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Review

The Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review

1
EBMC Squared CIC, 11 Laura Place, Bath BA2 4BL, UK
2
Independent Researcher
*
Author to whom correspondence should be addressed.
J 2023, 6(2), 220-235; https://doi.org/10.3390/j6020017
Submission received: 1 January 2023 / Revised: 4 April 2023 / Accepted: 4 April 2023 / Published: 17 April 2023
(This article belongs to the Section Public Health & Healthcare)

Abstract

:
Pharmacovigilance databases are showing evidence of injury in the context of the modified COVID-19 mRNA products. According to recent publications, adverse event reports linked to the mRNA COVID-19 injections largely point to the spike protein as an aetiological agent of adverse events, but we propose that the platform itself may be culpable. To assess the safety of current and future mRNA vaccines, further analysis is needed on the risks due to the platform itself, and not specifically the expressed antigen. If harm can be exclusively and conclusively attributed to the spike protein, then it is possible that future mRNA vaccines expressing other antigens will be safe. If harms are attributable to the platform itself, then regardless of the toxicity, or lack thereof, of the antigen to be expressed, the platform may be inherently unsafe, pending modification. In this work, we examine previous studies of RNA-based delivery by a lipid nanoparticle (LNP) and break down the possible aetiological elements of harm.

1. Introduction

Pharmaceutical drug and medical device approvals are predicated on the completion of a structured approval process through various regulatory agencies. Historically, the approval process has contributed to patient safety by subjecting all new approvals to a rigorous safety assessment. However, there are many examples of over-turnings of approvals of pharmaceuticals post facto, due to the emergence of oversights of particular safety factors that occurred during the approval process [1]. These failures of regulatory bodies to sufficiently assess safety during the approval process is costly in terms of health and economic harms [2]. To put this issue into perspective, of 309 novel cardiovascular, orthopaedic, and neurologic devices approved in the EU between 2005 and 2010, 73 (24%) were subjected to either a safety alert or product recall [3], consistent with reported rates for other medical devices [4]. Importantly, as the complexity of novel products increases, approval success rates decrease [5]; for example, new drug approvals are marred by low phase III trial success rates (~10%) [6].
Given the low success rates of novel and unprecedented drugs [6,7,8], and the potential risks to the population, it is important to adopt the precautionary principle [9] when approving any pharmacological products, especially those given to large populations. COVID-19 mRNA vaccine products have a novel delivery system, being the first mRNA vaccines approved for use in humans, as well as the first approved coronavirus vaccines in humans. The speed at which they were designed, developed, approved, and administered is also unprecedented in pharmaceutical history [10], and defies traditional timelines for testing of biological products for use in humans.
With the approval of the mRNA platform by health regulators across the globe, the industry is poised to develop new vaccines using mRNA, as it is a versatile platform that only requires the genetic sequence of the target antigen. The administration of billions of doses has resulted in great industry enthusiasm for the platform, and other mRNA products are being developed using the same core technology [11,12].
To assess the novelty of COVID-19 mRNA products, we look at the history of mRNA vaccines, which begins with experiments on in-vitro-transcribed RNA, i.e., delivering RNA to a cell for expression of a protein of interest [13]. Synthetic RNA technology has a wide variety of applications, from the delivery of small interfering RNAs (siRNAs) to reduce gene expression, or messenger RNAs (mRNAs) to encode for a protein of therapeutic value, or to encode for an antigen to stimulate an immune response, as in the strategy of mRNA vaccination (Supplementary Table S1) [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34].
Early attempts to express proteins from injected mRNA faced several challenges [35,36]. First, bare RNA produces an inflammatory response, limiting the expression potential of the RNA, as it is broken down [37]. Secondly, it is difficult for the bare RNA to enter through a cell membrane [38]. These issues were addressed through the processes of pseudouridylation [39] and encapsulation of mRNA in a lipid nanoparticle (LNP), respectively [40]. The former discovery decreased the lability of RNA, enabling it to remain in the body for longer periods of time [41]. The latter discovery not only shielded the RNA from the host’s immune response, as well as from RNAses, but it also enabled efficient uptake by cells [40,42], where it could be efficiently translated by host ribosomes. Pseudouridine was later replaced by N1-methyl-psuedouridine [43], owing to its greater translation fidelity, higher expression, and better evasion of the host immune response [44].
LNP development was improved through two innovations, PEGylation [45], and the use of cationic lipids [46] (Figure 1). LNP surface modifications by polyethylene glycol (PEG) enable lipid nanoparticles to survive for longer lengths of time [47], so that their package contents can be delivered to cells to provoke an immune response when the antigen is expressed [48]. Another important development for LNPs is the use of cationic lipids, enabling efficient self-assembly and encapsulation of the mRNA [49]. Cationic lipids can additionally be modified to deliver drugs to certain cell types, an important consideration when delivering mRNA [50,51].
There is a prior history of drug delivery by lipid nanoparticles (LNP), beginning with LNP-encapsulated small molecules (Ambisome, approved in the EU in 1990) [40]. Later, the first drug (Onpattro) consisting of RNA encapsulated in an LNP was approved in 2018 by the US Food and Drug Administration [52]. The first mRNA vaccines delivered by lipid nanoparticles were the Pfizer/BioNTech BNT162b2 vaccine and the Moderna mRNA-1273 vaccines [40].
Several of the assumptions have been either challenged or overturned by experimental [53] and clinical evidence [54]. Quoted theoretical safety advantages were the ease of production without contamination (mRNA vaccines do not require the use of live viruses) [55], and lower (in theory non-existent) risks of infection or host genome integration [55,56]. Beforehand, concerns existed over the induction of type I interferon responses by mRNA vaccines [57,58], which are associated with inflammation and autoimmunity [59,60].
For example, the dual assumptions that LNPs remain at the injection site, and that the mRNA degrades quickly, have been demonstrated to be false; biodistribution and bioaccumulation data indicate that LNPs can enter the bloodstream [53], and studies have shown the durability of both mRNA and spike protein in vivo 2 months after injection [61]. Another study found circulating spike protein 4 months post-injection [62]. Given the novelty of mRNA vaccines, and the increasing evidence of harm from clinical reports [54], epidemiology [63], and laboratory science [64], there are open safety concerns to be addressed by future research.
This review summarises known mechanisms of harm to mRNA vaccine recipients, where we examine historical data on mRNA vaccines to determine if safety signals were apparent during production or testing. Prior to the trials on COVID-19 vaccines involving tens of thousands of people, public data exist on only 285 patients administered various mRNA vaccines, with the earliest trials finishing in 2018 and exhibiting high rates (>10%) of severe adverse events (Supplementary Table S1). The novelty of mRNA/LNP products must be stressed in guiding their safety assessment, as current approvals still leave many questions unanswered, and serious risks cannot be definitively ruled out based on current evidence.
In this review, we summarise what is known about the distinct components of mRNA vaccines, by reviewing the literature on past therapeutics. Additionally, we review the known safety impacts of mRNA vaccines prior to COVID-19, as well as other coronavirus vaccines, which, while using a non-mRNA platform, inform us of safety risks when vaccinating against coronaviruses.

2. mRNA Vaccine Elements and Potential for Harm

2.1. Harms Due to Lipid Nanoparticle (LNP)

Lipid nanoparticles have been used in the delivery of drugs for decades, beginning with the 1990 EU approval of the drug AmBisome (LNP-encapsulated amphotericin B) for fungal infections [52]. In the US environment, the first LNP-administered drugs were Doxil (LNP-encapsulated doxorubicin) for Kaposi’s sarcoma and Abelcet (LNP-encapsulated amphotericin B) for aspergillosis [52].
The simplest form of LNP is a liposome, which is produced endogenously [65]. This consists merely of a lipid bilayer that separates the contents from the outside environment [66]. While simple liposomes are detected and destroyed by the body’s immune system [67,68], the addition of polyethylene glycol (PEG) enables the liposome to evade the host’s immune response and last longer in the body to deliver the encapsulated product [69]. While PEG is often inert in the body, the injection of PEG does elicit anti-IgM antibodies, and subsequent injections containing PEG are cleared faster due to this immune response [70]. Additionally, a small proportion of the population has an allergy to PEG, and injection can trigger anaphylaxis, as did happen for several people receiving COVID-19 vaccines [71,72,73,74].
The safety of 1,2-Distearoyl-Sn-Glycero-3-Phosphocholine (DSPC), a component of the LNP used in both the Pfizer and Moderna COVID-19 vaccines, has been studied [75]. Studies in mice ruled that it was likely not toxic to humans, as no clinical manifestations were present [75]. LNPs have been claimed as safe for the delivery of therapeutic agents, according to a review [76]. However, pro-inflammatory concerns remain over LNPs, even in isolation [77,78].

2.2. Harms Due to Exogenous RNA

Foreign RNA triggers an inflammatory response, as toll-like receptors (TLR) [79] and retinoic acid-inducible gene I (RIG-I) [80] are activated. Extracellular RNA exists as a pro-coagulant [81], and increases the permeability of the endothelial cells in brain microvasculature [82]. The initial reason for modification of the RNA by pseudouridylation was to bypass activation of TLR [83]. As pseudouridylated RNA was translated at lower fidelity than RNA [84], the nucleosides were modified to N1-methyl-pseudouridine, which brought translation fidelity to near that of RNA [85].
The properties of both ΨRNA and N1-mΨRNA have been studied in some depth, though questions still remain. For example, through some application of the central dogma of molecular biology, it is assumed that RNA vaccines cannot be incorporated into the genome. This statement is not supported by experiments [86], and is, in fact, contradicted by experiments showing reverse transcription of the Pfizer BioNTech COVID-19 mRNA vaccine into a human liver cell line [64].
ΨRNA exists in nature and comprises between 0.2% and 0.6% of uridine content in human cell lines, and has biologically significant differences from RNA [87]. While N1-mΨRNA exists in nature, found within archaea [88], studies on its properties go back only as recently as 2015 [44]. Additionally, important biological differences exist between unmodified and modified RNA.

2.3. Harms Due to In-Vitro-Transcribed (IVT) RNA

The next step in complexity is moving onto RNA therapeutics that are actively transcribed by host ribosomes. These applications typically replace a damaged protein of interest by supplying it exogenously [89]. Using an LNP–mRNA platform here is better than supplying the protein itself, as a protein expressed from IVT RNA is more likely to have the correct post-transcriptional modifications (and subsequent conformation) for its target cell type than an exogenously supplied protein [90]. For these applications, it is typically necessary for the drug to be administered repetitively over long time periods [90,91]. With repetitive dosing, safety is very important, as even a low per-dose AE rate can compound over the many doses of the treatment.
Most studies of this therapeutic modality so far focus on drug efficacy, and limited safety data exist. In a 2021 review of non-immunologic application of mRNA, all studies using LNP–mRNA as protein replacement therapy demonstrated liver toxicity or lacked safety data [90]. Several studies also demonstrate the development of anti-drug antibodies (ADAs) [92,93,94], which can deactivate the drug and prevent treatment [95,96,97,98]. Immune-mediated toxicity is also a cause for concern [99,100].
Another concern is the potential development of cross-reactivity to endogenous proteins, which can occur if the endogenous protein possesses similar structural motifs to the protein expressed from the administered mRNA [101]. Thromboembolic events have been observed in ADA reactions [96]. Typically, ADA reactions are decreased in cases where the encoded protein is a ‘self’ protein, as opposed to an exogenous protein [102].
Recent work demonstrated a class switch towards an IgG4 antibody response, observed after three doses of Pfizer BNT162b2 (COVID-19 vaccine) and not adenoviral vector COVID-19 vaccines [103], which raises concerns over possible immune tolerance, which is linked to an IgG4-dominated response [104,105].

2.4. Harms of RNA Vaccination

In addition to the other harms present in IVT RNAs, RNA vaccines also have the additional safety challenges of expressing an exogenous protein for the express purpose of generating an immune response and immune memory [106]. Of the RNA therapeutic systems introduced so far in this review, the mRNA vaccines are the most complex drug-like therapeutic biologic.
Limited safety data exist on RNA vaccines against infection [16,17,18,19,20,21,22,23] (Supplementary Table S1). Prior to the trials for COVID-19 vaccines, there were data on 285 patients, with the earliest trials on a non-HIV vaccine only completed in 2018. The serious adverse event (SAE) rate of these exploratory trials was 14 ± 2% (grade 3 or above (event classification available at: https://rsc.niaid.nih.gov/sites/default/files/corrected-grading-table-v-2-1-with-all-changes-highlighted.pdf (accessed on 2 February 2023))). As a comparison, a post-marketing surveillance study of influenza vaccines in the UK found an SAE rate of 0.16% [107], almost 100 times less than the SAE rate for mRNA vaccines.
Given their novelty, mRNA vaccines have limited long-term safety data. While the type of vaccination (i.e., attenuated live virus, inactivated virus, mRNA) should not have a significant impact on the IgG antibodies produced, an important consideration must be mentioned: mRNA vaccines encode for a single antigen in most cases, which better enables immune escape rather than a broader antibody response including other proteins. Recent evidence revealed a subclass switch from IgG1 to IgG4 in the context of the Comirnaty mRNA product, which may have consequences with regard to cancer [108], pregnancy [109], and IgG4-related diseases [103,110]. COVID-19 mRNA vaccines are commonly used in Europe and North America; these encode specifically and exclusively for the spike (S) protein [111,112]. Since the introduction of vaccines, mutations have occurred, lessening the neutralizing capacity of these vaccines [113,114].

2.5. Harms of Coronavirus Vaccination

In addition to the considerations on the novelty of mRNA vaccines, the C19 mRNA vaccines are also unprecedented in terms of another quality, namely, they are the first coronavirus vaccines approved in humans. Following the 2002/2003 outbreak of SARS-CoV [115] and the 2012 outbreak of MERS-CoV [116], vaccines against coronaviruses infecting humans gained more attention, and were subsequently tested on both animal models as well as on human subjects [117].
A SARS-CoV candidate vaccine given to ferrets elicited enhanced hepatitis [118]. Animal trials on four SARS vaccine candidates in ferrets demonstrated an initial protective period against infection, followed by hypersensitivity to rechallenge with SARS-CoV. The ferrets developed histopathological changes in the lungs induced from virus challenge after all four vaccine candidates, suggesting immune-mediated damage [119]. However, a study of MERS-CoV vaccines on mice and rhesus macaques [120] demonstrated protection without visible histopathology.
Mice given an inactivated virus later developed a pro-inflammatory pulmonary response upon challenge [121]. Anti-spike IgG antibodies are produced by all mRNA COVID-19 vaccines [122], and at significantly lower levels by other COVID-19 vaccines [123]. Anti-spike IgG antibodies are demonstrated to cause severe acute lung injury in rhesus macaques on re-exposure to the virus, suggesting a negative impact of a narrow immune response [124].
Immune-mediated danger from vaccines has been widely acknowledged to be an extant issue in the development of coronavirus vaccines [125,126,127,128,129,130,131], and is supported by current evidence [132]. During the rapid development of COVID-19 vaccines, it was an issue of concern that sufficient long-term monitoring for antibody-dependent enhancement (ADE) be established [133,134]. Unfortunately, as of the time of writing, there are no data available on the long-term impacts of COVID-19 vaccines, including effects resulting from rechallenge with the virus.
Veterinary vaccines for other coronaviruses are available, and are summarised in a recent review [135]. Evidence of immune-dependent enhancement was present for cell culture experiments on vaccination against feline coronaviruses [136,137,138]. ADE is also a concern for avian infectious bronchitis virus (IBV), a coronavirus [139,140]. In IBV, suboptimal vaccination alters the evolutionary dynamics of the viruses and can contribute to the production of escape mutants [141,142,143]. Finding broadly neutralizing IBV vaccines remains a significant challenge for the poultry industry [144,145,146,147,148].
Early canine coronavirus vaccines were withdrawn due to neurological symptoms [149,150], though current vaccines do not carry the same safety issues [151,152]. Bovine coronavirus vaccinations often fail to provide immunity against subsequent reinfections [153,154,155]. Immunizations against transmissible gastroenteritis virus (TGEV) in swine have historically had issues in inducing immune protection [156,157], but are widely used now. Too-frequent exposure to vaccine antigens can lower the immune response against TGEV [158]. Another swine coronavirus vaccine, porcine epidemic diarrhoea virus (PEDV), is widely used [159]. Extant safety concerns for the PEDV vaccine are minor, and mostly deal with lack of efficacy; these are summarised in a review [159].
There were several human trials of coronavirus vaccines prior to the approval of COVID-19 vaccines (Table 1). In addition to the endemic coronaviruses that infect humans, several epidemic strains of coronaviruses have occurred in the past two decades, namely, the coronaviruses associated with severe acute respiratory syndrome (SARS-CoV) in 2003 [115] and Middle East respiratory syndrome (MERS-CoV) in 2012 [160]. These outbreaks impelled the production of coronavirus vaccine candidates, summarised in a recent review [117] (Table 1). In total, before the development of the COVID-19 vaccines, data existed on a total of 179 human participants given a SARS or MERS vaccine candidate, of which, 7 (4 ± 2%) experienced a serious adverse event (Table 1). A human trial of 63 adults for a MERS vaccine candidate showed no severe adverse events, but infections in 36% of participants [161,162].
Studies of coronavirus vaccines have a limited number of human participants and still represent a novel technique, though the recent implementation of large-scale vaccination programs for COVID-19 increases the data available to assess the safety of human coronavirus vaccines.

2.6. Harms of RNA Vaccination with SARS-CoV-2 Spike (S) Antigen

There is reason to believe that vaccines encoding the spike (S) protein of SARS-CoV-2 have additional mechanisms of harm, owing to the biological impacts of S protein specifically. There is some research in the literature [169,170,171,172], and it is beyond the scope of this review to cover this in significant depth. However, the addition of spike protein adds another factor in assessing the complexity of RNA vaccines. The complexity, as well as uncertainties about possible harms, are non-trivial and cannot be dismissed based on current data. This section briefly covers some of the hypothesised mechanisms of harm from spike-protein-encoding mRNA vaccines and the evidence for each from a clinical/epidemiological outlook, as well as any mechanistic data from laboratory work.
Several observations have been made that contradict fundamental claims of RNA vaccine safety. For example, it was assumed that the RNA was relatively labile and transient in the cell. However, several studies identified spike protein and vaccine mRNA months post-injection [61,62]. Spike protein has been shown in laboratory settings to cause inflammation [173,174], vascular damage [175], and to act as a seed for amyloid formation [176].

3. Discussion

There is limited information to make a safety assessment of mRNA vaccines. In the category of mRNA vaccines, there are patient data for 385 patients. For mRNA vaccines against an infection, there are data for 285 patients. The rate of serious adverse events was 64 out of 385 for the broad category of RNA vaccines (including cancer vaccines), or 17%; restricting the definition to vaccines against infection, the rate of SAEs is 41/285 or 14%. While high levels can be expected for trials of a novel technology where dosage levels must be determined (many of these trials are phase I) [177], these findings showcase the relative immaturity of mRNA vaccination as a strategy. Given the low efficacy and short duration of protection of SARS-CoV-2 mRNA products [178,179], and the low risk of many populations from COVID-19 complications [180], it may be advisable to suspend mRNA vaccines in certain risk cohorts.
The key to the reactivity of mRNA vaccines is the fact that they express a foreign antigen, for which the antigen-presenting cells are marked for destruction. While the lipid nanoparticle exhibits an acute inflammatory response by itself [77,78,181], the trials using LNPs, so far, have not found a large safety signal when using LNPs to deliver small molecules, non-expressing RNAs, or RNAs for endogenous proteins [77,78,181].
In addition to there being harms attributable to the general immune response from an LNP–RNA delivery system, there are also some harms specific to the spike protein. Several of these mechanisms are supported by laboratory experiments and clinical findings, but need more investigation. Medicine is replete with cases for which safety was assumed without adequate evidence at the time, which later regretfully led to loss of health and life. mRNA vaccines are demonstrating great unintended harms, and these harms demand further investigation into the mechanisms, which is important for identifying treatment modalities.
Novel biomedical technologies can bring relief for a wide variety of conditions and diseases. However, their use must take into consideration their possible harms. Here, we argue that the mRNA technology is novel enough that safety concerns in current and future products cannot be definitively ruled out, and further research must be performed to ensure their safety for current and future users. Other vaccine platforms have longer term data on their mechanisms, and these have fewer unknown long-term impacts. Considering the lack of data on the platform itself, we recommend a robust, independent, and wide-ranging safety audit of mRNA–LNP formulations and call on regulators to hold manufacturers to high safety standards, especially for products used prophylactically in the general population.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/j6020017/s1, Table S1: Safety profile of previous LNP–mRNA products.

Author Contributions

Conceptualization, M.T.J.H.; writing—original draft preparation, M.T.J.H.; research, M.T.J.H., J.R. and T.L.; writing—review and editing, M.T.J.H., J.R. and T.L.; supervision, M.T.J.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analysed in this study. Data sharing is not applicable to this article.

Acknowledgments

We thank Cristof Plothe for his comments.

Conflicts of Interest

M.T.J.H and T.L. are members of The World Council for Health, a non-profit organisation for holistic health promotion.

References

  1. Nagaich, U.; Sadhna, D. Drug Recall: An Incubus for Pharmaceutical Companies and Most Serious Drug Recall of History. Int. J. Pharm. Investig. 2015, 5, 13–19. [Google Scholar] [CrossRef] [PubMed]
  2. Wang, B.; Gagne, J.J.; Choudhry, N.K. The Epidemiology of Drug Recalls in the United States. Arch. Intern. Med. 2012, 172, 1109–1110. [Google Scholar] [CrossRef] [PubMed]
  3. Hwang, T.J.; Sokolov, E.; Franklin, J.M.; Kesselheim, A.S. Comparison of Rates of Safety Issues and Reporting of Trial Outcomes for Medical Devices Approved in the European Union and United States: Cohort Study. BMJ 2016, 353, i3323. [Google Scholar] [CrossRef] [PubMed]
  4. Vajapey, S.P.; Li, M. Medical Device Recalls in Orthopedics: Recent Trends and Areas for Improvement. J. Arthroplast. 2020, 35, 2259–2266. [Google Scholar] [CrossRef]
  5. Young, R.; Bekele, T.; Gunn, A.; Chapman, N.; Chowdhary, V.; Corrigan, K.; Dahora, L.; Martinez, S.; Permar, S.; Persson, J.; et al. Developing New Health Technologies for Neglected Diseases: A Pipeline Portfolio Review and Cost Model. Gates Open Res. 2020, 2, 23. [Google Scholar] [CrossRef]
  6. Dowden, H.; Munro, J. Trends in Clinical Success Rates and Therapeutic Focus. Nat. Rev. Drug Discov. 2019, 18, 495–496. [Google Scholar] [CrossRef]
  7. Wong, C.H.; Siah, K.W.; Lo, A.W. Estimation of Clinical Trial Success Rates and Related Parameters. Biostatistics 2019, 20, 273–286. [Google Scholar] [CrossRef]
  8. Dahlin, E.; Nelson, G.M.; Haynes, M.; Sargeant, F. Success Rates for Product Development Strategies in New Drug Development. J. Clin. Pharm. Ther. 2016, 41, 198–202. [Google Scholar] [CrossRef]
  9. Hayes, A.W. The Precautionary Principle. Arh. Hig. Rada Toksikol. 2005, 56, 161–166. [Google Scholar]
  10. Ball, P. The Lightning-Fast Quest for COVID Vaccines—And What It Means for Other Diseases. Nature 2020, 589, 16–18. [Google Scholar] [CrossRef]
  11. Le, T.; Sun, C.; Chang, J.; Zhang, G.; Yin, X. MRNA Vaccine Development for Emerging Animal and Zoonotic Diseases. Viruses 2022, 14, 401. [Google Scholar] [CrossRef] [PubMed]
  12. Ladak, R.J.; He, A.J.; Huang, Y.-H.; Ding, Y. The Current Landscape of MRNA Vaccines Against Viruses and Cancer-A Mini Review. Front. Immunol. 2022, 13, 885371. [Google Scholar] [CrossRef] [PubMed]
  13. Dolgin, E. The Tangled History of MRNA Vaccines. Nature 2021, 597, 318–324. [Google Scholar] [CrossRef] [PubMed]
  14. Mu, X.; Hur, S. Immunogenicity of In Vitro-Transcribed RNA. Acc. Chem. Res. 2021, 54, 4012–4023. [Google Scholar] [CrossRef]
  15. Guo, S.; Li, H.; Ma, M.; Fu, J.; Dong, Y.; Guo, P. Size, Shape, and Sequence-Dependent Immunogenicity of RNA Nanoparticles. Mol. Ther. Nucleic Acids 2017, 9, 399–408. [Google Scholar] [CrossRef]
  16. Wadhwa, A.; Aljabbari, A.; Lokras, A.; Foged, C.; Thakur, A. Opportunities and Challenges in the Delivery of MRNA-Based Vaccines. Pharmaceutics 2020, 12, 102. [Google Scholar] [CrossRef]
  17. Pandey, M.; Ojha, D.; Bansal, S.; Rode, A.B.; Chawla, G. From Bench Side to Clinic: Potential and Challenges of RNA Vaccines and Therapeutics in Infectious Diseases. Mol. Asp. Med. 2021, 81, 101003. [Google Scholar] [CrossRef]
  18. Anderson, B.R.; Muramatsu, H.; Nallagatla, S.R.; Bevilacqua, P.C.; Sansing, L.H.; Weissman, D.; Karikó, K. Incorporation of Pseudouridine into MRNA Enhances Translation by Diminishing PKR Activation. Nucleic Acids Res. 2010, 38, 5884–5892. [Google Scholar] [CrossRef]
  19. Hou, X.; Zaks, T.; Langer, R.; Dong, Y. Lipid Nanoparticles for MRNA Delivery. Nat. Rev. Mater. 2021, 6, 1078–1094. [Google Scholar] [CrossRef]
  20. Morais, P.; Adachi, H.; Yu, Y.-T. The Critical Contribution of Pseudouridine to MRNA COVID-19 Vaccines. Front. Cell Dev. Biol. 2021, 9, 789427. [Google Scholar] [CrossRef]
  21. Strachan, J.B.; Dyett, B.P.; Nasa, Z.; Valery, C.; Conn, C.E. Toxicity and Cellular Uptake of Lipid Nanoparticles of Different Structure and Composition. J. Colloid Interface Sci. 2020, 576, 241–251. [Google Scholar] [CrossRef] [PubMed]
  22. Nance, K.D.; Meier, J.L. Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines. ACS Cent. Sci. 2021, 7, 748–756. [Google Scholar] [CrossRef] [PubMed]
  23. Andries, O.; Mc Cafferty, S.; De Smedt, S.C.; Weiss, R.; Sanders, N.N.; Kitada, T. N(1)-Methylpseudouridine-Incorporated MRNA Outperforms Pseudouridine-Incorporated MRNA by Providing Enhanced Protein Expression and Reduced Immunogenicity in Mammalian Cell Lines and Mice. J. Control. Release 2015, 217, 337–344. [Google Scholar] [CrossRef] [PubMed]
  24. Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGylation as a Strategy for Improving Nanoparticle-Based Drug and Gene Delivery. Adv. Drug Deliv. Rev. 2016, 99, 28–51. [Google Scholar] [CrossRef] [PubMed]
  25. Kulkarni, J.A.; Darjuan, M.M.; Mercer, J.E.; Chen, S.; van der Meel, R.; Thewalt, J.L.; Tam, Y.Y.C.; Cullis, P.R. On the Formation and Morphology of Lipid Nanoparticles Containing Ionizable Cationic Lipids and SiRNA. ACS Nano 2018, 12, 4787–4795. [Google Scholar] [CrossRef] [PubMed]
  26. Yuan, H.; Chen, C.-Y.; Chai, G.; Du, Y.-Z.; Hu, F.-Q. Improved Transport and Absorption through Gastrointestinal Tract by PEGylated Solid Lipid Nanoparticles. Mol. Pharm. 2013, 10, 1865–1873. [Google Scholar] [CrossRef] [PubMed]
  27. Teijaro, J.R.; Farber, D.L. COVID-19 Vaccines: Modes of Immune Activation and Future Challenges. Nat. Rev. Immunol. 2021, 21, 195–197. [Google Scholar] [CrossRef]
  28. Brader, M.L.; Williams, S.J.; Banks, J.M.; Hui, W.H.; Zhou, Z.H.; Jin, L. Encapsulation State of Messenger RNA inside Lipid Nanoparticles. Biophys. J. 2021, 120, 2766–2770. [Google Scholar] [CrossRef]
  29. Kim, M.; Jeong, M.; Hur, S.; Cho, Y.; Park, J.; Jung, H.; Seo, Y.; Woo, H.A.; Nam, K.T.; Lee, K.; et al. Engineered Ionizable Lipid Nanoparticles for Targeted Delivery of RNA Therapeutics into Different Types of Cells in the Liver. Sci. Adv. 2021, 7, eabf4398. [Google Scholar] [CrossRef]
  30. Han, X.; Zhang, H.; Butowska, K.; Swingle, K.L.; Alameh, M.-G.; Weissman, D.; Mitchell, M.J. An Ionizable Lipid Toolbox for RNA Delivery. Nat. Commun. 2021, 12, 7233. [Google Scholar] [CrossRef]
  31. Akinc, A.; Maier, M.A.; Manoharan, M.; Fitzgerald, K.; Jayaraman, M.; Barros, S.; Ansell, S.; Du, X.; Hope, M.J.; Madden, T.D.; et al. The Onpattro Story and the Clinical Translation of Nanomedicines Containing Nucleic Acid-Based Drugs. Nat. Nanotechnol. 2019, 14, 1084–1087. [Google Scholar] [CrossRef] [PubMed]
  32. Ogata, A.F.; Cheng, C.-A.; Desjardins, M.; Senussi, Y.; Sherman, A.C.; Powell, M.; Novack, L.; Von, S.; Li, X.; Baden, L.R.; et al. Circulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in the Plasma of MRNA-1273 Vaccine Recipients. Clin. Infect. Dis. 2022, 74, 715–718. [Google Scholar] [CrossRef]
  33. Deb, A.; Abdelmalek, J.; Iwuji, K.; Nugent, K. Acute Myocardial Injury Following COVID-19 Vaccination: A Case Report and Review of Current Evidence from Vaccine Adverse Events Reporting System Database. J. Prim. Care Community Health 2021, 12, 21501327211029230. [Google Scholar] [CrossRef]
  34. Pardi, N.; Hogan, M.J.; Porter, F.W.; Weissman, D. MRNA Vaccines—A New Era in Vaccinology. Nat. Rev. Drug Discov. 2018, 17, 261–279. [Google Scholar] [CrossRef]
  35. Park, J.W.; Lagniton, P.N.P.; Liu, Y.; Xu, R.-H. MRNA Vaccines for COVID-19: What, Why and How. Int. J. Biol. Sci. 2021, 17, 1446–1460. [Google Scholar] [CrossRef] [PubMed]
  36. Pepini, T.; Pulichino, A.-M.; Carsillo, T.; Carlson, A.L.; Sari-Sarraf, F.; Ramsauer, K.; Debasitis, J.C.; Maruggi, G.; Otten, G.R.; Geall, A.J.; et al. Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design. J. Immunol. 2017, 198, 4012–4024. [Google Scholar] [CrossRef] [PubMed]
  37. Edwards, D.K.; Jasny, E.; Yoon, H.; Horscroft, N.; Schanen, B.; Geter, T.; Fotin-Mleczek, M.; Petsch, B.; Wittman, V. Adjuvant Effects of a Sequence-Engineered MRNA Vaccine: Translational Profiling Demonstrates Similar Human and Murine Innate Response. J. Transl. Med. 2017, 15, 1. [Google Scholar] [CrossRef]
  38. Theofilopoulos, A.N.; Baccala, R.; Beutler, B.; Kono, D.H. Type I Interferons (α/β) in Immunity and Autoimmunity. Annu. Rev. Immunol. 2005, 23, 307–335. [Google Scholar] [CrossRef]
  39. Nestle, F.O.; Conrad, C.; Tun-Kyi, A.; Homey, B.; Gombert, M.; Boyman, O.; Burg, G.; Liu, Y.-J.; Gilliet, M. Plasmacytoid Predendritic Cells Initiate Psoriasis through Interferon-α Production. J. Exp. Med. 2005, 202, 135–143. [Google Scholar] [CrossRef]
  40. Röltgen, K.; Nielsen, S.C.A.; Silva, O.; Younes, S.F.; Zaslavsky, M.; Costales, C.; Yang, F.; Wirz, O.F.; Solis, D.; Hoh, R.A.; et al. Immune Imprinting, Breadth of Variant Recognition, and Germinal Center Response in Human SARS-CoV-2 Infection and Vaccination. Cell 2022, 185, 1025–1040.e14. [Google Scholar] [CrossRef]
  41. Bansal, S.; Perincheri, S.; Fleming, T.; Poulson, C.; Tiffany, B.; Bremner, R.M.; Mohanakumar, T. Cutting Edge: Circulating Exosomes with COVID Spike Protein Are Induced by BNT162b2 (Pfizer–BioNTech) Vaccination Prior to Development of Antibodies: A Novel Mechanism for Immune Activation by MRNA Vaccines. J. Immunol. 2021, 207, 2405–2410. [Google Scholar] [CrossRef] [PubMed]
  42. Welsh, K.J.; Baumblatt, J.; Chege, W.; Goud, R.; Nair, N. Thrombocytopenia Including Immune Thrombocytopenia after Receipt of MRNA COVID-19 Vaccines Reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine 2021, 39, 3329–3332. [Google Scholar] [CrossRef] [PubMed]
  43. Aldén, M.; Olofsson Falla, F.; Yang, D.; Barghouth, M.; Luan, C.; Rasmussen, M.; De Marinis, Y. Intracellular Reverse Transcription of Pfizer BioNTech COVID-19 MRNA Vaccine BNT162b2 In Vitro in Human Liver Cell Line. Curr. Issues Mol. Biol. 2022, 44, 1115–1126. [Google Scholar] [CrossRef] [PubMed]
  44. Tenchov, R.; Bird, R.; Curtze, A.E.; Zhou, Q. Lipid Nanoparticles─From Liposomes to MRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement. ACS Nano 2021, 15, 16982–17015. [Google Scholar] [CrossRef]
  45. Nsairat, H.; Khater, D.; Sayed, U.; Odeh, F.; Al Bawab, A.; Alshaer, W. Liposomes: Structure, Composition, Types, and Clinical Applications. Heliyon 2022, 8, e09394. [Google Scholar] [CrossRef] [PubMed]
  46. Harashima, H.; Hiraiwa, T.; Ochi, Y.; Kiwada, H. Size Dependent Liposome Degradation in Blood: In Vivo/In Vitro Correlation by Kinetic Modeling. J. Drug Target. 1995, 3, 253–261. [Google Scholar] [CrossRef]
  47. Vemuri, S.; Rhodes, C.T. Preparation and Characterization of Liposomes as Therapeutic Delivery Systems: A Review. Pharm. Acta Helv. 1995, 70, 95–111. [Google Scholar] [CrossRef]
  48. Hattori, Y. Delivery of Plasmid DNA into Tumors by Intravenous Injection of PEGylated Cationic Lipoplexes into Tumor-Bearing Mice. Pharmacol. Pharm. 2016, 7, 272–282. [Google Scholar] [CrossRef]
  49. Wang, X.; Ishida, T.; Kiwada, H. Anti-PEG IgM Elicited by Injection of Liposomes Is Involved in the Enhanced Blood Clearance of a Subsequent Dose of PEGylated Liposomes. J. Control. Release 2007, 119, 236–244. [Google Scholar] [CrossRef]
  50. Kuehn, B.M. Rare PEG Allergy Triggered Postvaccination Anaphylaxis. JAMA 2021, 325, 1931. [Google Scholar] [CrossRef]
  51. Cox, F.; Khalib, K.; Conlon, N. PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol. J. Clin. Pharmacol. 2021, 61, 832–835. [Google Scholar] [CrossRef] [PubMed]
  52. Sellaturay, P.; Nasser, S.; Ewan, P. Polyethylene Glycol-Induced Systemic Allergic Reactions (Anaphylaxis). J. Allergy Clin. Immunol. Pract. 2021, 9, 670–675. [Google Scholar] [CrossRef] [PubMed]
  53. Castells, M.C.; Phillips, E.J. Maintaining Safety with SARS-CoV-2 Vaccines. N. Engl. J. Med. 2020, 384, 643–649. [Google Scholar] [CrossRef] [PubMed]
  54. Ohgoda, O.; Robinson, I. Toxicological Evaluation of DSPC (1,2-Distearoyl-Sn-Glycero- 3-Phosphocholine). Fundam. Toxicol. Sci. 2020, 7, 55–76. [Google Scholar] [CrossRef]
  55. Doktorovová, S.; Kovačević, A.B.; Garcia, M.L.; Souto, E.B. Preclinical Safety of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Current Evidence from in Vitro and in Vivo Evaluation. Eur. J. Pharm. Biopharm. 2016, 108, 235–252. [Google Scholar] [CrossRef]
  56. Moghimi, S.M.; Simberg, D. Pro-Inflammatory Concerns with Lipid Nanoparticles. Mol. Ther. 2022, 30, 2109–2110. [Google Scholar] [CrossRef]
  57. Ndeupen, S.; Qin, Z.; Jacobsen, S.; Bouteau, A.; Estanbouli, H.; Igyártó, B.Z. The MRNA-LNP Platform’s Lipid Nanoparticle Component Used in Preclinical Vaccine Studies Is Highly Inflammatory. iScience 2021, 24, 103479. [Google Scholar] [CrossRef]
  58. Kawasaki, T.; Kawai, T. Toll-Like Receptor Signaling Pathways. Front. Immunol. 2014, 5, 461. [Google Scholar] [CrossRef]
  59. Wienert, B.; Shin, J.; Zelin, E.; Pestal, K.; Corn, J.E. In Vitro–Transcribed Guide RNAs Trigger an Innate Immune Response via the RIG-I Pathway. PLoS Biol. 2018, 16, e2005840. [Google Scholar] [CrossRef]
  60. Kannemeier, C.; Shibamiya, A.; Nakazawa, F.; Trusheim, H.; Ruppert, C.; Markart, P.; Song, Y.; Tzima, E.; Kennerknecht, E.; Niepmann, M.; et al. Extracellular RNA Constitutes a Natural Procoagulant Cofactor in Blood Coagulation. Proc. Natl. Acad. Sci. USA 2007, 104, 6388–6393. [Google Scholar] [CrossRef]
  61. Fischer, S.; Gerriets, T.; Wessels, C.; Walberer, M.; Kostin, S.; Stolz, E.; Zheleva, K.; Hocke, A.; Hippenstiel, S.; Preissner, K.T. Extracellular RNA Mediates Endothelial-Cell Permeability via Vascular Endothelial Growth Factor. Blood 2007, 110, 2457–2465. [Google Scholar] [CrossRef] [PubMed]
  62. Karikó, K.; Buckstein, M.; Ni, H.; Weissman, D. Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA. Immunity 2005, 23, 165–175. [Google Scholar] [CrossRef] [PubMed]
  63. Eyler, D.E.; Franco, M.K.; Batool, Z.; Wu, M.Z.; Dubuke, M.L.; Dobosz-Bartoszek, M.; Jones, J.D.; Polikanov, Y.S.; Roy, B.; Koutmou, K.S. Pseudouridinylation of MRNA Coding Sequences Alters Translation. Proc. Natl. Acad. Sci. USA 2019, 116, 23068–23074. [Google Scholar] [CrossRef] [PubMed]
  64. Kim, K.Q.; Burgute, B.D.; Tzeng, S.-C.; Jing, C.; Jungers, C.; Zhang, J.; Yan, L.L.; Vierstra, R.D.; Djuranovic, S.; Evans, B.S.; et al. N1-Methylpseudouridine Found within COVID-19 MRNA Vaccines Produces Faithful Protein Products. Cell Rep. 2022, 40, 111300. [Google Scholar] [CrossRef]
  65. Domazet-Lošo, T. MRNA Vaccines: Why Is the Biology of Retroposition Ignored? Genes 2022, 13, 719. [Google Scholar] [CrossRef]
  66. Borchardt, E.K.; Martinez, N.M.; Gilbert, W.V. Regulation and Function of RNA Pseudouridylation in Human Cells. Annu. Rev. Genet. 2020, 54, 309–336. [Google Scholar] [CrossRef]
  67. Pang, H.; Ihara, M.; Kuchino, Y.; Nishimura, S.; Gupta, R.; Woese, C.R.; McCloskey, J.A. Structure of a Modified Nucleoside in Archaebacterial TRNA Which Replaces Ribosylthymine. 1-Methylpseudouridine. J. Biol. Chem. 1982, 257, 3589–3592. [Google Scholar] [CrossRef]
  68. Kwon, H.; Kim, M.; Seo, Y.; Moon, Y.S.; Lee, H.J.; Lee, K.; Lee, H. Emergence of Synthetic MRNA: In Vitro Synthesis of MRNA and Its Applications in Regenerative Medicine. Biomaterials 2018, 156, 172–193. [Google Scholar] [CrossRef]
  69. Vlatkovic, I. Non-Immunotherapy Application of LNP-MRNA: Maximizing Efficacy and Safety. Biomedicines 2021, 9, 530. [Google Scholar] [CrossRef]
  70. Kowalski, P.S.; Rudra, A.; Miao, L.; Anderson, D.G. Delivering the Messenger: Advances in Technologies for Therapeutic MRNA Delivery. Mol. Ther. 2019, 27, 710–728. [Google Scholar] [CrossRef]
  71. Zhu, X.; Yin, L.; Theisen, M.; Zhuo, J.; Siddiqui, S.; Levy, B.; Presnyak, V.; Frassetto, A.; Milton, J.; Salerno, T.; et al. Systemic MRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-Human Primates. Am. J. Hum. Genet. 2019, 104, 625–637. [Google Scholar] [CrossRef] [PubMed]
  72. An, D.; Schneller, J.L.; Frassetto, A.; Liang, S.; Zhu, X.; Park, J.-S.; Theisen, M.; Hong, S.-J.; Zhou, J.; Rajendran, R.; et al. Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. Cell Rep. 2018, 24, 2520. [Google Scholar] [CrossRef] [PubMed]
  73. Jiang, L.; Berraondo, P.; Jericó, D.; Guey, L.T.; Sampedro, A.; Frassetto, A.; Benenato, K.E.; Burke, K.; Santamaría, E.; Alegre, M.; et al. Systemic Messenger RNA as an Etiological Treatment for Acute Intermittent Porphyria. Nat. Med. 2018, 24, 1899–1909. [Google Scholar] [CrossRef]
  74. Bartelds, G.M.; Krieckaert, C.L.M.; Nurmohamed, M.T.; van Schouwenburg, P.A.; Lems, W.F.; Twisk, J.W.R.; Dijkmans, B.A.C.; Aarden, L.; Wolbink, G.J. Development of Antidrug Antibodies against Adalimumab and Association with Disease Activity and Treatment Failure during Long-Term Follow-Up. JAMA 2011, 305, 1460–1468. [Google Scholar] [CrossRef] [PubMed]
  75. Moots, R.J.; Xavier, R.M.; Mok, C.C.; Rahman, M.U.; Tsai, W.-C.; Al-Maini, M.H.; Pavelka, K.; Mahgoub, E.; Kotak, S.; Korth-Bradley, J.; et al. The Impact of Anti-Drug Antibodies on Drug Concentrations and Clinical Outcomes in Rheumatoid Arthritis Patients Treated with Adalimumab, Etanercept, or Infliximab: Results from a Multinational, Real-World Clinical Practice, Non-Interventional Study. PLoS ONE 2017, 12, e0175207. [Google Scholar] [CrossRef]
  76. Pratt, K.P. Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity. Antibodies 2018, 7, 19. [Google Scholar] [CrossRef] [PubMed]
  77. Krishna, M.; Nadler, S.G. Immunogenicity to Biotherapeutics—The Role of Anti-Drug Immune Complexes. Front. Immunol. 2016, 7, 21. [Google Scholar] [CrossRef]
  78. Clarke, J.B. Mechanisms of Adverse Drug Reactions to Biologics. In Handbook of Experimental Pharmacology; Springer: Berlin/Heidelberg, Germany, 2010; pp. 453–474. [Google Scholar] [CrossRef]
  79. Pichler, W.J. Adverse Side-Effects to Biological Agents. Allergy 2006, 61, 912–920. [Google Scholar] [CrossRef]
  80. Sathish, J.G.; Sethu, S.; Bielsky, M.-C.; de Haan, L.; French, N.S.; Govindappa, K.; Green, J.; Griffiths, C.E.M.; Holgate, S.; Jones, D.; et al. Challenges and Approaches for the Development of Safer Immunomodulatory Biologics. Nat. Rev. Drug Discov. 2013, 12, 306–324. [Google Scholar] [CrossRef]
  81. Banugaria, S.G.; Prater, S.N.; Ng, Y.-K.; Kobori, J.A.; Finkel, R.S.; Ladda, R.L.; Chen, Y.-T.; Rosenberg, A.S.; Kishnani, P.S. The Impact of Antibodies on Clinical Outcomes in Diseases Treated with Therapeutic Protein: Lessons Learned from Infantile Pompe Disease. Genet. Med. 2011, 13, 729–736. [Google Scholar] [CrossRef]
  82. Irrgang, P.; Gerling, J.; Kocher, K.; Lapuente, D.; Steininger, P.; Habenicht, K.; Wytopil, M.; Beileke, S.; Schäfer, S.; Zhong, J.; et al. Class Switch towards Non-Inflammatory, Spike-Specific IgG4 Antibodies after Repeated SARS-CoV-2 MRNA Vaccination. Sci. Immunol. 2022, 8, eade2798. [Google Scholar] [CrossRef] [PubMed]
  83. Vidarsson, G.; Dekkers, G.; Rispens, T. IgG Subclasses and Allotypes: From Structure to Effector Functions. Front. Immunol. 2014, 5, 520. [Google Scholar] [CrossRef] [PubMed]
  84. Bianchini, R.; Roth-Walter, F.; Ohradanova-Repic, A.; Flicker, S.; Hufnagl, K.; Fischer, M.B.; Stockinger, H.; Jensen-Jarolim, E. IgG4 Drives M2a Macrophages to a Regulatory M2b-like Phenotype: Potential Implication in Immune Tolerance. Allergy 2019, 74, 483–494. [Google Scholar] [CrossRef] [PubMed]
  85. Chaudhary, N.; Weissman, D.; Whitehead, K.A. MRNA Vaccines for Infectious Diseases: Principles, Delivery and Clinical Translation. Nat. Rev. Drug Discov. 2021, 20, 817–838. [Google Scholar] [CrossRef]
  86. Suhr, O.B.; Coelho, T.; Buades, J.; Pouget, J.; Conceicao, I.; Berk, J.; Schmidt, H.; Waddington-Cruz, M.; Campistol, J.M.; Bettencourt, B.R.; et al. Efficacy and Safety of Patisiran for Familial Amyloidotic Polyneuropathy: A Phase II Multi-Dose Study. Orphanet J. Rare Dis. 2015, 10, 109. [Google Scholar] [CrossRef]
  87. Balwani, M.; Sardh, E.; Ventura, P.; Peiró, P.A.; Rees, D.C.; Stölzel, U.; Bissell, D.M.; Bonkovsky, H.L.; Windyga, J.; Anderson, K.E.; et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N. Engl. J. Med. 2020, 382, 2289–2301. [Google Scholar] [CrossRef]
  88. Alberer, M.; Gnad-Vogt, U.; Hong, H.S.; Mehr, K.T.; Backert, L.; Finak, G.; Gottardo, R.; Bica, M.A.; Garofano, A.; Koch, S.D.; et al. Safety and Immunogenicity of a MRNA Rabies Vaccine in Healthy Adults: An Open-Label, Non-Randomised, Prospective, First-in-Human Phase 1 Clinical Trial. Lancet 2017, 390, 1511–1520. [Google Scholar] [CrossRef]
  89. Aldrich, C.; Leroux-Roels, I.; Huang, K.B.; Bica, M.A.; Loeliger, E.; Schoenborn-Kellenberger, O.; Walz, L.; Leroux-Roels, G.; von Sonnenburg, F.; Oostvogels, L. Proof-of-Concept of a Low-Dose Unmodified MRNA-Based Rabies Vaccine Formulated with Lipid Nanoparticles in Human Volunteers: A Phase 1 Trial. Vaccine 2021, 39, 1310–1318. [Google Scholar] [CrossRef]
  90. Feldman, R.A.; Fuhr, R.; Smolenov, I.; Ribeiro, A.M.; Panther, L.; Watson, M.; Senn, J.J.; Smith, M.; Almarsson, Ӧ.; Pujar, H.S.; et al. MRNA Vaccines against H10N8 and H7N9 Influenza Viruses of Pandemic Potential Are Immunogenic and Well Tolerated in Healthy Adults in Phase 1 Randomized Clinical Trials. Vaccine 2019, 37, 3326–3334. [Google Scholar] [CrossRef]
  91. Bahl, K.; Senn, J.J.; Yuzhakov, O.; Bulychev, A.; Brito, L.A.; Hassett, K.J.; Laska, M.E.; Smith, M.; Almarsson, Ö.; Thompson, J.; et al. Preclinical and Clinical Demonstration of Immunogenicity by MRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol. Ther. 2017, 25, 1316–1327. [Google Scholar] [CrossRef]
  92. Jacobson, J.M.; Routy, J.-P.; Welles, S.; DeBenedette, M.; Tcherepanova, I.; Angel, J.B.; Asmuth, D.M.; Stein, D.K.; Baril, J.-G.; McKellar, M.; et al. Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J. Acquir. Immune Defic. Syndr. 2016, 72, 31–38. [Google Scholar] [CrossRef] [PubMed]
  93. de Jong, W.; Aerts, J.; Allard, S.; Brander, C.; Buyze, J.; Florence, E.; van Gorp, E.; Vanham, G.; Leal, L.; Mothe, B.; et al. IHIVARNA Phase IIa, a Randomized, Placebo-Controlled, Double-Blinded Trial to Evaluate the Safety and Immunogenicity of IHIVARNA-01 in Chronically HIV-Infected Patients under Stable Combined Antiretroviral Therapy. Trials 2019, 20, 361. [Google Scholar] [CrossRef] [PubMed]
  94. Leal, L.; Guardo, A.C.; Morón-López, S.; Salgado, M.; Mothe, B.; Heirman, C.; Pannus, P.; Vanham, G.; van den Ham, H.J.; Gruters, R.; et al. Phase I Clinical Trial of an Intranodally Administered MRNA-Based Therapeutic Vaccine against HIV-1 Infection. AIDS 2018, 32, 2533–2545. [Google Scholar] [CrossRef] [PubMed]
  95. Gandhi, R.T.; Kwon, D.S.; Macklin, E.A.; Shopis, J.R.; McLean, A.P.; McBrine, N.; Flynn, T.; Peter, L.; Sbrolla, A.; Kaufmann, D.E.; et al. Immunization of HIV-1-Infected Persons With Autologous Dendritic Cells Transfected With MRNA Encoding HIV-1 Gag and Nef: Results of a Randomized, Placebo-Controlled Clinical Trial. JAIDS J. Acquir. Immune Defic. Syndr. 2016, 71, 246–253. [Google Scholar] [CrossRef]
  96. Sahin, U.; Oehm, P.; Derhovanessian, E.; Jabulowsky, R.A.; Vormehr, M.; Gold, M.; Maurus, D.; Schwarck-Kokarakis, D.; Kuhn, A.N.; Omokoko, T.; et al. An RNA Vaccine Drives Immunity in Checkpoint-Inhibitor-Treated Melanoma. Nature 2020, 585, 107–112. [Google Scholar] [CrossRef]
  97. Papachristofilou, A.; Hipp, M.M.; Klinkhardt, U.; Früh, M.; Sebastian, M.; Weiss, C.; Pless, M.; Cathomas, R.; Hilbe, W.; Pall, G.; et al. Phase Ib Evaluation of a Self-Adjuvanted Protamine Formulated MRNA-Based Active Cancer Immunotherapy, BI1361849 (CV9202), Combined with Local Radiation Treatment in Patients with Stage IV Non-Small Cell Lung Cancer. J. Immunother. Cancer 2019, 7, 38. [Google Scholar] [CrossRef]
  98. Eigentler, T.; Bauernfeind, F.G.; Becker, J.C.; Brossart, P.; Fluck, M.; Heinzerling, L.; Krauss, J.; Mohr, P.; Ochsenreither, S.; Schreiber, J.S.; et al. A Phase I Dose-Escalation and Expansion Study of Intratumoral CV8102 as Single-Agent or in Combination with Anti-PD-1 Antibodies in Patients with Advanced Solid Tumors. JCO 2020, 38, 3096. [Google Scholar] [CrossRef]
  99. Doener, F.; Hong, H.S.; Meyer, I.; Tadjalli-Mehr, K.; Daehling, A.; Heidenreich, R.; Koch, S.D.; Fotin-Mleczek, M.; Gnad-Vogt, U. RNA-Based Adjuvant CV8102 Enhances the Immunogenicity of a Licensed Rabies Vaccine in a First-in-Human Trial. Vaccine 2019, 37, 1819–1826. [Google Scholar] [CrossRef]
  100. Translate Bio Announces Results from Second Interim Data Analysis from Ongoing Phase 1/2 Clinical Trial of MRT5005 in Patients with Cystic Fibrosis (CF). Available online: https://www.biospace.com/article/translate-bio-announces-results-from-second-interim-data-analysis-from-ongoing-phase-1-2-clinical-trial-of-mrt5005-in-patients-with-cystic-fibrosis-cf-/ (accessed on 13 October 2022).
  101. Burris, H.A.; Patel, M.R.; Cho, D.C.; Clarke, J.M.; Gutierrez, M.; Zaks, T.Z.; Frederick, J.; Hopson, K.; Mody, K.; Binanti-Berube, A.; et al. A Phase I Multicenter Study to Assess the Safety, Tolerability, and Immunogenicity of MRNA-4157 Alone in Patients with Resected Solid Tumors and in Combination with Pembrolizumab in Patients with Unresectable Solid Tumors. JCO 2019, 37, 2523. [Google Scholar] [CrossRef]
  102. Costello, C.L.; Gregory, T.K.; Ali, S.A.; Berdeja, J.G.; Patel, K.K.; Shah, N.D.; Ostertag, E.; Martin, C.; Ghoddusi, M.; Shedlock, D.J.; et al. Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME). Blood 2019, 134, 3184. [Google Scholar] [CrossRef]
  103. Gregory, T.; Cohen, A.D.; Costello, C.L.; Ali, S.A.; Berdeja, J.G.; Ostertag, E.M.; Martin, C.; Shedlock, D.J.; Resler, M.L.; Spear, M.A.; et al. Efficacy and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM). Blood 2018, 132, 1012. [Google Scholar] [CrossRef]
  104. Anttila, V.; Saraste, A.; Knuuti, J.; Jaakkola, P.; Hedman, M.; Svedlund, S.; Lagerström-Fermér, M.; Kjaer, M.; Jeppsson, A.; Gan, L.-M. Synthetic MRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial. Mol. Ther. Methods Clin. Dev. 2020, 18, 464–472. [Google Scholar] [CrossRef] [PubMed]
  105. Late-Breaking Science Abstracts and Featured Science Abstracts From the American Heart Association’s Scientific Sessions 2021 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2021. Circulation 2021, 144, e564–e593. [CrossRef]
  106. Gan, L.-M.; Lagerström-Fermér, M.; Carlsson, L.G.; Arfvidsson, C.; Egnell, A.-C.; Rudvik, A.; Kjaer, M.; Collén, A.; Thompson, J.D.; Joyal, J.; et al. Intradermal Delivery of Modified MRNA Encoding VEGF-A in Patients with Type 2 Diabetes. Nat. Commun. 2019, 10, 871. [Google Scholar] [CrossRef]
  107. de Lusignan, S.; Damaso, S.; Ferreira, F.; Byford, R.; McGee, C.; Pathirannehelage, S.; Shende, V.; Yonova, I.; Schmidt, A.; Schuind, A.; et al. Brand-Specific Enhanced Safety Surveillance of GSK’s Fluarix Tetra Seasonal Influenza Vaccine in England: 2017/2018 Season. Hum. Vaccines Immunother. 2020, 16, 1762–1771. [Google Scholar] [CrossRef]
  108. Crescioli, S.; Correa, I.; Karagiannis, P.; Davies, A.M.; Sutton, B.J.; Nestle, F.O.; Karagiannis, S.N. IgG4 Characteristics and Functions in Cancer Immunity. Curr. Allergy Asthma Rep. 2016, 16, 7. [Google Scholar] [CrossRef]
  109. Schlaudecker, E.P.; McNeal, M.M.; Dodd, C.N.; Ranz, J.B.; Steinhoff, M.C. Pregnancy Modifies the Antibody Response to Trivalent Influenza Immunization. J. Infect. Dis. 2012, 206, 1670–1673. [Google Scholar] [CrossRef]
  110. Zhang, X.; Lu, H.; Peng, L.; Zhou, J.; Wang, M.; Li, J.; Liu, Z.; Zhang, W.; Zhao, Y.; Zeng, X.; et al. The Role of PD-1/PD-Ls in the Pathogenesis of IgG4-Related Disease. Rheumatology 2022, 61, 815–825. [Google Scholar] [CrossRef]
  111. Pfizer-BioNTech COVID-19 Vaccine, COMIRNATY® (Tozinameran). Available online: https://www.who.int/publications/m/item/comirnaty-covid-19-mrna-vaccine (accessed on 30 December 2022).
  112. Moderna MRNA-1273, COVID-19 Vaccine. Available online: https://www.who.int/publications/m/item/moderna-covid-19-vaccine-(mrna-1273) (accessed on 30 December 2022).
  113. Chakraborty, C.; Bhattacharya, M.; Sharma, A.R. Present Variants of Concern and Variants of Interest of Severe Acute Respiratory Syndrome Coronavirus 2: Their Significant Mutations in S-Glycoprotein, Infectivity, Re-Infectivity, Immune Escape and Vaccines Activity. Rev. Med. Virol. 2022, 32, e2270. [Google Scholar] [CrossRef]
  114. Chakraborty, C.; Sharma, A.R.; Bhattacharya, M.; Lee, S.-S. A Detailed Overview of Immune Escape, Antibody Escape, Partial Vaccine Escape of SARS-CoV-2 and Their Emerging Variants With Escape Mutations. Front. Immunol. 2022, 13, 801522. [Google Scholar] [CrossRef]
  115. Zhong, N.; Zheng, B.; Li, Y.; Poon, L.; Xie, Z.; Chan, K.; Li, P.; Tan, S.; Chang, Q.; Xie, J.; et al. Epidemiology and Cause of Severe Acute Respiratory Syndrome (SARS) in Guangdong, People’s Republic of China, in February, 2003. Lancet 2003, 362, 1353–1358. [Google Scholar] [CrossRef] [PubMed]
  116. Gastañaduy, P.A. Update: Severe Respiratory Illness Associated with Middle East Respiratory Syndrome Coronavirus (MERS-CoV)—Worldwide, 2012–2013. MMWR Morb. Mortal. Wkly. Rep. 2013, 62, 480–483. [Google Scholar]
  117. Li, Y.-D.; Chi, W.-Y.; Su, J.-H.; Ferrall, L.; Hung, C.-F.; Wu, T.-C. Coronavirus Vaccine Development: From SARS and MERS to COVID-19. J. Biomed. Sci. 2020, 27, 104. [Google Scholar] [CrossRef] [PubMed]
  118. Weingartl, H.; Czub, M.; Czub, S.; Neufeld, J.; Marszal, P.; Gren, J.; Smith, G.; Jones, S.; Proulx, R.; Deschambault, Y.; et al. Immunization with Modified Vaccinia Virus Ankara-Based Recombinant Vaccine against Severe Acute Respiratory Syndrome Is Associated with Enhanced Hepatitis in Ferrets. J. Virol. 2004, 78, 12672–12676. [Google Scholar] [CrossRef] [PubMed]
  119. Tseng, C.-T.; Sbrana, E.; Iwata-Yoshikawa, N.; Newman, P.C.; Garron, T.; Atmar, R.L.; Peters, C.J.; Couch, R.B. Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus. PLoS ONE 2012, 7, e35421. [Google Scholar] [CrossRef]
  120. van Doremalen, N.; Haddock, E.; Feldmann, F.; Meade-White, K.; Bushmaker, T.; Fischer, R.J.; Okumura, A.; Hanley, P.W.; Saturday, G.; Edwards, N.J.; et al. A Single Dose of ChAdOx1 MERS Provides Broad Protective Immunity against a Variety of MERS-CoV Strains. bioRxiv 2020, preprint. [Google Scholar]
  121. Bolles, M.; Deming, D.; Long, K.; Agnihothram, S.; Whitmore, A.; Ferris, M.; Funkhouser, W.; Gralinski, L.; Totura, A.; Heise, M.; et al. A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge. J. Virol. 2011, 85, 12201–12215. [Google Scholar] [CrossRef]
  122. Bliden, K.P.; Liu, T.; Sreedhar, D.; Kost, J.; Hsiung, J.; Zhao, S.; Shan, D.; Usman, A.; Walia, N.; Cho, A.; et al. Evolution of Anti-SARS-CoV-2 IgG Antibody and IgG Avidity Post Pfizer and Moderna MRNA Vaccinations. medRxiv 2021. [Google Scholar] [CrossRef]
  123. Macdonald, P.J.; Schaub, J.M.; Ruan, Q.; Williams, C.L.; Prostko, J.C.; Tetin, S.Y. Affinity of Anti-Spike Antibodies to Three Major SARS-CoV-2 Variants in Recipients of Three Major Vaccines. Commun. Med. 2022, 2, 109. [Google Scholar] [CrossRef]
  124. Liu, L.; Wei, Q.; Lin, Q.; Fang, J.; Wang, H.; Kwok, H.; Tang, H.; Nishiura, K.; Peng, J.; Tan, Z.; et al. Anti-Spike IgG Causes Severe Acute Lung Injury by Skewing Macrophage Responses during Acute SARS-CoV Infection. JCI Insight 2019, 4, 123158. [Google Scholar] [CrossRef]
  125. Lee, W.S.; Wheatley, A.K.; Kent, S.J.; DeKosky, B.J. Antibody-Dependent Enhancement and SARS-CoV-2 Vaccines and Therapies. Nat. Microbiol. 2020, 5, 1185–1191. [Google Scholar] [CrossRef] [PubMed]
  126. Wen, J.; Cheng, Y.; Ling, R.; Dai, Y.; Huang, B.; Huang, W.; Zhang, S.; Jiang, Y. Antibody-Dependent Enhancement of Coronavirus. Int. J. Infect. Dis. 2020, 100, 483–489. [Google Scholar] [CrossRef] [PubMed]
  127. Xu, L.; Ma, Z.; Li, Y.; Pang, Z.; Xiao, S. Antibody Dependent Enhancement: Unavoidable Problems in Vaccine Development. Adv. Immunol. 2021, 151, 99–133. [Google Scholar] [CrossRef] [PubMed]
  128. Sánchez-Zuno, G.A.; Matuz-Flores, M.G.; González-Estevez, G.; Nicoletti, F.; Turrubiates-Hernández, F.J.; Mangano, K.; Muñoz-Valle, J.F. A Review: Antibody-Dependent Enhancement in COVID-19: The Not so Friendly Side of Antibodies. Int. J. Immunopathol. Pharm. 2021, 35, 20587384211050200. [Google Scholar] [CrossRef] [PubMed]
  129. Thomas, S.; Smatti, M.K.; Ouhtit, A.; Cyprian, F.S.; Almaslamani, M.A.; Thani, A.A.; Yassine, H.M. Antibody-Dependent Enhancement (ADE) and the Role of Complement System in Disease Pathogenesis. Mol. Immunol. 2022, 152, 172–182. [Google Scholar] [CrossRef] [PubMed]
  130. Ricke, D.O. Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies. Front. Immunol. 2021, 12, 640093. [Google Scholar] [CrossRef]
  131. Wan, Y.; Shang, J.; Sun, S.; Tai, W.; Chen, J.; Geng, Q.; He, L.; Chen, Y.; Wu, J.; Shi, Z.; et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J. Virol. 2020, 94, e02015–e02019. [Google Scholar] [CrossRef]
  132. Shimizu, J.; Sasaki, T.; Koketsu, R.; Morita, R.; Yoshimura, Y.; Murakami, A.; Saito, Y.; Kusunoki, T.; Samune, Y.; Nakayama, E.E.; et al. Reevaluation of Antibody-Dependent Enhancement of Infection in Anti-SARS-CoV-2 Therapeutic Antibodies and MRNA-Vaccine Antisera Using FcR- and ACE2-Positive Cells. Sci. Rep. 2022, 12, 15612. [Google Scholar] [CrossRef]
  133. Lurie, N.; Saville, M.; Hatchett, R.; Halton, J. Developing Covid-19 Vaccines at Pandemic Speed. N. Engl. J. Med. 2020, 382, 1969–1973. [Google Scholar] [CrossRef]
  134. London, A.J.; Kimmelman, J. Against Pandemic Research Exceptionalism. Science 2020, 368, 476–477. [Google Scholar] [CrossRef]
  135. Tizard, I.R. Vaccination against Coronaviruses in Domestic Animals. Vaccine 2020, 38, 5123–5130. [Google Scholar] [CrossRef] [PubMed]
  136. Olsen, C.W.; Corapi, W.V.; Ngichabe, C.K.; Baines, J.D.; Scott, F.W. Monoclonal Antibodies to the Spike Protein of Feline Infectious Peritonitis Virus Mediate Antibody-Dependent Enhancement of Infection of Feline Macrophages. J. Virol. 1992, 66, 956–965. [Google Scholar] [CrossRef] [PubMed]
  137. Hohdatsu, T.; Yamada, M.; Tominaga, R.; Makino, K.; Kida, K.; Koyama, H. Antibody-Dependent Enhancement of Feline Infectious Peritonitis Virus Infection in Feline Alveolar Macrophages and Human Monocyte Cell Line U937 by Serum of Cats Experimentally or Naturally Infected with Feline Coronavirus. J. Vet. Med. Sci. 1998, 60, 49–55. [Google Scholar] [CrossRef] [PubMed]
  138. Takano, T.; Nakaguchi, M.; Doki, T.; Hohdatsu, T. Antibody-Dependent Enhancement of Serotype II Feline Enteric Coronavirus Infection in Primary Feline Monocytes. Arch. Virol. 2017, 162, 3339–3345. [Google Scholar] [CrossRef]
  139. Hamilton, Z.; Simpson, B.; Donald Reynolds, D.V.M. Antibody Dependent Enhancement of Infectious Bronchitis Virus in Poultry; UCARE Research Products: Minneapolis, MN, USA, 2022. [Google Scholar]
  140. Toro, H.; Pennington, D.; Gallardo, R.A.; van Santen, V.L.; van Ginkel, F.W.; Zhang, J.; Joiner, K.S. Infectious Bronchitis Virus Subpopulations in Vaccinated Chickens after Challenge. Avian Dis. 2012, 56, 501–508. [Google Scholar] [CrossRef]
  141. Brandão, P.E.; Berg, M.; Silva, S.O.S.; Taniwaki, S.A. Emergence of Avian Coronavirus Escape Mutants Under Suboptimal Antibody Titers. J. Mol. Evol. 2022, 90, 176–181. [Google Scholar] [CrossRef]
  142. Bande, F.; Arshad, S.S.; Bejo, M.H.; Moeini, H.; Omar, A.R. Progress and Challenges toward the Development of Vaccines against Avian Infectious Bronchitis. J. Immunol. Res. 2015, 2015, 424860. [Google Scholar] [CrossRef]
  143. Eldemery, F.; Li, Y.; Yu, Q.; van Santen, V.L.; Toro, H. Infectious Bronchitis Virus S2 of 4/91 Expressed from Recombinant Virus Does Not Protect Against Ark-Type Challenge. Avian Dis. 2017, 61, 397–401. [Google Scholar] [CrossRef]
  144. Ravikumar, R.; Chan, J.; Prabakaran, M. Vaccines against Major Poultry Viral Diseases: Strategies to Improve the Breadth and Protective Efficacy. Viruses 2022, 14, 1195. [Google Scholar] [CrossRef]
  145. Shao, G.; Chen, T.; Feng, K.; Zhao, Q.; Zhang, X.; Li, H.; Lin, W.; Xie, Q. Efficacy of Commercial Polyvalent Avian Infectious Bronchitis Vaccines against Chinese QX-like and TW-like Strain via Different Vaccination Strategies. Poult. Sci. 2020, 99, 4786–4794. [Google Scholar] [CrossRef]
  146. Sjaak de Wit, J.J.; Cook, J.K.A.; van der Heijden, H.M.J.F. Infectious Bronchitis Virus Variants: A Review of the History, Current Situation and Control Measures. Avian Pathol. 2011, 40, 223–235. [Google Scholar] [CrossRef] [PubMed]
  147. Cavanagh, D. Severe Acute Respiratory Syndrome Vaccine Development: Experiences of Vaccination against Avian Infectious Bronchitis Coronavirus. Avian Pathol. 2003, 32, 567–582. [Google Scholar] [CrossRef] [PubMed]
  148. Legnardi, M.; Tucciarone, C.M.; Franzo, G.; Cecchinato, M. Infectious Bronchitis Virus Evolution, Diagnosis and Control. Vet. Sci. 2020, 7, E79. [Google Scholar] [CrossRef] [PubMed]
  149. Wilson, R.B.; Holladay, J.A.; Cave, J.S. A Neurologic Syndrome Associated with Use of a Canine Coronavirus-Parvovirus Vaccine in Dogs. Compend. Contin. Educ. Pract. Vet. 1986, 8, 117–118, 120–122, 124. [Google Scholar]
  150. Martin, M. Canine Coronavirus Enteritis and a Recent Outbreak Following Modified Live Virus Vaccination. Compend. Contin. Educ. Pract. Vet. 1985, 7, 1012–1017. [Google Scholar]
  151. Pratelli, A.; Tinelli, A.; Decaro, N.; Martella, V.; Camero, M.; Tempesta, M.; Martini, M.; Carmichael, L.E.; Buonavoglia, C. Safety and Efficacy of a Modified-Live Canine Coronavirus Vaccine in Dogs. Vet. Microbiol. 2004, 99, 43–49. [Google Scholar] [CrossRef]
  152. Pratelli, A. High-cell-passage Canine Coronavirus Vaccine Providing Sterilising Immunity. J. Small Anim. Pract. 2007, 48, 574–578. [Google Scholar] [CrossRef]
  153. Cho, K.-O.; Hasoksuz, M.; Nielsen, P.R.; Chang, K.-O.; Lathrop, S.; Saif, L.J. Cross-Protection Studies between Respiratory and Calf Diarrhea and Winter Dysentery Coronavirus Strains in Calves and RT-PCR and Nested PCR for Their Detection. Arch. Virol. 2001, 146, 2401–2419. [Google Scholar] [CrossRef]
  154. Heckert, R.A.; Saif, L.J.; Hoblet, K.H.; Agnes, A.G. A Longitudinal Study of Bovine Coronavirus Enteric and Respiratory Infections in Dairy Calves in Two Herds in Ohio. Vet. Microbiol. 1990, 22, 187–201. [Google Scholar] [CrossRef]
  155. Fulton, R.W.; d’Offay, J.M.; Landis, C.; Miles, D.G.; Smith, R.A.; Saliki, J.T.; Ridpath, J.F.; Confer, A.W.; Neill, J.D.; Eberle, R.; et al. Detection and Characterization of Viruses as Field and Vaccine Strains in Feedlot Cattle with Bovine Respiratory Disease. Vaccine 2016, 34, 3478–3492. [Google Scholar] [CrossRef]
  156. Hu, S.; Bruszewski, J.; Smalling, R.; Browne, J.K. Studies of TGEV Spike Protein Gp195 Expressed in E. Coli and by a TGE-Vaccinia Virus Recombinant. Adv. Exp. Med. Biol. 1985, 185, 63–82. [Google Scholar] [CrossRef] [PubMed]
  157. Gómez, N.; Wigdorovitz, A.; Castañón, S.; Gil, F.; Ordá, R.; Borca, M.V.; Escribano, J.M. Oral Immunogenicity of the Plant Derived Spike Protein from Swine-Transmissible Gastroenteritis Coronavirus. Arch. Virol. 2000, 145, 1725–1732. [Google Scholar] [CrossRef] [PubMed]
  158. Lamphear, B.J.; Streatfield, S.J.; Jilka, J.M.; Brooks, C.A.; Barker, D.K.; Turner, D.D.; Delaney, D.E.; Garcia, M.; Wiggins, B.; Woodard, S.L.; et al. Delivery of Subunit Vaccines in Maize Seed. J. Control. Release 2002, 85, 169–180. [Google Scholar] [CrossRef] [PubMed]
  159. Gerdts, V.; Zakhartchouk, A. Vaccines for Porcine Epidemic Diarrhea Virus and Other Swine Coronaviruses. Vet. Microbiol. 2017, 206, 45–51. [Google Scholar] [CrossRef]
  160. Al-Abdallat, M.M.; Payne, D.C.; Alqasrawi, S.; Rha, B.; Tohme, R.A.; Abedi, G.R.; Al Nsour, M.; Iblan, I.; Jarour, N.; Farag, N.H.; et al. Hospital-Associated Outbreak of Middle East Respiratory Syndrome Coronavirus: A Serologic, Epidemiologic, and Clinical Description. Clin. Infect. Dis. 2014, 59, 1225–1233. [Google Scholar] [CrossRef]
  161. Yoon, I.-K.; Kim, J.H. First Clinical Trial of a MERS Coronavirus DNA Vaccine. Lancet Infect. Dis. 2019, 19, 924–925. [Google Scholar] [CrossRef]
  162. Modjarrad, K.; Roberts, C.C.; Mills, K.T.; Castellano, A.R.; Paolino, K.; Muthumani, K.; Reuschel, E.L.; Robb, M.L.; Racine, T.; Oh, M.; et al. Safety and Immunogenicity of an Anti-Middle East Respiratory Syndrome Coronavirus DNA Vaccine: A Phase 1, Open-Label, Single-Arm, Dose-Escalation Trial. Lancet Infect. Dis. 2019, 19, 1013–1022. [Google Scholar] [CrossRef]
  163. Lin, J.-T.; Zhang, J.-S.; Su, N.; Xu, J.-G.; Wang, N.; Chen, J.-T.; Chen, X.; Liu, Y.-X.; Gao, H.; Jia, Y.-P.; et al. Safety and Immunogenicity from a Phase I Trial of Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine. Antivir. Ther. 2007, 12, 1107–1113. [Google Scholar] [CrossRef]
  164. Martin, J.E.; Louder, M.K.; Holman, L.A.; Gordon, I.J.; Enama, M.E.; Larkin, B.D.; Andrews, C.A.; Vogel, L.; Koup, R.A.; Roederer, M.; et al. A SARS DNA Vaccine Induces Neutralizing Antibody and Cellular Immune Responses in Healthy Adults in a Phase I Clinical Trial. Vaccine 2008, 26, 6338–6343. [Google Scholar] [CrossRef]
  165. Koch, T.; Dahlke, C.; Fathi, A.; Kupke, A.; Krähling, V.; Okba, N.M.A.; Halwe, S.; Rohde, C.; Eickmann, M.; Volz, A.; et al. Safety and Immunogenicity of a Modified Vaccinia Virus Ankara Vector Vaccine Candidate for Middle East Respiratory Syndrome: An Open-Label, Phase 1 Trial. Lancet Infect. Dis. 2020, 20, 827–838. [Google Scholar] [CrossRef]
  166. Fathi, A.; Dahlke, C.; Krähling, V.; Kupke, A.; Okba, N.M.A.; Raadsen, M.P.; Heidepriem, J.; Müller, M.A.; Paris, G.; Lassen, S.; et al. Increased Neutralization and IgG Epitope Identification after MVA-MERS-S Booster Vaccination against Middle East Respiratory Syndrome. Nat. Commun. 2022, 13, 4182. [Google Scholar] [CrossRef] [PubMed]
  167. Folegatti, P.M.; Bittaye, M.; Flaxman, A.; Lopez, F.R.; Bellamy, D.; Kupke, A.; Mair, C.; Makinson, R.; Sheridan, J.; Rohde, C.; et al. Safety and Immunogenicity of a Candidate Middle East Respiratory Syndrome Coronavirus Viral-Vectored Vaccine: A Dose-Escalation, Open-Label, Non-Randomised, Uncontrolled, Phase 1 Trial. Lancet Infect. Dis. 2020, 20, 816–826. [Google Scholar] [CrossRef] [PubMed]
  168. Bosaeed, M.; Balkhy, H.H.; Almaziad, S.; Aljami, H.A.; Alhatmi, H.; Alanazi, H.; Alahmadi, M.; Jawhary, A.; Alenazi, M.W.; Almasoud, A.; et al. Safety and Immunogenicity of ChAdOx1 MERS Vaccine Candidate in Healthy Middle Eastern Adults (MERS002): An Open-Label, Non-Randomised, Dose-Escalation, Phase 1b Trial. Lancet Microbe 2022, 3, e11–e20. [Google Scholar] [CrossRef] [PubMed]
  169. Buzhdygan, T.P.; DeOre, B.J.; Baldwin-Leclair, A.; Bullock, T.A.; McGary, H.M.; Khan, J.A.; Razmpour, R.; Hale, J.F.; Galie, P.A.; Potula, R.; et al. The SARS-CoV-2 Spike Protein Alters Barrier Function in 2D Static and 3D Microfluidic in-Vitro Models of the Human Blood-Brain Barrier. Neurobiol. Dis. 2020, 146, 105131. [Google Scholar] [CrossRef]
  170. Forsyth, C.B.; Zhang, L.; Bhushan, A.; Swanson, B.; Zhang, L.; Mamede, J.I.; Voigt, R.M.; Shaikh, M.; Engen, P.A.; Keshavarzian, A. The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-KB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells. Microorganisms 2022, 10, 1996. [Google Scholar] [CrossRef]
  171. Bhargavan, B.; Kanmogne, G.D. SARS-CoV-2 Spike Proteins and Cell-Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis. Int. J. Mol. Sci. 2022, 23, 10436. [Google Scholar] [CrossRef]
  172. Choi, J.-Y.; Park, J.H.; Jo, C.; Kim, K.-C.; Koh, Y.H. SARS-CoV-2 Spike S1 Subunit Protein-Mediated Increase of Beta-Secretase 1 (BACE1) Impairs Human Brain Vessel Cells. Biochem. Biophys. Res. Commun. 2022, 626, 66–71. [Google Scholar] [CrossRef]
  173. Hsu, A.C.-Y.; Wang, G.; Reid, A.T.; Veerati, P.C.; Pathinayake, P.S.; Daly, K.; Mayall, J.R.; Hansbro, P.M.; Horvat, J.C.; Wang, F.; et al. SARS-CoV-2 Spike Protein Promotes Hyper-Inflammatory Response That Can Be Ameliorated by Spike-Antagonistic Peptide and FDA-Approved ER Stress and MAP Kinase Inhibitors in Vitro. Biorxiv 2020. [Google Scholar] [CrossRef]
  174. Khan, S.; Shafiei, M.S.; Longoria, C.; Schoggins, J.W.; Savani, R.C.; Zaki, H. SARS-CoV-2 Spike Protein Induces Inflammation via TLR2-Dependent Activation of the NF-ΚB Pathway. eLife 2021, 10, e68563. [Google Scholar] [CrossRef]
  175. Lei, Y.; Zhang, J.; Schiavon, C.R.; He, M.; Chen, L.; Shen, H.; Zhang, Y.; Yin, Q.; Cho, Y.; Andrade, L.; et al. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circ. Res. 2021, 128, 1323–1326. [Google Scholar] [CrossRef] [PubMed]
  176. Nyström, S.; Hammarström, P. Amyloidogenesis of SARS-CoV-2 Spike Protein. J. Am. Chem. Soc. 2022, 144, 8945–8950. [Google Scholar] [CrossRef] [PubMed]
  177. Muglia, J.J.; DiGiovanna, J.J. Phase 1 Clinical Trials. J. Cutan. Med. Surg. 1998, 2, 236–241. [Google Scholar] [CrossRef] [PubMed]
  178. Meyer-Arndt, L.; Schwarz, T.; Loyal, L.; Henze, L.; Kruse, B.; Dingeldey, M.; Gürcan, K.; Uyar-Aydin, Z.; Müller, M.A.; Drosten, C.; et al. Cutting Edge: Serum but Not Mucosal Antibody Responses Are Associated with Pre-Existing SARS-CoV-2 Spike Cross-Reactive CD4+ T Cells Following BNT162b2 Vaccination in the Elderly. J. Immunol. 2022, 208, 1001–1005. [Google Scholar] [CrossRef] [PubMed]
  179. Chau, N.V.V.; Ngoc, N.M.; Nguyet, L.A.; Quang, V.M.; Ny, N.T.H.; Khoa, D.B.; Phong, N.T.; Toan, L.M.; Hong, N.T.T.; Tuyen, N.T.K.; et al. Transmission of SARS-CoV-2 Delta Variant among Vaccinated Healthcare Workers, Vietnam. 2021; preprint. [Google Scholar] [CrossRef]
  180. Pezzullo, A.M.; Axfors, C.; Contopoulos-Ioannidis, D.G.; Apostolatos, A.; Ioannidis, J.P.A. Age-Stratified Infection Fatality Rate of COVID-19 in the Non-Elderly Population. Environ. Res. 2023, 216, 114655. [Google Scholar] [CrossRef]
  181. Kedmi, R.; Ben-Arie, N.; Peer, D. The Systemic Toxicity of Positively Charged Lipid Nanoparticles and the Role of Toll-like Receptor 4 in Immune Activation. Biomaterials 2010, 31, 6867–6875. [Google Scholar] [CrossRef]
Figure 1. Overview of mRNA–LNP vaccine components.
Figure 1. Overview of mRNA–LNP vaccine components.
J 06 00017 g001
Table 1. Summary of human trials of non-COVID-19 coronavirus vaccines. Adapted from [117].
Table 1. Summary of human trials of non-COVID-19 coronavirus vaccines. Adapted from [117].
PlatformVaccineGroupStatusSevere Adverse EventsNCT IDStudy
SARS Vaccine Clinical Trials
Inactivated virusInactivated SARS-CoV vaccine (ISCV)SinovacPhase I, completed[0/24, 0%]No NCT ID[163]
DNA vaccineVRC-SRSDNA015-00-VPNIAIDPhase I, completed[0/9, 0%]NCT00099463[164]
MERS Vaccine Clinical Trials
DNA vaccineGLS-5300 (INO-4700)GeneOne Life Science/Inovio Pharmaceuticals/International Vaccine InstitutePhase I, completed[0/75, 0%]
Infections in 36% of participants
NCT02670187[162]
DNA vaccineGLS-5300 (INO-4700)GeneOne Life Science/Inovio Pharmaceuticals/
International Vaccine Institute
Phase I/IIa, completedNo results availableNCT03721718
Viral vector vaccineMVA-MERS-SCTC North GmbH & Co. KGPhase I, completed[0/23, 0%]NCT03615911[165]
Viral vector vaccineMVA-MERS-S_DF1CTC North GmbH & Co. KGPhase Ib, not yet recruitingNo dataNCT04119440[166]
Viral vector vaccineChAdOx1 MERSUniversity of OxfordPhase I, recruiting[1/24, 4%] NCT03399578[167]
Viral vector vaccineChAdOx1 MERSKing Abdullah International Medical Research Center/University of OxfordPhase I, recruiting[6/24, 25%]NCT04170829[168]
Viral vector vaccineBVRS-GamVac-CombiGamaleya Research Institute of Epidemiology and Microbiology/Acellena Contract Drug Research and DevelopmentPhase I/II, recruitingNo dataNCT04128059
Viral vector vaccineBVRS-GamVacGamaleya Research Institute of Epidemiology and MicrobiologyPhase I/II, recruitingNo dataNCT04130594
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Halma, M.T.J.; Rose, J.; Lawrie, T. The Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review. J 2023, 6, 220-235. https://doi.org/10.3390/j6020017

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Halma MTJ, Rose J, Lawrie T. The Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review. J. 2023; 6(2):220-235. https://doi.org/10.3390/j6020017

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Halma, Matthew T.J., Jessica Rose, and Theresa Lawrie. 2023. "The Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review" J 6, no. 2: 220-235. https://doi.org/10.3390/j6020017

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