International Immunopharmacology 96 (2021) 107763 Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Review An update review of globally reported SARS-CoV-2 vaccines in preclinical and clinical stages Hamid Motamedi a, Marzie Mahdizade Ari b, Shirin Dashtbin b, Matin Fathollahi a, Hadi Hossainpour a, Amirhoushang Alvandi a,c, Jale Moradi a, Ramin Abiri a,d,* a Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran b Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran c Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran d Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran ARTICLE INFO ABSTRACT Keywords: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the rapidly spreading COVID-19 pandemic COVID-19 in the world. As an effective therapeutic strategy is not introduced yet and the rapid genetic SARS-CoV-2 variations in the virus, there is an emerging necessity to design, evaluate and apply effective new vaccines. An Vaccines acceptable vaccine must elicit both humoral and cellular immune responses, must have the least side effects and the storage and transport systems should be available and affordable for all countries. These vaccines can be classified into different types: inactivated vaccines, live-attenuated virus vaccines, subunit vaccines, virus-like particles (VLPs), nucleic acid-based vaccines (DNA and RNA) and recombinant vector-based vaccines (repli­ cating and non-replicating viral vector). According to the latest update of the WHO report on April 2nd, 2021, at least 85 vaccine candidates were being studied in clinical trial phases and 184 candidate vaccines were being evaluated in pre-clinical stages. In addition, studies have shown that other vaccines, including the Bacillus Calmette-Gu´erin (BCG) vaccine and the Plant-derived vaccine, may play a role in controlling pandemic COVID- 19. Herein, we reviewed the different types of COVID-19 candidate vaccines that are currently being evaluated in preclinical and clinical trial phases along with advantages, disadvantages or adverse reactions, if any. 1. Introduction coughing and even talking, as well as contact with surfaces that were previously touched and infected by patients suffering COVID-19 [3]. The recent pandemic of coronavirus disease 19 (COVID-19) caused Disease is characterized by fever (98%), dry cough (75%) and tiredness by coronavirus is spreading in the world very rapidly. Coronavirus is a (45%) as the most common symptoms as well as diarrhea, loss of taste or single-stranded RNA virus with a ~27- to 32-kb size positive sense smell and rash on skin as less common symptoms (20–30%). Moreover, genome that encodes 27 proteins including spike (S), envelope (E), uncommon serious complication including Guillain-Barre syndrome nucleocapsid (N) and glycoprotein (M) as structural proteins, RNA- (GBS) associated COVID-19 as neuropathy complication [4] and car­ dependent RNA polymerase (RdRP) and protease as non-structural diovascular disorders [5] was reported which can be consider life- proteins, as well as hemagglutinin (HE) as viral envelope glycopro­ threatening for patients. However according to the WHO report, teins [1]. serious symptoms including difficulty in breathing, chest pain and loss The infection firstoriginated in Wuhan, China in December 2019 and of speech or movement [6]. Any chronic pulmonary diseases, hyper­ spread to almost all countries of the world with a high spreading po­ tension and cardiovascular diseases, obesity (body mass index ≥ 30), tential. According to World Health Organization (WHO) report [2], type 2 diabetes mellitus and immunocompromised state are considered COVID-19 has infected more than 100 million (123,419,065) people as risk factors [7]. worldwide and caused 2.7 million deaths (Fig. 1). This pandemic as a Currently, there is no definite treatment for COVID-19 and only zoonotic breakout was transmitted to human and spread among humans supportive methods including oxygen therapy, plasma (or antibody) by close contacts and respiratory droplets which formed by sneezing, therapy, antipyretic and anti-inflammatorydrugs that prevent cytokine * Corresponding author at: Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran. E-mail address: [email protected] (R. Abiri). https://doi.org/10.1016/j.intimp.2021.107763 Received 26 February 2021; Received in revised form 21 April 2021; Accepted 4 May 2021 Available online 6 May 2021 1567-5769/© 2021 Elsevier B.V. All rights reserved. H. Motamedi et al. International Immunopharmacology 96 (2021) 107763 storm such as monoclonal antibody against specific receptor like inter­ doses. Fig. 4-A shows that 13 (15%) of vaccines are administrated in a leukin receptor (e.g. tocilizumab and pegylated interferon α-2a and single dose (blue). Double-dose vaccines (light to dark brown) are 52 2b) are currently prescribed for the patients. Inhibitors of RdRP, (61%) and are given on two different days at regular intervals, for reverse transcriptase and protease of SARS- CoV-2 and antiviral antibi­ instance, on the day 0 and day 14 (7%), day 0 and day 21 (24%) as well otics (e.g. favipiravir and remdesivir etc.) usage are still in doubt and as day 0 and day 28 (31%). Moreover, only one vaccine candidate is their exact effects on the process of the infection are still unclear [7,8]. administrated in three-doses in days 0, 28 and 56. However, this pandemic is not going to be stopped unless access to Vaccine administration categorized into two oral-based and inject­ effective and safe vaccines becomes available. An ideal coronavirus able routes, while injective vaccines can be administrated subcutaneous vaccine must elicit strong humoral and cellular immune responses, it (SC), intradermal (ID) and intramuscular (IM) routs. Among injectable must have easy storage and transport requirement which must be vaccines, 64 (75%) are IM, 3 (4%) are SC and 3 (4%) are ID adminis­ available and affordable for all the countries, especially lower- middle- trated (Fig. 4-B). income ones [9]. According to the last update of the WHO report on April 2nd, 2021, 3. Innate immunity there are 85 vaccine candidates in clinical trial phase of study and 184 candidate vaccines are being evaluates in pre-clinical stages (Fig. 2). Both innate and adaptive immunity are involved in identifying and These vaccines can be classified into six different types (Fig. 3): inacti­ eliminating invading pathogens but, non-optimal and uncontrolled vated vaccines, live-attenuated virus vaccines as a combination of both response contributes disease progression. Therefore, understanding the protein and gene-based vaccines, subunit vaccines and VLPs as protein- mechanism and changes of immune responses will help to understand­ based vaccines, nucleic acid-based vaccines (DNA and RNA) and re­ ing the disease and treatment approaches [24]. combinant vector-based vaccines (replicating and non-replicating viral SARS-CoV-2 disease occurs following a lung infection through a vector) as gene delivery based vaccines [8,10]. person-to-person transmission. Development of disease and outcome of Immunogenic candidates are several viral structural proteins (spike infection is affected by the interaction between the virus and the im­ protein) [11] and non-structural proteins (RdRP and protease) [12,13], mune system [25]. however, spike protein is paid more attention in designing vaccines SARS-CoV-2 genomic structure contains 14 open reading frames 0 [14]. This structural protein which was encoded in the 3 end of the (ORFs). Non-structural proteins (NSPs 1–16) are encoded by ORF1a and 0 0 SARS-CoV-2 RNA sequence, was targeted in vaccines to be detected by ORF1b, located at the 5 -untranslated region (5 -UTR), encodes two the host immune system [15,16]. Spike protein, as a fusion protein, polyproteins (pp1a, pp1b) that are processed by two virally encoded helps to attach and uptake of coronavirus by host cells, specially lung cysteine proteases such as the papain-like protease (PLpro) and a 3C-like alveolar epithelial cells following interaction between angiotensin- protease (3CLpro). Pp1a, pp1b imply in genome transcription and converting enzyme 2 (ACE2) receptor on cells surface and receptor- replication with forming a replication-transcription complex (RTC). On binding domain (RBD) of spike on SARS-CoV-2 [9,17,18]. the other hand, RTC synthesize a nested set of subgenomic RNAs Some of the vaccine candidates have effective results against the new (sgRNAs). Structural proteins are encoded by other ORFs located at the 0 coronavirus in primates [14]. Moreover, the production of neutralizing 3 -UTR [1,24,26]. In addition to the aforementioned structures, there antibodies has been detected following different clinical trials in humans are 8 accessory proteins that are species-specific(ORF3a, ORF3b, ORF6, [12,19–21]. Some developers including Sinopharm, Sinovac, Pfizer- ORF7a, ORF7b, ORF8, ORF9b and ORF14) [27]. BioNTech, Moderna, Oxford-AstraZeneca, Johnson & Johnson, Bharat Spike proteins are enveloped-anchored proteins consisting S1 (re­ Biotech (Covaxin) and Sputnik V (Gamaleya Research Institute) are ceptor- binding) and S2 (membrane fusion) subunits