Recent challenges and progress of potential vaccines for Coronavirus disease 2019 (COVID-19)

Arvind Kumar Yadav, Rohit Shukla, Harish Changotra, Tiratha Raj Singh


The pandemic of COVID-19 emerged at the end of 2019 and spread rapidly in almost all the countries around the world. This has become a severe global health concern. COVID-19 pandemic is still spreading and reoccurring, so vaccines are urgently needed to control the spreading of this epidemic. Facts have shown that vaccines are the most successful and efficient way to combat and manage infectious diseases. Enormous efforts have been made by government, industry, and academia to develop successful vaccines in a few months span. Some vaccines have been evaluated for efficiency in animal and preliminary clinical trials. This brief review summarizes the approaches used in the vaccines design and focuses on the progress of COVID-19 vaccine development. We have also highlighted the challenges faced in the development of COVID-19 vaccines.


Coronavirus, COVID-19, Vaccine, Antigenic protein, Immunoinformatics

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Banerjee A, Kulcsar K, Misra V, Frieman M, Mossman K. Bats and Coronaviruses. Viruses. 2019;11(1).

Available from:

Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annual Review of Virology.


Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W. Perspectives on monoclonal

antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac

J Allergy Immunol. 2020;38(1):10–8.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell

Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell.


Du L, He Y, Zhou Y, Liu S, Zheng B-J, Jiang S. The spike protein of SARS-CoV — a target for vaccine

and therapeutic development. Nature Reviews Microbiology. 2009;7(3):226–36.

Whitworth J. COVID-19: a fast evolving pandemic. Trans R Soc Trop Med Hyg. 2020;114(4):241–8.

Gralinski LE, Menachery VD. Return of the Coronavirus: 2019-nCoV. Viruses [Internet]. 2020 Feb [cited

;12(2). Available from:

Lai C-C, Shih T-P, Ko W-C, Tang H-J, Hsueh P-R. Severe acute respiratory syndrome coronavirus 2

(SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges.

International Journal of Antimicrobial Agents. 2020;55(3):105924.

Coleman CM, Frieman MB. Coronaviruses: Important Emerging Human Pathogens. J Virol.


Coronavirus disease (COVID-19): Vaccines. Available from:

Shamim S, Khan M, Kharaba ZJ, Ijaz M, Murtaza G. Potential strategies for combating COVID-19. Arch

Virol. 2020; Available from:

Shukla R, Yadav AK, Singh TR. Application of Deep Learning in Biological Big Data Analysis

[Internet]. Large-Scale Data Streaming, Processing, and Blockchain Security. IGI Global; 2021. p. 117–

Available from:

Chandra Kaushik A, Raj U. AI-driven drug discovery: A boon against COVID-19? AI Open. 2020;1:1–4.

Gupta E, Mishra RK, Niraj RRK. Identification of potential vaccine candidates against SARS-CoV-2, A

step forward to fight novel coronavirus 2019-nCoV: A Reverse Vaccinology Approach. bioRxiv. 2020


Crossman LC. Leveraging Deep Learning to Simulate Coronavirus Spike proteins has the potential to

predict future Zoonotic sequences. bioRxiv. 2020;2020.04.20.046920.

Keshavarzi Arshadi A, Webb J, Salem M, Cruz E, Calad-Thomson S, Ghadirian N, et al. Artificial

Intelligence for COVID-19 Drug Discovery and Vaccine Development. Front Artif Intell. 2020;3.

Available from:

Rémy V, Zöllner Y, Heckmann U. Vaccination: the cornerstone of an efficient healthcare system. J Mark

Access Health Policy. 2015;3. Available from:

Sagar M, Yadav AK. Computer-aided vaccine design for liver cancer using epitopes of HBx protein

isolates from HBV substrains. Int J Bioinform Res Appl. 2011;7(3):299–316.

Shin MD, Shukla S, Chung YH, Beiss V, Chan SK, Ortega-Rivera OA, et al. COVID-19 vaccine

development and a potential nanomaterial path forward. Nature Nanotechnology. 2020;15(8):646–55.

Lundstrom K. Coronavirus Pandemic—Therapy and Vaccines. Biomedicines. 2020;8(5). Available from:

Naz A, Shahid F, Butt TT, Awan FM, Ali A, Malik A. Designing Multi-Epitope Vaccines to Combat

Emerging Coronavirus Disease 2019 (COVID-19) by Employing Immuno-Informatics Approach. Front

Immunol. 2020;11. Available from:

De Groot AS, Moise L, Terry F, Gutierrez AH, Hindocha P, Richard G, et al. Better Epitope Discovery,

Precision Immune Engineering, and Accelerated Vaccine Design Using Immunoinformatics Tools. Front

Immunol. 2020;11. Available from:

Chandra S, Singh TR. Linear B cell epitope prediction for epitope vaccine design against meningococcal

disease and their computational validations through physicochemical properties. Netw Model Anal Health

Inform Bioinforma. 2012;1(4):153–9.

Gupta A, Chaukiker D, Singh TR. Comparative analysis of epitope predictions: proposed library of

putative vaccine candidates for HIV. Bioinformation. 2011;5(9):386–9.

Chandra S, Singh D, Singh TR. Prediction and characterization of T-cell epitopes for epitope vaccine

design from outer membrane protein of Neisseria meningitidis serogroup B. Bioinformation.


Baruah V, Bose S. Immunoinformatics-aided identification of T cell and B cell epitopes in the surface

glycoprotein of 2019-nCoV. Journal of Medical Virology. 2020;92(5):495–500.

Calina D, Docea AO, Petrakis D, Egorov AM, Ishmukhametov AA, Gabibov AG, et al. Towards effective

COVID-19 vaccines: Updates, perspectives and challenges (Review). Int J Mol Med. 2020;46(1):3–16.

van Riel D, de Wit E. Next-generation vaccine platforms for COVID-19. Nature Materials.


Siu YL, Teoh KT, Lo J, Chan CM, Kien F, Escriou N, et al. The M, E, and N Structural Proteins of the

Severe Acute Respiratory Syndrome Coronavirus Are Required for Efficient Assembly, Trafficking, and

Release of Virus-Like Particles. Journal of Virology. 2008;82(22):11318–30.

Zhang J, Zeng H, Gu J, Li H, Zheng L, Zou Q. Progress and Prospects on Vaccine Development against

SARS-CoV-2. Vaccines (Basel). 2020;8(2).

Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virology Journal.


Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, et al. Cryo-EM structure of the

-nCoV spike in the prefusion conformation. Science. 2020 13;367(6483):1260–3.

Roper RL, Rehm KE. SARS vaccines: where are we? Expert Rev Vaccines. 2009;8(7):887–98.

de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging

coronaviruses. Nat Rev Microbiol. 2016;14(8):523–34.

McBride R, van Zyl M, Fielding BC. The Coronavirus Nucleocapsid Is a Multifunctional Protein.

Viruses. 2014;6(8):2991–3018.

Leung DTM, Chi Hang TF, Chun Hung M, Sheung Chan PK, Cheung JLK, Niu H, et al. Antibody

Response of Patients with Severe Acute Respiratory Syndrome (SARS) Targets the Viral Nucleocapsid. J

Infect Dis. 2004;190(2):379–86.

Neuman BW, Kiss G, Kunding AH, Bhella D, Baksh MF, Connelly S, et al. A structural analysis of M

protein in coronavirus assembly and morphology. J Struct Biol. 201;174(1):11–22.

Liu J, Sun Y, Qi J, Chu F, Wu H, Gao F, et al. The membrane protein of severe acute respiratory

syndrome coronavirus acts as a dominant immunogen revealed by a clustering region of novel

functionally and structurally defined cytotoxic T-lymphocyte epitopes. J Infect Dis. 2010;202(8):1171–

Nieto-Torres JL, DeDiego ML, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, FernandezDelgado R, et al. Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel

Activity Promotes Virus Fitness and Pathogenesis. PLOS Pathogens. 2014;10(5):e1004077.

Amanat F, Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020;52(4):583–9.

Vartak A, Sucheck SJ. Recent Advances in Subunit Vaccine Carriers. Vaccines. 2016;4(2). Available


Dhama K, Sharun K, Tiwari R, Dadar M, Malik YS, Singh KP, et al. COVID-19, an emerging

coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics,

and therapeutics. Hum Vaccin Immunother. 2020;1–7.

Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug

Discov. 2018;17(4):261–79.

Liu MA. A Comparison of Plasmid DNA and mRNA as Vaccine Technologies. Vaccines. 2019;7(2).

Available from:

Gonzalez-Nicolini V, Sanchez-Bustamante CD, Hartenbach S, Fussenegger M. Adenoviral vector

platform for transduction of constitutive and regulated tricistronic or triple-transcript transgene expression

in mammalian cells and microtissues. J Gene Med. 2006;8(10):1208–22.

Bull JJ, Smithson MW, Nuismer SL. Transmissible Viral Vaccines. Trends Microbiol. 2018;26(1):6–15.

Azmi F, Ahmad Fuaad AAH, Skwarczynski M, Toth I. Recent progress in adjuvant discovery for peptidebased subunit vaccines. Hum Vaccin Immunother. 2014;10(3):778–96.

Li W, Joshi MD, Singhania S, Ramsey KH, Murthy AK. Peptide Vaccine: Progress and Challenges.

Vaccines (Basel). 2014;2(3):515–36.

Delrue I, Verzele D, Madder A, Nauwynck HJ. Inactivated virus vaccines from chemistry to prophylaxis:

merits, risks and challenges. Expert Rev Vaccines. 2012;11(6):695–719.

Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, et al. Gene therapy of X-linked severe

combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004


Ura T, Okuda K, Shimada M. Developments in Viral Vector-Based Vaccines. Vaccines (Basel). 2014


Draft landscape of COVID-19 candidate vaccines. 2020. Available from:

Noranate N, Takeda N, Chetanachan P, Sittisaman P, A-nuegoonpipat A, Anantapreecha S.

Characterization of Chikungunya Virus-Like Particles. PLOS ONE. 2014;9(9):e108169.

Changotra H, Vij A. Rotavirus virus-like particles (RV-VLPs) vaccines: An update. Rev Med Virol.


Dong H, Guo H-C, Sun S-Q. Virus-like particles in picornavirus vaccine development. Appl Microbiol

Biotechnol. 2014;98(10):4321–9.

Steinmetz KL, Spack EG. The basics of preclinical drug development for neurodegenerative disease

indications. BMC Neurol. 2009;9(Suppl 1):S2.

Honek J. Preclinical research in drug development. MEW. 2017;26:5–8.

Poland GA, Ovsyannikova IG, Jacobson RM. Application of pharmacogenomics to vaccines.

Pharmacogenomics. 2009;10(5):837–52.

Nandal S, Burt T. Integrating Pharmacoproteomics into Early-Phase Clinical Development: State-of-theArt, Challenges, and Recommendations. Int J Mol Sci. 2017;18(2). Available from:

Sutton TC, Subbarao K. Development of animal models against emerging coronaviruses: From SARS to

MERS coronavirus. Virology. 2015;479–480:247–58.

Gretebeck LM, Subbarao K. Animal models for SARS and MERS coronaviruses. Curr Opin Virol.


Yang X-H, Deng W, Tong Z, Liu Y-X, Zhang L-F, Zhu H, et al. Mice transgenic for human angiotensinconverting enzyme 2 provide a model for SARS coronavirus infection. Comp Med. 2007;57(5):450–9.

Falzarano D, Wit E de, Feldmann F, Rasmussen AL, Okumura A, Peng X, et al. Infection with MERSCoV Causes Lethal Pneumonia in the Common Marmoset. PLOS Pathogens. 2014;10(8):e1004250.

Muñoz-Fontela C, Dowling WE, Funnell SGP, Gsell P-S, Riveros-Balta AX, Albrecht RA, et al. Animal

models for COVID-19. Nature. 2020;586(7830):509–15.

Yong CY, Ong HK, Yeap SK, Ho KL, Tan WS. Recent Advances in the Vaccine Development Against

Middle East Respiratory Syndrome-Coronavirus. Front Microbiol. 2020;10. Available from:

Gerdts V, Wilson HL, Meurens F, van Drunen Littel-van den Hurk S, Wilson D, Walker S, et al. Large

animal models for vaccine development and testing. ILAR J. 2015;56(1):53–62.

Kristensen DD, Lorenson T, Bartholomew K, Villadiego S. Can thermostable vaccines help address coldchain challenges? Results from stakeholder interviews in six low- and middle-income countries. Vaccine.


Luzze H, Badiane O, Mamadou Ndiaye EH, Ndiaye AS, Atuhaire B, Atuhebwe P, et al. Understanding

the policy environment for immunization supply chains: Lessons learned from landscape analyses in

Uganda and Senegal. Vaccine. 2017;35(17):2141–7.

Azimi T, Franzel L, Probst N. Seizing market shaping opportunities for vaccine cold chain equipment.

Vaccine. 2017;35(17):2260–4.

Sun T, Han H, Hudalla GA, Wen Y, Pompano RR, Collier JH. Thermal stability of self-assembled peptide

vaccine materials. Acta Biomater. 2016;30:62–71.

Konar M, Pajon R, Beernink PT. A meningococcal vaccine antigen engineered to increase thermal

stability and stabilize protective epitopes. Proc Natl Acad Sci U S A. 2015;112(48):14823–8.

Rossi R, Konar M, Beernink PT. Meningococcal Factor H Binding Protein Vaccine Antigens with

Increased Thermal Stability and Decreased Binding of Human Factor H. Infect Immun. 2016;84(6):1735–

Campeotto I, Goldenzweig A, Davey J, Barfod L, Marshall JM, Silk SE, et al. One-step design of a stable

variant of the malaria invasion protein RH5 for use as a vaccine immunogen. Proceedings of the National

Academy of Sciences of the United States of America. 2017;114(5):998–1002.

Stobart CC, Rostad CA, Ke Z, Dillard RS, Hampton CM, Strauss JD, et al. A live RSV vaccine with

engineered thermostability is immunogenic in cotton rats despite high attenuation. Nat Commun.


Leung V, Mapletoft J, Zhang A, Lee A, Vahedi F, Chew M, et al. Thermal Stabilization of Viral Vaccines

in Low-Cost Sugar Films. Scientific Reports. 2019;9(1):7631.

Pelliccia M, Andreozzi P, Paulose J, D’Alicarnasso M, Cagno V, Donalisio M, et al. Additives for

vaccine storage to improve thermal stability of adenoviruses from hours to months. Nature

Communications. 2016;7(1):13520.

Chu LY, Ye L, Dong K, Compans RW, Yang C, Prausnitz MR. Enhanced Stability of Inactivated

Influenza Vaccine Encapsulated in Dissolving Microneedle Patches. Pharm Res. 2016;33(4):868–78.

Mistilis MJ, Joyce JC, Esser ES, Skountzou I, Compans RW, Bommarius AS, et al. Long-term stability of

influenza vaccine in a dissolving microneedle patch. Drug Deliv Transl Res. 2017;7(2):195–205.

Hassett KJ, Vance DJ, Jain NK, Sahni N, Rabia LA, Cousins MC, et al. Glassy-state stabilization of a

dominant negative inhibitor anthrax vaccine containing aluminum hydroxide and glycopyranoside lipid A

adjuvants. J Pharm Sci. 2015;104(2):627–39.

Hassett KJ, Cousins MC, Rabia LA, Chadwick CM, O’Hara JM, Nandi P, et al. Stabilization of a

recombinant ricin toxin A subunit vaccine through lyophilization. European Journal of Pharmaceutics and

Biopharmaceutics. 2013;85(2):279–86.

Chen D, Kapre S, Goel A, Suresh K, Beri S, Hickling J, et al. Thermostable formulations of a hepatitis B

vaccine and a meningitis A polysaccharide conjugate vaccine produced by a spray drying method.

Vaccine. 2010 12;28(31):5093–9.