A Snapshot of the Global Race for Vaccines Targeting SARS-CoV-2 and the COVID-19 Pandemic

Abstract

A novel coronavirus SARS-CoV-2 causing Coronavirus disease 2019 (COVID-19) has entered the human population and has spread rapidly around the world in the first half of 2020 causing a global pandemic. The virus uses its spike glycoprotein receptor-binding domain to interact with host cell angiotensin-converting enzyme 2 (ACE2) sites to initiate a cascade of events that culminate in severe acute respiratory syndrome in some individuals. In efforts to curtail viral spread, authorities initiated far-reaching lockdowns that have disrupted global economies. The scientific and medical communities are mounting serious efforts to limit this pandemic and subsequent waves of viral spread by developing preventative vaccines and repurposing existing drugs as potential therapies. In this review, we focus on the latest developments in COVID-19 vaccine development, including results of the first Phase I clinical trials and describe a number of the early candidates that are emerging in the field. We seek to provide a balanced coverage of the seven main platforms used in vaccine development that will lead to a desired target product profile for the "ideal" vaccine. Using tales of past vaccine discovery efforts that have taken many years or that have failed, we temper over exuberant enthusiasm with cautious optimism that the global medical community will reach the elusive target to treat COVID-19 and end the pandemic.

Keywords: COVID-19; SARS-CoV-2; clinical trial; coronavirus; immune response; public health; vaccine.

Figure 1

Transmission and life-cycle of SARS-CoV-2 causing COVID-19. SARS-CoV-2 is transmitted via respiratory droplets of infected cases to oral and respiratory mucosal cells. The virus, possessing a single-stranded RNA genome wrapped in nucleocapsid (N) protein and three major surface proteins: membrane (M), envelope (E) and Spike, replicates and passes to the lower airways potentially leading to severe pneumonia. The gateway to host cell entry (magnified view) is via Spike-converting enzyme 2 (ACE2) interaction with cleavage of Spike in the prefusion state by proteases TMPRSS-2/furin. A simplified depiction of the life cycle of the virus is shown along with potential immune responses elicited.

Figure 2

Timelines for the development of various vaccines for polio, Ebola virus, and three betacoronaviruses (SARS-CoV-1, MERS-CoV and SARS-CoV-2). On the left side of each timeline is a reference point for the first clinical case description and/or first recognized cases) for each type of viral infection. Significant events are depicted along the timeline (not according to scale). Solid horizontal red bars indicate the approximate period from first outbreak/vaccine to clinically approved use. Dotted red lines indicate no availability of vaccines since first outbreak and the green dotted line represents a rapid emergency use authorization timeline for a putative SARS-CoV-2 vaccine.

Figure 3

Development of the “ideal” vaccine for COVID-19 depicted by concentric circles converging to the target. Normally, development occurs in three discrete phases: Research and Development (R&D) involving platform selection, designing targets (e.g. whether that might be selection of an RNA sequence and decisions on nucleoside substitutions, lipid nanoparticle (LNP) formulation, etc, or decisions on how to create a live-attenuated viral preparation) and preclinical testing in vitro in cell culture and in vivo in animals. For SARS-CoV-2 R&D, some of the animal models used are transgenic mice that overexpress the Spike-binding protein ACE-2, Syrian hamsters, ferrets, and non-human primates (NHPs). If encouraging results are apparent in the preclinical phase (indicated by various parameters in green boxes), the candidate vaccine is taken to the second phase, which consists of testing in human volunteers in three stages of clinical trials (Phase I, Phase II, and Phase III). These may be concatenated to expedite approval (e.g. Phase II/III). Due to the pandemic nature of COVID-19, both these outer concentric phases are being pursued simultaneously under expedited approvals with potential for emergency use authorizations. If, and only when, vaccine safety and efficacy is achieved in human volunteers, the logistical operations become the major hurdles to ensure worldwide distribution in a coordinated and inter-connected manner (manufacturing, supply chain distribution, storage, etc.). Vaccine candidates that do not achieve satisfactory results in clinical trials, due to various factors shown in the red boxes, will be dropped from further development. ADE, antibody-dependent enhancement; ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cellular cytotoxicity; VAERD, vaccine-associated enhanced respiratory disease; AE, adverse event.

Figure 4

Vaccine candidates in development for SARS-CoV-2. (A) For our analyses, we have divided potential vaccines into 7 (seven) main platforms (DNA, RNA, Protein-based, Viral vector-based (non-replicating), Viral vector-based (replicating), Virus (inactivated), and Virus (live, attenuated). An additional “Other” category for those platforms where there is uncertainty from described sources is also included but not shown. The platforms are represented by various simple drawings. LNPs, lipid nanoparticles. (B) Numbers of vaccine candidates in development late May 2020, depicted in pie chart format, in each platform. Sources include: The Milken Institute, WHO, BioCentury, and our own investigations. Categorization of platforms differs slightly in each source.

Figure 5

Current 2020 and projected timelines (shown in four quarters, Q1–Q4) for 14 vaccine candidates, grouped by platform, either funded by (CEPI/BARDA, and currently in (or approaching) clinical development for COVID-19. The two candidates using viral vector (replicating) from Pasteur/Themis (Merck) and live attenuated virus (Univ Hong Kong) funded by CEPI, covered in the main text body, are not included here because they are still too early in development and without sufficient information. M, million; B, billion; Ph, Phase. Sources include publicly available company websites.