Review A COVID-19 Vaccine: Big Strides Come with Big Challenges Juanita Mellet and Michael S. Pepper *   Citation: Mellet, J.; Pepper, M.S. A COVID-19 Vaccine: Big Strides Come with Big Challenges. Vaccines 2021, 9, 39. https://doi.org/10.3390/ vaccines9010039 Received: 16 November 2020 Accepted: 5 January 2021 Published: 11 January 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- ms in published maps and institutio- nal affiliations. Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). SAMRC Extramural Unit for Stem Cell Research and Therapy, Department of Immunology, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria 0001, South Africa; juanitamellet@yahoo.co.uk * Correspondence: michael.pepper@up.ac.za; Tel.: +27-72-209-6324 Abstract: As of 8 January 2021, there were 86,749,940 confirmed coronavirus disease 2019 (COVID- 19) cases and 1,890,342 COVID-19-related deaths worldwide, as reported by the World Health Organization (WHO). In order to address the COVID-19 pandemic by limiting transmission, an intense global effort is underway to develop a vaccine against SARS-CoV-2. The development of a safe and effective vaccine usually requires several years of pre-clinical and clinical stages of evaluation and requires strict regulatory approvals before it can be manufactured in bulk and distributed. Since the global impact of COVID-19 is unprecedented in the modern era, the development and testing of a new vaccine are being expedited. Given the high-level of attrition during vaccine development, simultaneous testing of multiple candidates increases the probability of finding one that is effective. Over 200 vaccines are currently in development, with over 60 candidate vaccines being tested in clinical trials. These make use of various platforms and are at different stages of development. This review discusses the different phases of vaccine development and the various platforms in use for candidate COVID-19 vaccines, including their progress to date. The potential challenges once a vaccine becomes available are also addressed. Keywords: COVID-19; SARS-CoV-2; vaccine; vaccine development; vaccine platforms; immune response 1. Introduction Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) was responsible for 86,749,940 reported infections and 1,890,342 reported deaths as of 8 January 2021, as indicated by the World Health Organization (WHO) [1]. An effective vaccine is urgently needed to control the pandemic and to prevent future outbreaks. Due to the novelty of the virus, there are currently few approved treat- ments for COVID-19 and a limited number of vaccines have only recently been approved for SARS-CoV-2. Vaccines have been effective in protecting against several deadly diseases and at present prevent roughly 2.5 million deaths per year [2,3]. Although their mechanism of action is complex and not completely understood, this involves both innate and adaptive immunity as they prime the immune system to respond to invading pathogens [4]. Follow- ing initial exposure to an antigen, the immune system is activated in a primary immune response, where pathogens are recognized by pattern recognition receptors (PRRs) directed against evolutionarily conserved pathogen-associated products that are not contained in self-antigens [5]. This leads to secretion of various signaling molecules including interferon gamma (IFN-γ) to initiate and direct innate and adaptive antiviral immune responses. Specific cell types such as natural killer (NK) and dendritic cells (DCs) are recruited to sites of inflammation. When DCs encounter pathogens they undergo rapid maturation, modu- late specific cell surface receptors, and secrete additional cytokines and chemokines. IFN receptor signaling is essential for DC maturation and migration to secondary lymph nodes, where they provide co-stimulatory signals to initiate antiviral B- and T-cell responses [5]. B- and T-cells bind to viral proteins through antigen receptors leading to activation, expansion, Vaccines 2021, 9, 39. https://doi.org/10.3390/vaccines9010039 https://www.mdpi.com/journal/vaccines