Review Biomol Ther 29(1), 1-10 (2021) COVID-19 Vaccine: Critical Questions with Complicated Answers Mohammad Faisal Haidere1,†, Zubair Ahmed Ratan2,3,†, Senjuti Nowroz4, Sojib Bin Zaman5, You-Jung Jung6, Hassan Hosseinzadeh2,* and Jae Youl Cho7,* 1Department of Soil, Water and Environment, University of Dhaka, Dhaka 1000, Bangladesh 2School of Health & Society, University of Wollongong, NSW 2500, Australia 3Department of Biomedical Engineering, Khulna University of Engineering and Technology, Khulna 9203, Bangladesh 4Department of Chemistry, University of Dhaka, Dhaka 1000, Bangladesh 5Department of Medicine, School of Clinical Sciences, Monash University, Victoria 3800, Australia 6Biological Resources Utilization Department, National Institute of Biological Resources, Incheon 22689, Republic of Korea 7Department of Integrative Biotechnology, and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea Abstract COVID-19 has caused extensive human casualties with significant economic impacts around the globe, and has imposed new challenges on health systems worldwide. Over the past decade, SARS, Ebola, and Zika also led to significant concerns among the scientific community. Interestingly, the SARS and Zika epidemics ended before vaccine development; however, the scholarly com- munity and the pharmaceutical companies responded very quickly at that time. Similarly, when the genetic sequence of SARS- CoV-2 was revealed, global vaccine companies and scientists have stepped forward to develop a vaccine, triggering a race toward vaccine development that the whole world is relying on. Similarly, an effective and safe vaccine could play a pivotal role in eradi- cating COVID-19. However, few important questions regarding SARS-CoV-2 vaccine development are explored in this review. Key Words: COVID-19, Vaccine, Vaccine backfires, Vaccine safety INTRODUCTION vember 2002 in the Guangdong province of China. After that epidemic, China reported more than 8,000 cases of disease Humans have a long history of battling against the viruses. and 774 deaths with a case-fatality rate of 7%. A decade later The constant battle between viruses and scientists has been in 2012, Middle East respiratory syndrome CoV (MERS-CoV) recognized as a key driver of medical advances. In this series first emerged in Saudi Arabia, with a total of 2,494 laboratory- of battles, the latest one is the outbreak of a novel coronavi- confirmed cases and 858 deaths with a case-fatality ratio of rus, COVID-19, originating in the Wuhan region of China in 34.4% (Corman et al., 2018; Peeri et al., 2020). However, CO- late December 2019 (Ratan et al., 2020). COVID-19 has af- VID-19 has caused a pandemic that has compelled the global fected at least 216 countries, areas or territories around the economy to grind to a halt. A vaccine remains the best op- world. So far, there had been approximately 54 million 301 tion for restoring normal life and global economies. This has thousand 156 cases and one million 316 thousand 994 deaths triggered a vaccine development race. According to Mullard’s confirmed globally due to this deadly virus by November 16, report (Mullard, 2020), as of 11 November 2020, there were 2020 (World Health Organization, 2020). Prior to the emer- 259 COVID-19 vaccine projects going on around the world. Of gence of Severe Acute Respiratory Syndrome CoV-2 (SARS- those, there were 79 protein, 16 virus-like particle, 22 DNA, 33 CoV-2), there were six human CoVs (HCoVs), including that RNA, 36 non-replicating and 20 replicating viral vector, 15 in- which caused the SARS global outbreak that started in No- activated and four live-attenuated, and 35 other vaccines can- Open Access https://doi.org/10.4062/biomolther.2020.178 Received Oct 13, 2020 Revised Nov 26, 2020 Accepted Dec 2, 2020 Published Online Jan 1, 2021 This is an Open Access article distributed under the terms of the Creative Com- mons Attribution Non-Commercial License (http://creativecommons.org/licens- *Corresponding Authors es/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, E-mail: [email protected] (Cho JY), and reproduction in any medium, provided the original work is properly cited. [email protected] (Hosseinzadeh H) Tel: +82-31-290-7868 (Cho JY), +61-2-4221-5351 (Hosseinzadeh H) Fax: +82-31-290-7870 (Cho JY), +61-2-4221-5945 (Hosseinzadeh H) †The first two authors contributed equally to this work. Copyright © 2021 The Korean Society of Applied Pharmacology www.biomolther.org 1 Biomol Ther 29(1), 1-10 (2021) Fig. 1. State of the vaccine race for COVID-19. Figure 1: State of the vaccine race for COVID-19 didate in development pipeline. Among them, 204 were still in 1a/b) comprises two-thirds of the total viral genome (~30 kb) the preclinical stage; 11 candidates were reached phase III and encodes 16 non-structure proteins. This ORF 1a/b has clinical trial stage, and the remaining were in between these the genetic function to roll-out the viral replication that con- stages (Fig. 1) (London School of Hygiene and Tropical Medi- trols the production of cellular proteins and keeps evading cine, 2020). the immune system of the host. The remaining portion of the A vaccine introduces the structure and biological agents of genome codes for four basic structural proteins, including a specific virus to antigen-presenting cells of the host, which spike (S) glycoprotein, small envelope (E) protein, matrix (M) engulf it and pass portions of it to activate helper T (Th) cells. protein, and nucleocapsid (N) protein, and several other ac- The Th cells then trigger other immune responses i.e., acti- cessory proteins (Guo et al., 2020). The crucial part of SARS- vation of B cells and cytotoxic T (Tc) cells. B cells produce CoV-19 and COVID-19 infection begins when the S protein antibodies that can prevent the virus from infecting cells, while of this pathogen binds to angiotensin-converting enzyme 2 Tc cells recognize and kill cells that are infected with the virus, (ACE2), a cellular receptor of the host (Fig. 2A). After binding that help the surveillance cells of the body to track the virus for to the ACE2 receptor, the conformation shift in the S protein long periods (Fig. 2B). In principle, understanding the etiology, enables fusion of the viral envelope with the cell membrane epidemiology, pathogenesis and immunobiology of the infec- via the endosomal pathway. Then, the virus enters the cell tion is of the utmost importance for the development of vac- and releases its RNA. This RNA then goes through transcrip- cines (Zepp, 2010). Thus, a few simple questions, although tion, translation, and replication. In this production line, RNA complicated to answer, have arisen regarding the basic prin- is translated into replicase polyproteins pp1a and 1ab, and ciples of vaccines that need to be resolved with regard to CO- those are then severed by viral proteinase into small products. VID-19 vaccine development. Here, we aim to address those Polymerase by discontinuous transcription yields a sequence simple questions. of subgenomic mRNAs that are eventually transformed into specific viral proteins. Subsequently, in the endoplasmic retic- ulum and Golgi apparatus, viral proteins and genome RNA are STRUCTURE AND PATHOPHYSIOLOGY OF packaged into the virion and then transported through vesicles COVID-19 to be released from the cell (Shereen et al., 2020). SARS-CoV-2 is a β-coronavirus belonging to the Sarbe- covirus subgenus of the Coronaviridae family, and is envel- TYPES OF VACCINE oped with non-segmented positive-sense RNA virus (Zhu et al., 2020). In broad terms, the genome of this virus can be The Coalition for Epidemic Preparedness Innovations divided into two parts. The first open reading frame (ORF (CEPI), a multilateral and multinational stakeholders foun- https://doi.org/10.4062/biomolther.2020.178 2 19 Haidere et al. COVID-19 Vaccine and Important Questions Fig. 2. COVID-19 and the vaccine. (A) A simple representation of the COVID-19 infection mechanism in the body. (B) Basic principles of vaccines in generalized form. Figure 2: COVID-19 and the vaccine. A) A simple representation of the COVID-19 infection dation for the development of vaccine against infectious dis- voke all the requisite steps leading to immune system activa- eases,mecha informednism in in theSeptember body. 2020 B) Bthatasic the princip nine separateles of vaccition nines vivo in, andgene to rprovidealized a for non-virulent,m. harmless type of technological platforms are being used to make an effective a given agent capable of generating a strong and adequate vaccine against SARS-CoV-2 (Gopinathan et al., 2020). Sci- immune response tailored against specific viral attack (Moser entist around the world using both the classical and next-gen- and Leo, 2010). Thus, some questions arise regarding the de- eration platforms. The classical platforms are whole-inactivat- velopment of the vaccine (see Table 1 for current development ed virus, live-attenuated virus, protein subunit, and virus-like state of COVID-19 vaccines) that will be administered to bil- particles, and the next-generation platforms are nucleic acids lions of people at risk of COVID-19 infection. (RNA and DNA), viral vectors (non-replicating and replicating), recombinant protein, and antigen-presenting cells (Le et al., 2020; van Riel and de Wit, 2020). However, as of September WILL VACCINE STIMULATE THE IMMUNE 2020 reported by CEPI, most of the frontrunner vaccines in RESPONSE? clinical studies have emphasized on spike protein of corona- virus and its versions as the key antigen responsible for the As mentioned earlier, ACE2 is the route of SARS-CoV-2 in- infection of COVID-19. CEPI also pointed out that eleven can- fection. However, this receptor plays a vital role in both innate didate vaccine in clinical stage using adjuvant to improve the and adaptive immune responses by modulating the antigen immunogenicity (Le et al., 2020).