A Comprehensive Review of Vaccines against Covid-19
Authors: Minh Phan Hong , Linh Vu Khanh , Hai Nguyen Thanh , Thanh Tung Bui 
Published: July 2022

The globe is engulfed by one of the most extensive public health crises as COVID-19 has become a leading cause of death worldwide. COVID-19 was first detected in Wuhan, China, in December 2019, causing the severe acute respiratory syndrome. This review discusses issues related to Covid-19 vaccines, such as vaccine development targets, vaccine types, efficacy, limitations and development prospects.
Keywords: Covid-19, SARS-CoV-2, vaccine, spike protein.
References
 [1] C. Wang, P. W. Horby, F. G. Hayden, G. F. Gao, A Novel Coronavirus Outbreak of Global Health Concern, The Lancet, Vol. 395, No. 10223, 2020, pp. 470-473, https://doi.org/10.1016/S0140-6736(20)30185-9.[2] T. Singhal, A Review of Coronavirus Disease-2019 (COVID-19), The Indian Journal of Pediatrics, Vol. 87, 2020, pp. 281-286, https://doi.org/10.1007/s12098-020-03263-6.[3] World Health Organization, WHO Coronavirus (COVID-19) Dashboard, https://covid19.who.int/, (accessed on: August 21st, 2021).[4] A. Alimolaie, A Review of Coronavirus Disease-2019 (COVID-19), Biological Science Promotion Vol. 3, No. 6, 2020, pp. 152-157.[5] J. Yang, Y. Zheng, X. Gou, K. Pu, Z. Chen, Q. Guo et al., Prevalence of Comorbidities and Its Effects in Patients Infected with SARS-Cov-2: A Systematic Review and Meta-Analysis, International Journal of Infectious Diseases, Vol. 94, 2020, pp. 91-95, https://doi.org/10.1016/j.ijid.2020.03.017.[6] H. E. Randolph, L. B. Barreiro, Herd Immunity: Understanding COVID-19, Immunity, Vol. 52, No. 5, 2020, pp. 737-741, https://doi.org/10.1016/j.immuni.2020.04.012.[7] F. Jung, V. Krieger, F. Hufert, J. H. Küpper, Herd Immunity or Suppression Strategy to Combat COVID-19, Clinical Hemorheology and Microcirculation, Vol. 75, No. 1, 2020, pp. 13-17, https://doi.org/10.3233/CH-209006.[8] O. Sharma, A. A. Sultan, H. Ding, C. R. Triggle, A Review of the Progress and Challenges of Developing a Vaccine for COVID-19, Frontiers in Immunology, Vol. 11, No. 2413, 2020, pp. 1-17, https://doi.org/10.3389/fimmu.2020.585354.[9] G. D. Sempowski, K. O. Saunders, P. Acharya, K. J. Wiehe, B. F. Haynes, Pandemic preparedness: Developing Vaccines and Therapeutic Antibodies for COVID-19, Cell, Vol. 181, No. 7, 2020, pp. 1458-1463, https://doi.org/10.1016/j.cell.2020.05. 041.[10] A. J. R. Morales, J. A. C. Ospina, E. G. Ocampo, R. V. Peña, Y. H. Rivera, J. P. E. Antezana et al., Clinical, Laboratory and Imaging Features of COVID-19: A Systematic Review and Meta-Analysis. Travel Medicine and Infectious Disease, Vol. 34, 2020, pp. 101-623, https://doi.org/10.1016/j.tmaid.2020.101623.[11] C. Huang, Y. Wang, X. Li, L. Ren, J. Zhao, Y. Hu et al., Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China, The Lancet, Vol. 395, No. 10223, 2020, pp. 497-506, https://doi.org/10.1016/S0140-6736(20)30183-5.[12] R. Lu, X. Zhao, J. Li, P. Niu, B. Yang, H. Wu et al., Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding, The Lancet, Vol. 395, No. 10224, 2020, pp. 565-574, https://doi.org/10.1016/S0140-6736(20)30251-8.[13] L. Chen, W. Liu, Q. Zhang, K. Xu, G. Ye, W. Wu et al., RNA Based mNGS Approach Identifies a Novel Human Coronavirus From Two Individual Pneumonia Cases in 2019 Wuhan Outbreak, Emerging Microbes & Infections, Vol. 9, No. 1, 2020, pp. 313-319, https://doi.org/10.1080/22221751.2020.1725399.[14] Y. Chen, Q. Liu, D. Guo, Emerging Coronaviruses: Genome Structure, Replication, and Pathogenesis, Journal of Medical Virology, Vol. 92, No. 4, 2020, pp. 418-423, https://doi.org/10.1002/jmv.25681.[15] D. R. Beniac, A. Andonov, E. Grudeski, T. F. Booth, Architecture of The SARS Coronavirus Prefusion Spike, Nature Structural & Molecular Biology, Vol. 13, No. 8, 2006, pp. 751-752, https://doi.org/10.1038/nsmb1123.[16] B. W. Neuman, G. Kiss, A. H. Kunding, D. Bhella, M. F. Baksh, S. Connelly et al., A Structural Analysis of M Protein in Coronavirus Assembly and Morphology, Journal of Structural Biology, Vol. 174, No. 1, 2011, pp. 11-22, https://doi.org/10.1016/j.jsb.2010.11.021.[17] J. L. N. Torres, M. L. DeDiego, C. V. Báguena, J. M. J. Guardeño, J. A. R. Nava, R. F. Delgado et al., Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis, Plos Pathogens Vol. 10, No. 5, 2014, https://doi.org/10.1371/journal.ppat.1004077.[18] A. R. Fehr, S. Perlman. Coronaviruses: An Overview of Their Replication and Pathogenesis. Coronaviruses, New York, 2015, pp. 1-23.[19] M. Letko, A. Marzi, V. Munster, Functional Assessment of Cell Entry and Receptor Usage for SARS-CoV-2 and Other Lineage B Betacoronaviruses,. Nature Microbiology, Vol. 5, No. 4, 2020, pp. 562-569, https://doi.org/10.1038/s41564-020-0688-y.[20] A. Grifoni, D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher et al., Targets of T Cell Responses to SARS-Cov-2 Coronavirus in Humans With COVID-19 Disease and Unexposed Individuals, Cell, Vol. 181, No. 7, 2020, pp. 1489-1501, https://doi.org/10.1016/j.cell.2020.05.015.[21] M. Leslie, T Cells Found in Coronavirus Patients Bode Well for Long-Term Immunity, American Association for the Advancement of Science, Vol. 368, No. 6493, 2020, pp. 809-810, https://doi.org/10.1126/science.368.6493.809.[22] N. L. Bert, A. T. Tan, K. Kunasegaran, C. Y. Tham, M. Hafezi, A. Chia et al., SARS-CoV-2-specific T Cell Immunity in Cases of COVID-19 and SARS, and Uninfected Controls, Nature, Vol. 584, No. 7821, 2020, pp. 457-462, https://doi.org/10.1038/s41586-020-2550-z .[23] E. R. Adams, M. Ainsworth, R. Anand, M. I. Andersson, K. Auckland, J. K. Baillie et al., Antibody Testing for COVID-19: A Report from the National COVID Scientific Advisory Panel, Wellcome Open Research, Vol. 5, 2020, pp. 139-156, https://doi.org/10.12688/wellcomeopenres.15927.1.[24] N. Vabret, G. J. Britton, C. Gruber, S. Hegde, J. Kim, M. Kuksin et al., Immunology of COVID-19: current state of the science, Immunity. Vol. 52, No. 6, 2020, pp. 910-941, https://doi.org/10.1016/j.immuni.2020.05.002[25] W. Liu, A. Fontanet, P. H. Zhang, L. Zhan, Z. T. Xin, L. Baril et al., Two-Year Prospective Study of The Humoral Immune Response of Patients with Severe Acute Respiratory Syndrome, The Journal of Infectious Diseases, Vol. 193, No. 6, 2006, pp. 792-795, https://doi.org/10.1086/500469.[26] E. Callaway, Coronavirus Vaccines Leap Through Safety Trials-But Which Will Work is Anybody's Guess, Nature, Vol. 583, No. 7818, 2020, pp. 669-671, https://doi.org/10.1038/d41586-020-02174-y.[27] Y. Dong, T. Dai, Y. Wei, L. Zhang, M. Zheng, F. Zhou. A Systematic Review of SARS-Cov-2 Vaccine Candidates, Signal Transduction and Targeted Therapy, Vol. 5, No. 1, 2020, pp. 1-14, https://doi.org/10.1038/s41392-020-00352-y. [28] E. P. Regalado, Vaccines for SARS-CoV-2: Lessons from Other Coronavirus Strains. Infectious Diseases and Therapy, Vol. 9, No. 2, 2020, pp. 255-274, https://doi.org/10.1007/s40121-020-00300-x.[29] Y. Cai, J. Zhang, T. Xiao, H. Peng, S. M. Sterling, R. M. Walsh et al., Distinct Conformational States of SARS-CoV-2 Spike Protein, Science, Vol. 369, No. 6511, 2020, pp. 1586-1592, https://doi.org/10.1126/science.abd4251.[30] M. S. Suthar, M. G. Zimmerman, R. C. Kauffman, G. Mantus, S. L. Linderman, W. H. Hudson et al., Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients, Cell Reports Medicine, Vol. 1, No. 3, 2020, pp. 100040-100047, https://doi.org/10.1016/j.xcrm.2020.100040.[31] Q. Gao, L. Bao, H. Mao, L. Wang, K. Xu, M. Yang et al., Development of an Inactivated Vaccine Candidate for SARS-CoV-2, Science, Vol. 36, No. 6499, 2020, pp. 77-81, https://doi.org/10.1126/science.abc1932.[32] L. Ni, F. Ye, M. L. Cheng, Y. Feng, Y. Q. Deng, H. Zhao et al., Detection of SARS-CoV-2-specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals, Immunity, Vol. 52, No. 6, 2020, pp. 971-977, https://doi.org/10.1016/j.immuni.2020.04.023.[33] B. D. Quinlan, H. Mou, L. Zhang, Y. Guo, W. He, A. Ojha et al., The SARS-CoV-2 Receptor-binding Domain Elicits a Potent Neutralizing Response Without Antibody-dependent Enhancement, Available at SSRN, Vol. 3575134, 2020, pp. 1-24, http://dx.doi.org/10.2139/ssrn.3575134.[34] D. B. Melo, B. E. N. Payant, W. C. Liu, S. Uhl, D. Hoagland, R. Moller et al., Imbalanced Host Responseto SARS-Cov-2 Drives Development of COVID-19, Cell, Vol. 181, No. 5, 2020, pp. 1036-1045, https://doi.org/10.1016/j.cell.2020.04.026.[35] J. Hadjadj, N. Yatim, L. Barnabei, A. Corneau, J. Boussier, N. Smith et al., Impaired Type I Interferon Activity and Inflammatory Responses in Severe COVID-19 Patients, Science, Vol. 36, No. 6504, 2020, pp. 718-724, https://doi.org/10.1126/science.abc6027.[36] H. Pang, Y. Liu, X. Han, Y. Xu, F. Jiang, D. Wu et al., Protective Humoral Responses to Severe Acute Respiratory Syndrome-associated Coronavirus: Implications for the Design of an Effective Protein-based Vaccine, Journal of General Virology, Vol. 85, No. 10, 2004, pp. 3109-3113, https://doi.org/10.1099/vir.0.80111-0.[37] Y. Li, R. Tenchov, J. Smoot, C. Liu, S. Watkins, Q. Zhou, A Comprehensive Review of The Global Efforts on COVID-19 Vaccine Development, ACS Central Science , Vol. 7, No. 4, 2021, pp. 512-533, https://doi.org/10.1021/acscentsci.1c00120.[38] J. A. Wolff, R. W. Malone, P. Williams, W. Chong, G. Acsadi, A. Jani et al., Direct Gene Transfer Into Mouse Muscle in Vivo, Science, Vol. 247, No. 4949, 1990, pp. 1465-1468,. https://doi.org/10.1126/science.1690918.[39] M. Ingolotti, O. Kawalekar, D. J. Shedlock, K. Muthumani, D. B. Weiner, DNA Vaccines for Targeting Bacterial Infections, Expert Review of Vaccines, Vol. 9, No. 7, 2010, pp. 747-763, https://doi.org/10.1586/erv.10.57.[40] S. Jones, K. Evans, H. M. Johnn, M. Sharpe, J. Oxford, R. L. Williams et al., DNA Vaccination Protects Against an Influenza Challenge in A Double-Blind Randomised Placebo-Controlled Phase 1b Clinical Trial, Vaccine, Vol. 27, No. 18, 2009, pp. 2506-2512, https://doi.org/10.1016/j.vaccine.2009.02.061.[41] J. Kim, INOVIO Doses First Subject in Phase 2 Segment of its INNOVATE Phase 2/3 Clinical Trial for INO-4800, its DNA Medicine to Prevent COVID-19, Cision PR Newswire: News Distribution, Targeting and Monitoring Home, https://www.prnewswire.com/newsreleases/inovio-doses-first-subject-in-phase-2-segment-of-its-innovate-phase-23-clinical-trial-for-ino-4800-its-dna-medicine-to-prevent-covid-19-301187002.html/, 2020, (accessed on: December 7th, 2020).[42] P. Tebas, S. Yang, J. D. Boyer, E. L. Reuschel, A. Patel, A. C. Quick et al., Safety and Immunogenicity of INO-4800 DNA Vaccine Against SARS-Cov-2: A Preliminary Report of an Open-Label, Phase 1 Clinical Trial, EClinical Medicine, Vol. 31, No. 1000689, 2021, https://doi.org/10.1016/j.eclinm.2020.100689.[43] T. Schlake, A. Thess, M. F. Mleczek, K. J. Kallen. Developing mRNA-vaccine Technologies, RNA Biology, Vol. 9, No. 11, 2012, pp. 1319-1330, https://doi.org/10.4161/rna.22269.[44] K. J. Hassett, K. E. Benenato, E. Jacquinet, A. Lee, A. Woods, O. Yuzhakov et al., Optimization of lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines, Molecular Therapy-Nucleic Acids, Vol. 15, 2019, pp. 1-11, https://doi.org/10.1016/j.omtn.2019.01.013.[45] A. Bashirullah, R. L. Cooperstock, H. D. Lipshitz, Spatial and Temporal Control of RNA Stability, Proceedings of the National Academy of Sciences, Vol. 98, No. 13, 2001, pp. 7025-7028. [46] K. Kariko, H. Muramatsu, J. Ludwig, D. Weissman, Generating the Optimal mRNA for Therapy: HPLC Purification Eliminates Immune Activation and Improves Translation of Nucleoside-Modified, Protein-Encoding mRNA, Nucleic Acids Research, Vol. 39, No. 21, 2011, pp. 142-152, https://doi.org/10.1093/nar/gkr695.[47] N. Pardi, M. J. Hogan, M. S. Naradikian, K. Parkhouse, D. W. Cain, L. Jones et al., Nucleoside-Modified mRNA Vaccines Induce Potent T Follicular Helper and Germinal Center B Cell Responses, Journal of Experimental Medicine, Vol. 215, No. 6, 2018, pp. 1571-1588, https://doi.org/10.1084/jem.20171450.[48] L. A. Jackson, E. J. Anderson, N. G. Rouphael, P. C. Roberts, M. Makhene, R. N. Coler et al., An mRNA Vaccine Against SARS-CoV-2-Preliminary Report, New England Journal of Medicine, Vol. 383, No. 20, 2020, pp. 1920-1931, https://doi.org/10.1056/NEJMoa2022483.[49] K. S. Corbett, D. K. Edwards, S. R. Leist, O. M. Abiona, S. B. Barnum, R. A. Gillespie et al., SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness, Nature, Vol. 586, No. 7830, 2020, pp. 567-571, https://doi.org/10.1038/s41586-020-2622-0.[50] K. S. Corbett, B. Flynn, K. E. Foulds, J. R. Francica, S. B. Barnum, A. P. Werner et al., Evaluation of the mRNA-1273 Vaccine Against SARS-CoV-2 in Nonhuman Primates, New England Journal of Medicine, Vol. 383, No. 16, 2020, pp. 1544-1555, https://doi.org/10.1056/NEJMoa2024671.[51] E. E. Walsh, R. Frenck, A. R. Falsey, N. Kitchin, J. Absalon, A. Gurtman et al., RNA-Based COVID-19 Vaccine BNT162b2 Selected for a Pivotal Efficacy Study, Medrxiv, Vol. 2, 2020, https://doi.org/10.1101/2020.08.17.20176651.[52] M. J. Mulligan, K. E. Lyke, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart et al., Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report, Medrxiv, Vol. 586, 2020, pp. 589-593, https://doi.org/10.1056/NEJMoa2028436.[53] E. J. Anderson, N. G. Rouphael, A. T. Widge, L. A. Jackson, P. C. Roberts, M. Makhene et al., Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults, New England Journal of Medicine, Vol. 383, No. 25, 2020, pp. 2427-2438, https://doi.org/10.1038/s41586-020-2639-4.[54] P. F. McKay, K. Hu, A. K. Blakney, K. Samnuan, J. C. Brown, R. Penn et al., Self-amplifying RNA SARS-CoV-2 Lipid Nanoparticle Vaccine Candidate Induces High Neutralizing Antibody Titers in Mice, Nature Communications, Vol. 11, No. 1, 2020, pp. 1-7, https://doi.org/10.1038/s41467-020-17409-9.[55] J. H. Erasmus, A. P. Khandhar, A. C. Walls, E. A. Hemann, M. A. O’Connor, P. Murapa et al., Single-dose Replicating RNA vaccine Induces Neutralizing Antibodies Against SARS-CoV-2 in Nonhuman Primates, BioRxiv, 2020, https://doi.org/10.1101/2020.05.28.121640.[56] R. D. Alwis, E. S. Gan, S. Chen, Y. S. Leong, H. C. Tan, S. L. Zhang et al., A Single Dose of Self-Transcribing and Replicating RNA-based SARS-CoV-2 Vaccine Produces Protective Adaptive Immunity in Mice, Molecular Therapy, Vol. 29, No. 6, 2021, pp. 1970-1983, https://doi.org/10.1016/j.ymthe.2021.04.001.[57] M. R. Guroff, Replicating and Non-Replicating Viral Vectors for Vaccine Development, Current Opinion in Biotechnology, Vol. 18, No. 6, 2007, pp. 546-556, https://doi.org/10.1016/j.copbio.2007.10.010.[58] K. Benihoud, P. Yeh, M. Perricaudet, Adenovirus Vectors for Gene Delivery, Current Opinion in Biotechnology, Vol. 10, No. 5,1999, pp. 440-447, https://doi.org/10.1016/s0958-1669(99)00007-5.[59] Z. Xiang, G. Gao, A. R. Sandoval, C. J. Cohen, Y. Li, J. M. Bergelson et al., Novel, Chimpanzee Serotype 68-Based Adenoviral Vaccine Carrier for Induction of Antibodies to A Transgene Product, Journal of Virology, Vol. 76, No. 6, 2002, pp. 2667-2675, https://doi.org/10.1128/JVI.76.6.2667-2675.2002.[60] F. C. Zhu, X. H. Guan, Y. H. Li, J. Y. Huang, T. Jiang, L. H. Hou et al., Immunogenicity and Safety Of A Recombinant Adenovirus Type-5-Vectored COVID-19 Vaccine in Healthy Adults Aged 18 Years or Older: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial, The Lancet, Vol. 396, No. 10249, 2020, pp. 479-488, https://doi.org/10.1016/S0140-6736(20)31605-6.[61] F. C. Zhu, Y. H. Li, X. H. Guan, L. H. Hou, W. J. Wang, J. X. Li et al., Safety, Tolerability, and Immunogenicity of A Recombinant Adenovirus Type-5 Vectored COVID-19 Vaccine: A Dose-Escalation, Open-Label, Non-Randomised, First-in-Human Trial, The Lancet. Vol. 395, No. 10240, 2020, pp. 1845-1854.[62] S. Wu, G. Zhong, J. Zhang, L. Shuai, Z. Zhang, Z. Wen, et al. A Single Dose of An Adenovirus-Vectored Vaccine Provides Protection Against SARS-Cov-2 Challenge, Nature Communications Vol. 1, No. 11, 2020, pp. 1-7, https://doi.org/10.1016/s41467-020-17972-1.[63] P. M. Folegatti, K. J. Ewer, P. K. Aley, B. Angus, S. Becker, S. B. Rammerstorfer 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, The Lancet, Vol. 396, No. 10249, 2020, pp. 467-478, https://doi.org/10.1016/S0140-6736(20)31604-4.[64] N. V. Doremalen, T. Lambe, A. Spencer, S. B. Rammerstorfer, J. N. Purushotham, J. R. Port et al., ChAdOx1 nCoV-19 Vaccine Prevents SARS-Cov-2 Pneumonia in Rhesus Macaques, Nature, Vol. 586, No. 7830, 2020, pp. 578-582, https://doi.org/10.1016/s41586-020-2608-y.[65] D. Y. Logunov, I. V. Dolzhikova, O. V. Zubkova, A. I. Tukhvatullin, D. V. Shcheblyakov, A. S. Dzharullaeva et al., Safety and Immunogenicity of an Rad26 And Rad5 Vector-Based Heterologous Prime-Boost COVID-19 Vaccine in Two Formulations: Two Open, Non-Randomised Phase 1/2 Studies From Russia, The Lancet, Vol. 396, No. 10255, 2020, pp. 887-897, https://doi.org/10.1016/S0140-6736(20)31866-3.[66] S. Y. Jung, K. W. Kang, E. Y. Lee, D. W. Seo, H. L. Kim, H. Kim et al., Heterologous Prime-Boost Vaccination with Adenoviral Vector and Protein Nanoparticles Induces Both Th1 and Th2 Responses Against Middle East Respiratory Syndrome Coronavirus, Vaccine, Vol. 36, No. 24, 2018, pp. 3468-3476, https://doi.org/10.1016/j.vaccine.2018.04.082.[67] S. Lu, Heterologous Prime-Boost Vaccination. Current Opinion in Immunology, Vol. 21, No. 3, 2009, pp. 346-351, https://doi.org/10.1016/j.coi.2009.05.016.[68] D. Y. Logunov, I. V. Dolzhikova, D. V. Shcheblyakov, A. I. Tukhvatulin, O. V. Zubkova, A. S. Dzharullaeva et al., Safety and Efficacy of an Rad26 and Rad5 Vector-Based Heterologous Prime-Boost COVID-19 Vaccine: an Interim Analysis of A Randomised Controlled Phase 3 Trial in Russia, The Lancet, Vol. 397, No. 10275, 2021, pp. 671-681, https://doi.org/10.1016/S0140-6736(21)00234-8.[69] T. Ura, K. Okuda, M. Shimada. Developments in Viral Vector-Based Vaccines, Vaccines, Vol. 2, No. 3, 2014, pp. 624-641, https://doi.org/10.3390/vaccines2030624.[70] B. E. Bache, M. P. Grobusch, S. T. Agnandji. Safety, Immunogenicity and Risk-Benefit Analysis of Rvsv-ΔG-ZEBOV-GP (V920) Ebola Vaccine in Phase I-III Clinical Trials Across Regions. Future Microbiology, Vol. 15, No. 2, 2020, pp. 85-106, https://doi.org/10.2217/fmb-2019-0237.[71] Ebola Vaccines, NIH: National Institute of Allergy and Infectious Diseases Logo, 2020, https://www.niaid.nih.gov/diseases-conditions/ebola-vaccines/, (accessed on: January 9th, 2020).[72] F. Krammer, SARS-CoV-2 Vaccines in Development, Nature, Vol. 586, No. 7830, 2020, pp. 516-527, https://doi.org/10.1038/s41586-020-2798-3.[73] Y. Zhang, G. Zeng, H. Pan, C. Li, Y. Hu, K. Chu 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, The Lancet Infectious Diseases, Vol. 21, No. 2, 2021, pp. 181-192, https://doi.org/10.1016/S1473-3099(20)30843-4.[74] Sinovac Announces Phase III Results of Its COVID-19 Vaccine, Sinovac, 2021. https://www.businessswwire.com/news/home/20210205005496/en/Sinovac-Announces-Phase-III-Results-of-Its-COVID-19-Vaccine/, 2021, (accessed on: February 5th,2021).[75] Sinovac Receives Conditional Marketing Authorization in China for its COVID-19 Vaccine. Sinovac, https://www.businessswwire.com/news/ home/20210208005305/en/Sinovac-Receives-Conditional-Marketing-Authorization-in-China-for-its-COVID-19-Vaccin/, 2021, (accessed on: February 8th, 2021).[76] L. M. Rossen, A. M. Branum, F. B. Ahmad, P. Sutton, R. N. Anderson, Excess Deaths Associated with COVID-19, by Age and Race and Ethnicity-United States, January 26-October 3, 2020, Morbidity and Mortality Weekly Report, Vol. 69, No. 42, 2020, pp. 1522-1527.[77] China Grants Conditional Market Approval for Sinopharm CNBG’s COVID-19 Vaccine. Sinopharm, http://www.sinopharm.com/en/s/1395-4173-38862.html/, 2021, (accessed on: January 2nd, 2021).[78] V. A. Fulginiti, J. J. Eller, A. W. Downie, C. H. Kempe, Altered Reactivity to Measles Virus: Atypical Measles in Children Previously Immunized with Inactivated Measles Virus Vaccines, Jama, Vol. 202, No. 12, 1967, pp. 1075-1080, https://doi.org/10.1001/jama.1967.03130250057008.[79] H. W. Kim, J. G. Canchola, C. D. Brandt, G. Pyles, R. M. Chanock, K. Jensen et al., Respiratory Syncytial Virus Disease in Infants Despite Prior Administration of Antigenic Inactivated Vaccine. American Journal of Epidemiology, Vol. 89, No. 4, 1969, pp. 422-434, https://doi.org/10.1093/oxfordjournals.aje.a120955.[80] Novavax Confirms High Levels of Efficacy Against Original and Variant COVID-19 Strains in United Kingdom and South Africa Trials, Novavax 2021, https://www.prnewswire.com/news-releases/novavax-confirms-high-levels-of-efficacy-against-original-and-variant-covid-19-strains-in-united-kingdom-and-south-africa-trials-301246019.html/, (accessed on: March 11th, 2021).[81] Our Vaccine, Covaxx, 2020, https://www.gavi.org/covax-vaccine-roll-out/, (accessed on: August 14th, 2021).[82] M. O. Mohsen, G. Augusto, M. F. Bachmann, The 3Ds in Virus‐like Particle Based‐vaccines: Design, Delivery and Dynamics, Immunological Reviews Vol. 296, No. 1, 2020, pp. 155-168, https://doi.org/10.1111/imr.12863.