MRNA-Based Vaccines: Comparison
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The mRNA-based vaccine approach is a promising alternative to traditional vaccines due to its ability for prompt development, high potency, and potential for secure administration and low-cost production.

  • IVT mRNA
  • mRNA vaccine
  • electroporation
  • protamine
  • LNPs

1. Introduction

Vaccines protect against millions of microbes and save thousands of lives from diseases each year [1]. Due to the use of extensive vaccines, the smallpox-causing virus (variola) has been eliminated and the cases of measles, polio, and various other childhood ailments have significantly declined throughout the world [2]. Traditional vaccine technologies including subunit vaccines and, live attenuated (or weakened) and inactivated (or killed) pathogens, offer long-lasting protection against various lethal ailments [3]. Despite this achievement, there exist key obstacles for the development of successful vaccines against diverse infectious disease-causing pathogens, particularly those better efficient to avoid adaptive immunity [1][4]. Besides, for the utmost evolving virus vaccines, the major difficulty is not the efficiency of established technologies but the demand for quick and large-scale production. Moreover, traditional vaccine technologies might be invalid for non-infectious disorders like cancer. Therefore, there is an urgent need for the progression of more versatile and effective vaccine platforms.

Nucleic acid-based treatments have developed as promising substitutes for traditional vaccine approaches. In animals, the first data of the use of successful in vitro transcribed (IVT) mRNA was reported in 1990, while reporter mRNAs were administered into in vivo mice model, and subsequently, protein expression was identified [5]. In 1992, a later study revealed that the use of messenger RNA encoding vasopressin in the brain hypothalamus can induce biological effects in rats [6]. Nonetheless, these primary but significant results could not make considerable investments in evolving mRNA-based vaccines, mainly due to concerns related to higher innate immunogenicity, mRNA instability, as well as inefficient drug delivery in vivo. Alternatively, the field approached DNA- and/or protein-based therapeutics [7][8]. Nonetheless, since the discovery of mRNA, it has been known the matter of consistent basic as well as applied research for many ailments [9][10]. In the initial decades of mRNA discovery, the main attention was on comprehensive investigations of structural as well as functional characteristics of eukaryotic mRNA and its metabolism. This is in order to make approaches for mRNA-based recombinant technology readily accessible to a wider research arena. In the late 1990s, preclinical investigation of IVT mRNAs was introduced for various applications, such as protein replacement and vaccination tools for cancer as well as infectious diseases [6][11][12][13][14][15][16][17][18]. Therefore, accumulated information allowed the latest scientific and technological improvements to overcome various difficulties related to mRNA, including its short half-life as well as adverse immunogenicity.

The administration of the mRNA-based vaccine has some benefits over subunit, live attenuated and inactivated virus, and DNA vaccines. Firstly, safety: there is no possible concern of insertional mutagenesis or infection since mRNA is non-integrating and non-infectious. Moreover, mRNA is generally destroyed under normal cellular conditions, and its in vivo half-life could be controlled via the use of diverse modification systems as well as delivery methods [19][20][21][22]. Besides, the innate immunogenicity of the mRNA could be downregulated to enhance the safety profile [19][22][23]. Secondly, efficacy: several modifications provide mRNA not only high stability but also translatability [19][22][23]. Efficient in vivo delivery of mRNA can be obtained by formulating them into carrier molecules such as polymers, peptides, lipid nanoparticles, micelles, allowing faster uptake and enhancing protein expression in the cytosol [20][21]. mRNA is considered the minimal hereditary material; hence, anti-vector mediated immunity is prevented, and these vaccines could be used recurrently. Finally, production: mostly due to the high yielding capability of IVT mRNA during transcription reactions, these vaccines have the potential for fast, low-priced, as well as scalable manufacturing.

The mRNA vaccine is a rapidly developing field; many preclinical investigations have been reported over the past few years [24][25][26][27][28][29][30]. Multiple human clinical trials have been initiated IVT mRNA-based therapeutics as protein-replacement therapy in the field of oncology [31][32][33][34], cardiology [35][36], endocrinology [37], hematology [38][39], pulmonary medicine [38][40], or the treatment of other diseases [14][41]. To further advance this revolutionary approach, unresolved issues like targeted mRNA delivery and its intricated pharmacology require to be developed.

2. Challenges and Safety Issues in the Development of mRNA-Based Vaccines against Novel Antigens

The potential benefit of RNA-based therapeutics is their rapid development with lower side effects. The single-stranded IVT mRNA therapeutics are free from the hazard of genomic integration with the host cell and are efficient to generate high-quality viral protein. Besides, mRNAs are rapidly expressed and thus allowing the protein to be manufactured inside the cell. Experimental analyses of mRNA for rapid biological therapy has revealed outstanding tolerability as well as safety profile and reported that mRNA-based vaccines have no potential platform-inherent concerns [42]. However, for a majority of other mRNA-based therapeutic applications, such as protein replacement therapy, where preclinical and clinical trials are still very limited, researchers are unclear about the potential challenges and types of safety issues that should be considered [43]. Nevertheless, vaccine developers have pointed out several challenges and safety trials for developing novel vaccines against new infections e.g., SARS-CoV2.

Like other viruses, the novel coronavirus is an RNA virus, which exerts its effect via ‘S’ protein consisting of 1273 amino acid residues. This virus showed high mutation efficacy and genetic instability that may hamper immune induction [44]. Therefore, it is vital to understand genetic changes in the coding as well as non-coding sequences, genetic variant, pathogenicity, and host–pathogen interrelations. Genetic alteration in the ‘S’ protein likely to stimulate its folding pattern, which may change antigenicity and, consequently, may disturb vaccine design [45][46][47]. Copious reports advocated that mutations in the target proteins may be interrelated with drug resistance, leading to vaccine inefficacy. Therefore, immunogen selection for the mRNA-based vaccine development should be carefully considered and designed.

It is also critical to focus that insecurity over long-durable protection still exists against COVID-19. In several reports, there is evidence of reinfections. In such cases, it is required to report how long a protective immune induction will be continued in a patient [48][49][50]. Regarding the immunogenicity of the COVID-19 mRNA therapeutic in elderly individuals, it has been demonstrated that after the second inoculation, serum neutralizing titer was noticed in all the populations. Surprisingly, the binding as well as antibody neutralizing efficiency was comparable to those stated among vaccine receivers from 18 to 55 years old and were over the average of a group of control populations [51].

In the present pandemic situation, several researchers advised that immune inductions against coronavirus can lead to ADE (antibody-dependent enhancement) [52][53]. Although it was reported that immunization of the COVID19 receptor-binding domain did not mediate ADE in rodents [54], this principle could contribute to the pathology of several feline coronaviruses and flavivirus [54], notably dengue virus [55]. Nevertheless, ADE should be taken into consideration while evolving therapeutics against novel viruses [56][57]. In addition, considering the emergency need for a COVID-19 vaccine worldwide, being over-precautions, the authority should not stop the release of safe, well-tolerated, and efficient vaccines to the general populations [57][58][59]. Some reports demonstrated the safety concern of vaccine-enhanced disorder for inactivated vaccine candidates, remarkably vaccine-associated enhanced respiratory disease (Table 13) [60][61][62][63].

Although mRNA vaccines can be manufactured with a minimum time; however, large-scale production of these therapeutics remains a challenging task owing to its huge uncertainty to meet the demand during the pandemic. Additionally, in recent years, nucleic acid-based vaccines could not produce effective platforms for human infections and other diseases using temperature-sensitive lipid nanoparticles, which may hamper for scaling up vaccine manufacture [60]. For example, BNT162b2 and the Pfizer-BioNTech COVID-19 vaccines, are lipid nanoparticle-formulated nucleoside-modified mRNA vaccines that encode SARS-CoV-2 spike protein [43]. Following the issuance of the emergency use authorization (EUA) for the BNT162b2 vaccine by the U.S. Food and Drug Administration in December 2020, the vaccination scheme of this vaccine was launched later in the U.S and other countries. However, the plan for massive immunization has been delayed by the stringent requirement of storage and transportation of the BNT162b2 vaccine. Besides, cold chain transportation is not available in many COVID-19 epidemic areas, so potent mRNA vaccines with enhanced temperature stability will be highly preferred in the future. Despite huge challenges and risk factors involved in the development of mRNA-based vaccines in clinical trials, several mRNA-based vaccines in human trials have been reported in the literature that has been summarized in Table 13.

Table 13. mRNA-based vaccines in human clinical trials with their major finding and adversity.

Antigen/Study Identifier/Phase Subjects/Numbers Route Major Findings Ref.
Rabies glycoprotein/NCT02241135/Phase I 18–40 years (volunteers), 101 healthy individuals ID and IM 94% of ID and 97% of IM vaccinated populations received severe injection site reactions, and 78% ID and 78% of IM injected peoples demonstrated severe systemic reactions, induce antibody response when administered with a needle free device, safe with a tolerability profile [64]
Melan-A, Tyrosinase, gp100, MAGE-A1, MAGE-A3, Survivin/NCT00204607/Phase I/II 18–80 years, 21 patients with metastatic melanoma ID No adversity was observed more than grade II, feasible and safe, rate of Foxp3+/CD4+ regulatory T lymphocytes were reduced significantly upon mRNA plus keyhole limpet hemocyanin (KLH) injection, CD11b+HLA-DR lo monocytes (myeloid suppressor cells) were decreased in the patients without KLH addition [28]
NY-ESO-1, MAGEC1, MAGEC2, 5T4, Survivin, MUC1/NCT01915524/ Phase 1b ≥18 years, 19 patients with NSCLC ID No serious toxicity was observed, only 7% patients experienced grade >3 related adversity, antigen-mediated immune induction was seen in more than 2/3 of patients [65]
HIV-1/NCT00672191/Phase II 18 to 60 years, 59 participants ID Develop immune control of HIV-1 reproduction [66]
Spike protein (COVID-19)/NCT04470427/Phase II 18 to 99 years, 30,000 participants IM Ongoing [67]
Spike protein/NCT04283461/Phase I 56 to 70 years,

40 healthy adults		 IM Mild or moderate adversity was observed, 100 μg mRNA produced higher virus neutralizing-antibody titers than 25 μg [51]
Spike protein/NCT04368728/Phase I and II 18 to 55 years, 45 adults IM Adversity was dose-dependent, transient, mostly mild to moderate [68]
Spike protein/NCT04283461/Phase I 18 to 55 years, 45 healthy adults IM This vaccine candidate induced immune responses against COVID-19 in all populations, and no trial-limiting safety issues were detected [69]
Spike protein/NCT04566276/Phase I and II 65 to 75 years, 600 healthy adults IM Ongoing [70]
Spike protein/NCT04515147/Phase II 18 to 60 years, 691 participants IM Ongoing  
ID = intradermal; IM = intramuscular; NSCLC = non-small cell lung cancer.

References

  1. 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.
  2. Younger, D.S.; Younger, A.P.J.; Guttmacher, S. Childhood Vaccination: Implications for Global and Domestic Public Health. Neurol. Clin. 2016, 34, 1035–1047.
  3. Plotkin, S.A. Vaccines: The fourth century. Clin. Vaccine Immunol. 2009, 16, 1709–1719.
  4. Rodrigues, C.M.C.; Pinto, M.V.; Sadarangani, M.; Plotkin, S.A. Whither vaccines? J. Infect. 2017.
  5. Wolff, J.A.; Malone, R.W.; Williams, P.; Chong, W.; Acsadi, G.; Jani, A.; Agnes, F.; Philip, L. Direct gene transfer into mouse muscle in vivo. Science (80-) 1990, 247, 1465–1468.
  6. Jirikowski, G.F.; Sanna, P.P.; Maciejewski-Lenoir, D.; Bloom, F.E. Reversal of diabetes insipidus in Brattleboro tats: Intrahypothalamic injection of vasopressin mRNA. Science (80-) 1992, 255, 996–998.
  7. Suschak, J.J.; Williams, J.A.; Schmaljohn, C.S. Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum. Vaccines Immunother. 2017, 13, 2837–2848.
  8. Schmidt, S.T.; Foged, C.; Korsholm, K.S.; Rades, T.; Christensen, D. Liposome-based adjuvants for subunit vaccines: Formulation strategies for subunit antigens and immunostimulators. Pharmaceutics 2016, 8, 1–22.
  9. Sahin, U.; Karikó, K.; Türeci, Ö. mRNA-based therapeutics-developing a new class of drugs. Nat. Rev. Drug Discov. 2014, 13, 759–780.
  10. Zhong, Z.; Mc Cafferty, S.; Combes, F.; Huysmans, H.; De Temmerman, J.; Gitsels, A.; Arlieke, V.; Daisy, P.C.; João, S.; Niek, N. mRNA therapeutics deliver a hopeful message. Nano Today 2018, 23, 16–39.
  11. Martinon, F.; Krishnan, S.; Lenzen, G.; Magné, R.; Gomard, E.; Guillet, J.-G.; Lévy, J.P.; Meulien, P. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 1993, 23, 1719–1722.
  12. Conry, R.M.; LoBuglio, A.F.; Wright, M.; Sumerel, L.; Pike, M.J.; Johanning, F.; Benjamin, R.; Lu, D.; Curiel, D.T. Characterization of a Messenger RNA Polynucleotide Vaccine Vector. Cancer Res. 1995, 55, 1397–1400.
  13. Boczkowski, D.; Nair, S.K.; Snyder, D.; Gilboa, E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J. Exp. Med. 1996, 184, 465–472.
  14. Qiu, P.; Ziegelhoffer, P.; Sun, J.; Yang, N.S. Gene gun delivery of mRNA in situ results in efficient transgene expression and genetic immunization. Gene Ther. 1996, 3, 262–268.
  15. Mandl, C.W.; Aberle, J.H.; Aberle, S.W.; Holzmann, H.; Allison, S.L.; Heinz, F.X. In vitro-synthesized infectious RNA as an attenuated live vaccine in a flavivirus model. Nat. Med. 1998, 4, 1438–1440.
  16. Zhou, W.Z.; Hoon, D.S.B.; Huang, S.K.S.; Fujii, S.; Hashimoto, K.; Morishita, R.; Kaneda, Y. RNA melanoma vaccine: Induction of antitumor immunity by human glycoprotein 100 mRNA immunization. Hum. Gene Ther. 1999, 10, 2719–2724.
  17. Hoerr, I.; Obst, R.; Rammensee, H.G.; Jung, G. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur. J. Immunol. 2000, 30, 1–7.
  18. Koido, S.; Kashiwaba, M.; Chen, D.; Gendler, S.; Kufe, D.; Gong, J. Induction of Antitumor Immunity by Vaccination of Dendritic Cells Transfected with MUC1 RNA. J. Immunol. 2000, 165, 5713–5719.
  19. Karikó, K.; Muramatsu, H.; Welsh, F.A.; Ludwig, J.; Kato, H.; Akira, S.; Weissman, D. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 2008, 16, 1833–1840.
  20. Kauffman, K.J.; Webber, M.J.; Anderson, D.G. Materials for non-viral intracellular delivery of messenger RNA therapeutics. J. Control Release 2016, 240, 227–234.
  21. Guan, S.; Rosenecker, J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 2017, 24, 133–143.
  22. Thess, A.; Grund, S.; Mui, B.L.; Hope, M.J.; Baumhof, P.; Fotin-Mleczek, M.; Schlake, T. Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals. Mol. Ther. 2015, 23, 1456–1464.
  23. Karikó, K.; Muramatsu, H.; Ludwig, J.; Weissman, D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. 2011, 39, e142.
  24. Heiser, A.; Coleman, D.; Dannull, J.; Yancey, D.; Maurice, M.A.; Lallas, C.D.; Dahm, P.; Niedzwiecki, D.; Gilboa, E.; Vieweg, J. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J. Clin. Investig. 2002, 109, 409–417.
  25. Morse, M.A.; Nair, S.K.; Boczkowski, D.; Tyler, D.; Hurwitz, H.I.; Proia, A.; Clay, T.M.; Schlom, J.; Gilboa, E.; Lyerly, H.K. The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer. Int. J. Gastrointest. Cancer 2002, 32, 1–6.
  26. Morse, M.A.; Nair, S.K.; Mosca, P.J.; Hobeika, A.C.; Clay, T.M.; Deng, Y.; Boczkowski, D.; Proia, A.; Neidzwiecki, D.; Clavien, P.A.; et al. Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Investig. 2003, 21, 341–349.
  27. Su, Z.; Dannull, J.; Yang, B.K.; Dahm, P.; Coleman, D.; Yancey, D.; Sichi, S.; Niedzwiecki, D.; Boczkowski, D.; Gilboa, E.; et al. Telomerase mRNA-Transfected Dendritic Cells Stimulate Antigen-Specific CD8 + and CD4 + T Cell Responses in Patients with Metastatic Prostate Cancer. J. Immunol. 2005, 174, 3798–3807.
  28. Weide, B.; Pascolo, S.; Scheel, B.; Derhovanessian, E.; Pflugfelder, A.; Eigentler, T.K.; Pawelec, G.; Hoerr, I.; Rammensee, H.G.; Garbe, C. Direct injection of protamine-protected mRNA: Results of a phase 1/2 vaccination trial in metastatic melanoma patients. J. Immunother. 2009, 32, 498–507.
  29. Rittig, S.M.; Haentschel, M.; Weimer, K.J.; Heine, A.; Muller, M.R.; Brugger, W.; Horger, M.S.; Maksimovic, O.; Stenzl, A.; Hoerr, I.; et al. Intradermal vaccinations with RNA coding for TAA generate CD8 and CD4 immune responses and induce clinical benefit in vaccinated patients. Mol. Ther. 2011, 19, 990–999.
  30. Wilgenhof, S.; Van Nuffel, A.M.T.; Benteyn, D.; Corthals, J.; Aerts, C.; Heirman, C.; Van Riet, I.; Bonehill, A.; Thielemans, K.; Neyns, B. A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients. Ann. Oncol. 2013, 24, 2686–2693.
  31. Wang, Y.; Su, H.H.; Yang, Y.; Hu, Y.; Zhang, L.; Blancafort, P.; Huang, L. Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy. Mol. Ther. 2013, 21, 358–367.
  32. Mitchell, D.A.; Karikari, I.; Cui, X.; Xie, W.; Schmittling, R.; Sampson, J.H. Selective modification of antigen-specific T cells by RNA electroporation. Hum. Gene Ther. 2008, 19, 511–521.
  33. Okumura, K.; Nakase, M.; Inui, M.; Nakamura, S.; Watanabe, Y.; Tagawa, T. Bax mRNA therapy using cationic liposomes for human malignant melanoma. J. Gene Med. 2008, 10, 910–917.
  34. Schirrmacher, V.; Förg, P.; Dalemans, W.; Chlichlia, K.; Zeng, Y.; Fournier, P.; Von Hoegen, P. Intra-pinna anti-tumor vaccination with self-replicating infectious RNA or with DNA encoding a model tumor antigen and a cytokine. Gene Ther. 2000, 7, 1137–1147.
  35. Zimmermann, O.; Homann, J.M.; Bangert, A.; Müller, A.M.; Hristov, G.; Goeser, S.; Wiehe, J.M.; Zittrich, S.; Rottbauer, W.; Torzewski, J.; et al. Successful use of mRNA-nucleofection for overexpression of interleukin-10 in murine monocytes/macrophages for anti-inflammatory therapy in a murine model of autoimmune myocarditis. J. Am. Heart Assoc. 2012, 1, e003293.
  36. Zangi, L.; Lui, K.O.; Von Gise, A.; Ma, Q.; Ebina, W.; Ptaszek, L.M.; Später, D.; Xu, H.; Tabebordbar, M.; Gorbatov, R.; et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 2013, 31, 898–907.
  37. Creusot, R.J.; Chang, P.; Healey, D.G.; Tcherepanova, I.Y.; Nicolette, C.A.; Fathman, C.G. A short pulse of IL-4 delivered by dcs electroporated with modified mRNA can both prevent and treat autoimmune diabetes in NOD mice. Mol. Ther. 2010, 18, 2112–2120.
  38. Kormann, M.S.D.; Hasenpusch, G.; Aneja, M.K.; Nica, G.; Flemmer, A.W.; Herber-Jonat, S.; Huppmann, M.; Mays, L.E.; Illenyi, M.; Schams, A.; et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat. Biotechnol. 2011, 29, 154–157.
  39. Karikó, K.; Muramatsu, H.; Keller, J.M.; Weissman, D. Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol. Ther. 2012, 20, 948–953.
  40. Mays, L.E.; Ammon-Treiber, S.; Mothes, B.; Alkhaled, M.; Rottenberger, J.; Müller-Hermelink, E.S.; Grimm, M.; Mezger, M.; Beer-Hammer, S.; Von Stebut, E.; et al. Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism. J. Clin. Investig. 2013, 123, 1216–1228.
  41. Levy, O.; Zhao, W.; Mortensen, L.J.; LeBlanc, S.; Tsang, K.; Fu, M.; Phillips, J.A.; Sagar, V.; Anandakumaran, P.; Ngai, J.; et al. mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation. Blood 2013, 122, e23–e32.
  42. Wadhwa, A.; Aljabbari, A.; Lokras, A.; Foged, C.; Thakur, A. Opportunities and challenges in the delivery of mrna-based vaccines. Pharmaceutics 2020, 12, 102.
  43. Polack, F.P.; Thomas, S.J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Pérez Marc, G.; Moreira, E.D.; Zerbini, C.; et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 2020, 38, 2603–2615.
  44. Silveira, M.M.; Moreira, G.M.S.G.; Mendonça, M. DNA vaccines against COVID-19: Perspectives and challenges. Life Sci. 2021, 267, 118921.
  45. Deng, X.; StJohn, S.E.; Osswald, H.L.; O’Brien, A.; Banach, B.S.; Sleeman, K.; Ghosh, A.K.; Mesecar, A.D.; Baker, S.C. Coronaviruses Resistant to a 3C-Like Protease Inhibitor Are Attenuated for Replication and Pathogenesis, Revealing a Low Genetic Barrier but High Fitness Cost of Resistance. J. Virol. 2014, 84, 11886–11898.
  46. Wang, X.W.; Li, J.S.; Jin, M.; Zhen, B.; Kong, Q.X.; Song, N.; Xiao, W.J.; Yin, J.; Wei, W.; Wang, G.J.; et al. Study on the resistance of severe acute respiratory syndrome-associated coronavirus. J. Virol. Methods 2005, 126, 171–177.
  47. Naqvi, A.A.T.; Fatima, K.; Mohammad, T.; Fatima, U.; Singh, I.K.; Singh, A.; Atif, S.M.; Hariprasad, G.; Hasan, G.M.; Hassan, M.I. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim. Biophys. Acta Mol. Basis Dis. 2020, 1866, 165878.
  48. Roy, S. COVID-19 Reinfection: Myth or Truth? SN Compr. Clin. Med. 2020, 2, 710–713.
  49. Alizargar, J. Risk of reactivation or reinfection of novel coronavirus (COVID-19). J Formos. Med. Assoc. 2020, 119, 1123.
  50. To, K.K.W.; Hung, I.F.N.; Ip, J.D.; Chu, A.W.H.; Chan, W.M.; Tam, A.R.; Fong, C.H.Y.; Yuan, S.; Tsoi, H.W.; Ng, A.C.K.; et al. Coronavirus Disease 2019 (COVID-19) Re-infection by a Phylogenetically Distinct Severe Acute Respiratory Syndrome Coronavirus 2 Strain Confirmed by Whole Genome Sequencing. Clin. Infect. Dis. 2020, 1–6.
  51. Anderson, E.J.; Rouphael, N.G.; Widge, A.T.; Jackson, L.A.; Roberts, P.C.; Makhene, M.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; Pruijssers, A.J.; et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N. Engl. J. Med. 2020, 383, 2427–2438.
  52. Sharma, O.; Sultan, A.A.; Ding, H.; Triggle, C.R. A Review of the Progress and Challenges of Developing a Vaccine for COVID-19. Front. Immunol. 2020, 11, 585354.
  53. 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. 2019, 94, e02015-19.
  54. Quinlan, B.D.; Mou, H.; Zhang, L.; Guo, Y.; He, W.; Ojha, A.; Parcells, M.S.; Luo, G.; Li, W.; Zhong, G.; et al. The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement. bioRxiv 2020.
  55. Henry, P.G.; Clemente, M.; Fernando, M.; Ferdinando, L.; Juan, E.L.; Rosa, M.A. Antibody-dependent enhancement of dengue virus infection in U937 cells requires cholesterol-rich membrane microdomains. J. Gen. Virol. 2010, 91 Pt 2, 394–403.
  56. Morris, K.V. The Improbability of the Rapid Development of a Vaccine for SARS-CoV-2. Mol. Ther. 2020, 28, 1548–1549.
  57. Garber, K. Coronavirus vaccine developers wary of errant antibodies. Nat. Biotechnol. 2020.
  58. Zhang, Y.; Zeng, G.; Pan, H.; Li, C.; Hu, Y.; Chu, K.; Han, W.; Chen, Z.; Tang, R.; Yin, W.; et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: A randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 2021, 21, 181–192.
  59. Graham, B.S. Rapid COVID-19 vaccine development. Science (80-) 2020, 368, 945–946.
  60. Sharpe, H.R.; Gilbride, C.; Allen, E.; Belij-Rammerstorfer, S.; Bissett, C.; Ewer, K.; Lambe, T. The early landscape of coronavirus disease 2019 vaccine development in the UK and rest of the world. Immunology 2020, 160, 223–232.
  61. Corey, L.; Mascola, J.R.; Fauci, A.S.; Collins, F.S. A strategic approach to COVID-19 vaccine R&D. Science (80-) 2020, 368, 948–950.
  62. Deming, M.E.; Michael, N.L.; Robb, M.; Cohen, M.S.; Neuzil, K.M. Accelerating Development of SARS-CoV-2 Vaccines—The Role for Controlled Human Infection Models. N. Engl. J. Med. 2020, 383, e63.
  63. Folegatti, P.M.; Ewer, K.J.; Aley, P.K.; Angus, B.; Becker, S.; Belij-Rammerstorfer, S.; Bellamy, D.; Bibi, S.; Bittaye, M.; Clutterbuck, E.A.; et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020, 396, 467–478.
  64. Jiang, S. Don’t rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees. Nature 2020, 579, 321.
  65. 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.
  66. Sebastian, M.; Papachristofilou, A.; Weiss, C.; Früh, M.; Cathomas, R.; Hilbe, W.; Wehler, T.; Rippin, G.; Koch, S.D.; Scheel, B.; et al. Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive®) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. BMC Cancer 2014, 14, 748.
  67. 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.
  68. Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis SARS CoV-2 Infection (COVID-19). Available online: (accessed on 28 February 2021).
  69. Mulligan, M.J.; Lyke, K.E.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Neuzil, K.; Raabe, V.; Bailey, R.; Swanson, K.A.; et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020, 586, 589–593.
  70. Jackson, L.A.; Anderson, E.J.; Rouphael, N.G.; Roberts, P.C.; Makhene, M.; Coler, R.N.; McCullough, M.P.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; et al. An mRNA Vaccine against SARS-CoV-2—Preliminary Report. N. Engl. J. Med. 2020, 383, 1920–1931.
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