pharmaceuticals Review COVID-19 Vaccines: A Review of the Safety and Efficacy of Current Clinical Trials Zhi-Peng Yan 1,*,† , Ming Yang 2,† and Ching-Lung Lai 1,* 1 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong 999077, China 2 Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; [email protected] * Correspondence: [email protected] (Z.-P.Y.); [email protected] (C.-L.L.); Tel.: +852-2255-4252 (C.-L.L.); Fax: +852-2816-2863 (C.-L.L.) † Co-first authors. Abstract: Various strategies have been designed to contain the COVID-19 pandemic. Among them, vaccine development is high on the agenda in spite of the unknown duration of the protection time. Various vaccines have been under clinical trials with promising results in different countries. The protective efficacy and the short-term and long-term side effects of the vaccines are of major concern. Therefore, comparing the protective efficacy and risks of vaccination is essential for the global control of COVID-19 through herd immunity. This study reviews the most recent data of 12 vaccines to evaluate their efficacy, safety profile and usage in various populations. Citation: Yan, Z.-P.; Yang, M.; Lai, C.-L. COVID-19 Vaccines: A Review Keywords: COVID-19; vaccine; safety; efficacy; herd immunity of the Safety and Efficacy of Current Clinical Trials. Pharmaceuticals 2021, 14, 406. https://doi.org/10.3390/ ph14050406 1. Introduction The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus Academic Editor: Juan Carlos Saiz 2 (SARS-CoV-2). Up till February 2021 it had infected more than 110 million patients, causing 2.4 million deaths worldwide, according to data recorded by the World Health Received: 25 March 2021 Organization (WHO) [1]. Accepted: 18 April 2021 The prevention and control of the epidemic in 2020, other than treatment of symp- Published: 25 April 2021 tomatic patients, has included monitoring of asymptomatic infections, follow-up and monitoring after cure and discharge, close contact tracking, high-risk population screening, Publisher’s Note: MDPI stays neutral and disinfection of the epidemic source, but the only way for the radical control of COVID- with regard to jurisdictional claims in 19 infections is by effective vaccination. Vaccines stimulate the body to produce specific published maps and institutional affil- antibodies, with anamnestic response when the body is exposed to this pathogen again. iations. During 2020, there has been extensive research to look into the use of vaccinations to prevent further transmission of SARS-CoV-2. Globally, several prospective vaccines have been produced and used by the public (Table1). The protective efficacy and immunogenic- ity profile of each vaccine is also documented (Table2). Copyright: © 2021 by the authors. There are currently two forms of messenger ribonucleic acid (mRNA) vaccines: non- Licensee MDPI, Basel, Switzerland. replicating mRNA (NRM) vaccines and self-amplifying mRNA (SAM) vaccines. The This article is an open access article constructed mRNA is formulated into a carrier—usually lipid nanoparticles—to protect distributed under the terms and them from degradation and promote cellular uptake [2]. After the carrier particles are conditions of the Creative Commons ingested into the cell, mRNA is released, which is translated by the ribosome to produce Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ the target protein (recognizable antigen) [3]. After the target protein is secreted by the cell, 4.0/). it is rec-ognized by the immune system and stimulates an immune response. Pharmaceuticals 2021, 14, 406. https://doi.org/10.3390/ph14050406 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 406 2 of 28 Table 1. Summary of vaccine trials. Population Characteristics of Title [Reference] Clinical Phase Doses Technology Immunogenicity Safety Profile the Latest Trial 45 adults in 3 groups: 10 µg, Lipid nanoparticle 30 µg, 100 µg nucleoside-modified mRNA Dose-dependent antibody BNT162b1 [4–6] 1–2 2 injections, 21 days apart No serious adverse events 12 vaccines: 3 placebo in each vaccine, encoding the spike response group glycoprotein of SARS-CoV-2 43,448 volunteers aged 16 or Lipid nanoparticle older in total: (1:1 ratio) 2 injections of 30 µg doses for nucleoside-modified mRNA Similar dose-dependent BNT162b2 [7,8] 1–3 No serious adverse events 21,720 received vaccines phase 3, 21 days apart vaccine, encoding the spike response as BNT162b 21,728 received placebo glycoprotein of SARS-CoV-2 30,420 adults in total: Lipid nanoparticle capsule of Similar grade 3 adverse events (1:1 ratio) 2 injections of 100 µg doses, 100% seroconversion rates by mRNA-1273 [9–11] 1–3 four lipids, encoding the S-2P in the placebo group (1.3%) and 15,210 received vaccines 28 days apart day 15 antigen. the vaccine group (1.5%) 15,210 received placebo Chimpanzee Median titre of booster-dose 23,848 adults randomised 1:1 2 injections of 3.5–6.5 × 1010 - 13 serious adverse events adenovirus-vectored vaccine group is more than 5 times ChAdOx1 nCoV-19 [12–14] 1–3 ratio to receive ChAdOx1 viral particles per mL, 28 days - None considered related to the with SARS-CoV-2 spike higher than the single-dose nCoV-19 or placebo apart vaccine glycoprotein group. Replication defective Higher antibody GMT in - 25 grade 3 or above adverse 508 adults randomised 2:1:1 to Ad5-vectored COVID-19 Ad5-vectored vaccine high-dose group, compared events 1 & 2 receive vaccine at the dosage of 1 injection [15–17] expressing the spike with medium and low-dose - All resolved within 3 to 4 days 1 × 1011, 5 × 1010, or placebo glycoprotein of SARS-CoV-2 groups. without medications Replication of Ad5-vectored 21,977 adults in total: 2 injections of 1011 viral and Ad-26 vectored vaccine rAd26-S and rAd5-S [18,19] 1–3 16,501 received vaccines particles in 0.5 mL vaccine, expressing the gene for 100% seroconversion rate No serious adverse events 5476 received placebo 21 days apart SARS-CoV-2 full-length glycoprotein S 30,000 adults in total: Nanoparticle of trimeric 2 injections of 5 mg protein IgG GMT and neutralization Randomised in 2:1 ratio to full-length SARS-CoV-2 spike NVX-CoV2373 [20–22] 1–3 with 50 mcg matrix-M responses exceeding No serious adverse events receive vaccine and saline glycoproteins and Matrix-M1 adjuvant, 21 days apart. convalescent serum placebo adjuvant 96 adults randomised 1:1:1:1 to Phase 1: WIV-04 strain inactivated Isolated from WIV-04 strain 100% seroconversion rates in Mild 1–2 receive low-dose, 3 injections on day 0, 28 and 56 vaccine [10] and cultivated in a Verco cell phase 1 trial and 85.7% in the injection site pain and fever medium-dose, high-dose and Phase 2: aluminium hydroxide, line, followed by serial phase 2 (23.4%) 2 injections on day 0 and 14, or inactivation respectively day 0 and 21 192 adults: 18–59 years (96 adults) Phase 1: ≥ HB02-strain in Verco cell line, - Higher seroconversion with One grade 3 adverse event: BBIBP-CorV [11,23] 1–2 60 years (96 adults). 2 injections separated 28 days ◦ 24 receiving vaccine of 2 µg, with serial inactivation higher dosage (8 µg) by day 14, self-limiting fever (>38.5 C) 4 µg or 8 µg on day 0 and 28; Phase 2: - Higher neutralizing antibody and 24 receiving placebo. Single-dose GMT in younger adults Pharmaceuticals 2021, 14, 406 3 of 28 Table 1. Cont. Population Characteristics of Title [Reference] Clinical Phase Doses Technology Immunogenicity Safety Profile the Latest Trial 13,000 adults randomised to -High seroconversion rates: One case of serious Inactivated vaccine from Vero receive vaccine or placebo 83% in the 3 µg group, 79% in hypersensitivity with urticaria, Coronavac [24] 1–3 2 injections, 28 days apart cell line with SARS-CoV-2 (randomisation ratio not the 6 µg group, and 4% in the recovered 3 months after (CN02 strain) provided) placebo group medical treatment. 40,000 adults randomised to replication-incompetent Comparable serious adverse receive vaccination or placebo 1 injection of 5 × 1010 virus adenovirus serotype 26 (Ad26) Ad26.COV2.S [25–29] 1–3 100% seroconversion day 57 events in vaccination group (randomisation ratio not particles vector encoding full-length and placebo group. provided) SARS-CoV-2 spike protein whole-virion inactivated Comparable local and systemic 380 participants (aged SARS-CoV-2 vaccine 92.9% (95% CI 88.2–96.2) adverse event profile in the 12–65 years) randomised by 1:1 2 intramuscular injections on formulated with a toll-like seroconversion rate in the 3 µg BBV152 [30–32] 1–2 3 µg (9.47%) and 6 µg (11.0%) ratio to receive vaccines of day 0 and day 28 receptor 7/8 agonist molecule group, and 98.3% (95% CI groups. No reported serious either 3 µg or 6 µg. (IMDG) adsorbed to alum 95.1–99.6) in the 6 µg group. adverse events. (Algel) Table 2. Efficacy and other immune responses of vaccines after completion of vaccinations. Title [Reference] Protective Efficacy Antigen-Specific IgG GMT Level Neutralizing Antibody Responses Cellular Responses - 10 µg: 4813 U/mL -Functional CD4+ and CD8+ responses in all - 30 µg: 27,873 U/mL Higher GMT compared to convalescent participants, predominantly Th1 helper Similar to BNT162b2 - Increase dosage to 100 µg did not increase serum panel BNT162b1 [4–6] responses. (actual figure not stated) the IgG GMC. - 10 µg: 1.8-fold - The mean fraction of RBD-specific T cells - Lower antigen-binding IgG in participants - 30 µg: 2.8-fold was higher than convalescent plasma.