. The mRNA vaccinology field started its development more than 30 years ago [11,31] and L1 retroelements in humans have been studied for more than 40 years [205,206] but obviously without any crosstalk between the two fields. This awkward silo effect points to the fact that, on some occasions, the structural drawbacks of contemporary science, despite its amassment, globalization and unprecedented dissemination, are deeper than we are willing to admit. ...
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The major advantage of mRNA vaccines over more conventional approaches is their potential for rapid development and large-scale deployment in pandemic situations. In the current COVID-19 crisis, two mRNA COVID-19 vaccines have been conditionally approved and broadly applied, while others are still in clinical trials. However, there is no previous experience with the use of mRNA vaccines on a large scale in the general population. This warrants a careful evaluation of mRNA vaccine safety properties by considering all available knowledge about mRNA molecular biology and evolution. Here, I discuss the pervasive claim that mRNA-based vaccines cannot alter genomes. Surprisingly, this notion is widely stated in the mRNA vaccine literature but never supported by referencing any primary scientific papers that would specifically address this question. This discrepancy becomes even more puzzling if one considers previous work on the molecular and evolutionary aspects of retroposition in murine and human populations that clearly documents the frequent integration of mRNA molecules into genomes, including clinical contexts. By performing basic comparisons, I show that the sequence features of mRNA vaccines meet all known requirements for retroposition using L1 elements—the most abundant autonomously active retrotransposons in the human genome. In fact, many factors associated with mRNA vaccines increase the possibility of their L1-mediated retroposition. I conclude that is unfounded to a priori assume that mRNA-based therapeutics do not impact genomes and that the route to genome integration of vaccine mRNAs via endogenous L1 retroelements is easily conceivable. This implies that we urgently need experimental studies that would rigorously test for the potential retroposition of vaccine mRNAs. At present, the insertional mutagenesis safety of mRNA-based vaccines should be considered unresolved.
... mRNA vaccines have been considered for over three decades and are comprised of self-replicating RNA or messenger RNA that cause cells to express an antigen that can elicit cytotoxic T lymphocyte responses. mRNA shows specific benefits in inducing transient expression and production of specific antigenic proteins that give rise to MHC-1 presentation [72]. This has made RNA a popular choice in several COVID-19 vaccines, including the approved Pfizer-BioNTech and Moderna vaccines. ...
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COVID-19 vaccines have been developed to confer immunity against the SARS-CoV-2 infection. Prior to the pandemic of COVID-19 which started in March 2020, there was a well-established understanding about the structure and pathogenesis of previously known Coronaviruses from the SARS and MERS outbreaks. In addition to this, vaccines for various Coronaviruses were available for veterinary use. This knowledge supported the creation of various vaccine platforms for SARS-CoV-2. Before COVID-19 there are no reports of a vaccine being developed in under a year and no vaccine for preventing coronavirus infection in humans had ever been developed. Approximately nine different technologies are being researched and developed at various levels in order to design an effective COVID-19 vaccine. As the spike protein of SARS-CoV-2 is responsible for generating a substantial adaptive immune response, mostly all the vaccine candidates have been targeting the whole spike protein or epitopes of spike protein as a vaccine candidates. In this review, we have compiled the immune response to SARS-CoV-2 infection and followed by the mechanism of action of various vaccine platforms such as mRNA vaccines, Adenoviral vectored vaccines, inactivated virus vaccines and subunit vaccines in the market. In the end, we have also summarized the various adjuvants used in the COVID-19 vaccine formulation.
... Induction of high levels of gp120-specific antibodies in rhesus macaques and rabbits [199] Ionizable lipid: structural lipid: sterol: PEG-lipid mRNA encoding the POWV prM and E genes Powassan virus (POWV), an emerging tick-borne flavivirus Induction of high levels of neutralizing antibodies and sterilizing immunity [200] more appropriate for targeting diseases via high genetic instability and infectivity than other vaccines. mRNAbased vaccines were first used as a therapeutic drug in 1989 [186,187]. It has been proven that the encapsulation of mRNA in LNP facilitates the control of biodistribution as well as cell targeting. Recently, six COVID-19 vaccines based on mRNA encapsulated in LNP have entered clinical trials, and mRNA-1273 (Moderna vaccine) and BNT162b2; Comirnaty (Pfizer/BioNTech vaccine) were given FDA emergency use authorization (EUA) in 2020 [188]. ...
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In the last decade, the development of messenger RNA (mRNA) therapeutics by lipid nanoparticles (LNP) leads to facilitate clinical trial recruitment, which improves the efficacy of treatment modality to a large extent. Although mRNA-LNP vaccine platforms for the COVID-19 pandemic demonstrated high efficiency, safety and adverse effects challenges due to the uncontrolled immune responses and inappropriate pharmacological interventions could limit this tremendous efficacy. The current study reveals the interplay of immune responses with LNP compositions and characterization and clarifies the interaction of mRNA-LNP therapeutics with dendritic, macrophages, neutrophile cells, and complement. Then, pharmacological profiles for mRNA-LNP delivery, including pharmacokinetics and cellular trafficking, were discussed in detail in cancer types and infectious diseases. This review study opens a new and vital landscape to improve multidisciplinary therapeutics on mRNA-LNP through modulation of immunopharmacological responses in clinical trials. Graphical Abstract
... There is also evidence that ionizable lipids within LNPs can trigger proinflammatory responses by activating Toll-like receptors (TLRs) [40]. A recent report showed that LNPs used in preclinical nucleoside-modified mRNA vaccine studies are (independently of the delivery route) highly inflammatory in mice, as evidenced by excessive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines [41]. ...
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Vaccination is a major tool for mitigating the COVID-19 pandemic and mRNA vaccines are central to the ongoing vaccination campaign that is undoubtedly saving thousands of lives. However, adverse effects (AEs) following vaccination have been noted which may relate to a pro-inflammatory action of the employed lipid nanoparticles or the delivered mRNA (i.e., vaccines formulation) as well as to the herein discussed unique nature, expression pattern, binding profile and pro-inflammatory effects of the produced antigens (S protein and/or its subunits-peptide fragments) in human tissues/organs. Current knowledge on this topic mostly originates from cell-based assays or from model organisms, therefore further research on the cellular-molecular basis of the mRNA vaccines induced AEs, will guarantee safety, maintain trust, and direct health policies.
... Myocarditis is also thought to be a result of this autoimmune response. 5 Potential mechanisms for myocarditis post-mRNA-based vaccination include a nonspecific innate inflammatory response or a molecular mimicry mechanism between viral spike protein and an unknown cardiac protein. 6 The incidence of myocarditis is 1.5 million cases per year. ...
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The mRNA vaccine platform has offered the greatest potential in fighting the COVID-19 pandemic owing to rapid development, effectiveness, and scalability to meet the global demand. There are many other mRNA vaccines currently being developed against different emerging viral diseases. As with the current COVID-19 vaccines, these mRNA-based vaccine candidates are being developed for parenteral administration via injections. However, most of the emerging viruses colonize the mucosal surfaces prior to systemic infection making it very crucial to target mucosal immunity. Although parenterally administered vaccines would induce a robust systemic immunity, they often provoke a weak mucosal immunity which may not be effective in preventing mucosal infection. In contrast, mucosal administration potentially offers the dual benefit of inducing potent mucosal and systemic immunity which would be more effective in offering protection against mucosal viral infection. There are however many challenges posed by the mucosal environment which impede successful mucosal vaccination. The development of an effective delivery system remains a major challenge to the successful exploitation of mucosal mRNA vaccination. Nonetheless, a number of delivery vehicles have been experimentally harnessed with different degrees of success in the mucosal delivery of mRNA vaccines. In this review, we provide a comprehensive overview of mRNA vaccines and summarise their application in the fight against emerging viral diseases with particular emphasis on COVID-19 mRNA platforms. Furthermore, we discuss the prospects and challenges of mucosal administration of mRNA-based vaccines, and we explore the existing experimental studies on mucosal mRNA vaccine delivery.
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The current applications of nanomedicine span from the treatment of an infection right up to the treatment of cancer. Lipid nanoparticles (LNPs) have established themselves as reliable delivery systems for delivering therapeutic agents including nucleic acids since they prevent in vivo degradation of nucleic acids and facilitate their target-specific delivery. The mRNA is one such nucleic acid that is delivered by the LNPs for the treatment of infectious diseases. This review provides a detailed insight into the concept of messenger RNA (mRNA) vaccines, their mechanism of action, manufacturing process, critical considerations in the formulation, development, and manufacturing of these vaccines, and explains the vital role of LNPs in the development of these vaccines. Certain shortcomings of the lipid nanoparticle-mRNA vaccine concerning the in vitro stability of the mRNA and the LNP have also been highlighted in this review.
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