SARS-CoV-2 vaccines in advanced clinical trials: Where do we stand?

Abstract

The ongoing SARS-CoV-2 pandemic has led to the focused application of resources and scientific expertise toward the goal of developing investigational vaccines to prevent COVID-19. The highly collaborative global efforts by private industry, governments and non-governmental organizations have resulted in a number of SARS-CoV-2 vaccine candidates moving to Phase III trials in a period of only months since the start of the pandemic. In this review, we provide an overview of the preclinical and clinical data on SARS-CoV-2 vaccines that are currently in Phase III clinical trials and in few cases authorized for emergency use. We further discuss relevant vaccine platforms and provide a discussion of SARS-CoV-2 antigens that may be targeted to increase the breadth and durability of vaccine responses.

Keywords: COVID-19; ORF3a; Phase III vaccine trials; Pre-fusion S protein; SARS-CoV-2 vaccine; Vaccine platform.

Graphical abstract

Fig. 1

An outline of the standard timeline for vaccine development and the expedition for SARS-CoV-2 vaccines. Standard vaccine development can take up to 15 years before a successful candidate makes it to market. Due to the expense and time of running clinical trials that meet regulatory benchmarks for approval, the length of time can vary significantly at each stage of the process. Compression of the normal timeline is being attempted in order to deliver a vaccine for SARS-CoV-2 within ~18 months of this novel pathogen being identified. Leveraging existing infrastructure for new, but as yet unproven, vaccine platforms like mRNA- and DNA-based vaccines, as well as ongoing work with related CoVs, like SARS1 and MERS, has enabled a shortened time from the preclinical data acquisition stage to almost immediate entry into Phase I clinical trials for some of the leading candidates. Additionally, conducting overlapping Phase I, II and III Clinical Trials, while scaling up the manufacturing of multiple candidates will provide support for rapid distribution once emergency approval is granted.

Fig. 2

SARS-CoV-2 virion, genome and strategies for stabilizing the spike protein. (A) SARS-CoV-2 virion with structural proteins (spike (S), membrane (M), nucleocapsid (N) and envelope (E)) and genome depicted. (B) Organization of the SARS-CoV-2 genome. (C) SARS-CoV-2 S protein organization. The S1 subunit (tan) consists of a 5′ signal sequence (SS) followed by the N-terminal domain (NTD) and the receptor binding domain (RBD). Arrows denote the two protease cleavage sites: the polybasic furin site between S1/ S2 and the S2′ site. Cleavage at these two sites in the S protein exposes the hydrophobic fusion peptide (FP) and triggers the fusion process. The other domains of the S2 subunit are the heptad repeat 1 (HR1), CH-central helix, CD-connector domain, heptad repeat 2 (HR2), transmembrane domain (TM) and cytoplasmic tail (CT). Domains that have no corresponding residues in the cryo-EM structures shown in (D) are colored in white. Multiple protein engineering strategies have been adopted to stabilize the pre-fusion conformation. Most of the full-length vaccine candidates have adopted one or all of the following strategies: 1) Introduction of two stabilizing proline mutations at residues 986 and 987 in the loop between HR1 and CH, 2) Removal of the polybasic cleavage site between S1 and S2, and 3) Stabilizing the trimeric spike by addition of a trimerization motif to maintain integrity of conformational epitopes. (D) Prefusion structure of the SARS-CoV-2 spike protein determined by cryo-EM (PDB ID: 6VSB). The spike is a homotrimeric protein. Two of the monomers are colored in gray, whereas the various structural domains have been mapped on one of the monomers in the identical color as shown in (C).

Fig. 3

SARS-CoV-2 vaccine platforms. The major vaccine platforms that are being used in current SARS-CoV-2 vaccine candidates. A combination of conventional and novel vaccine platforms are being tested. Conventional vaccine platforms that have been licensed for human use are the inactivated virus (IV), live attenuated virus (LAV), and recombinant protein-based (Protein Subunit (PS)). Novel vaccine platforms include nucleic acid based (DNA and RNA encoding the gene of interest (GOI)) and viral vector-based (non-replicating viral vector (NRVV) and replicating viral vector (RVV).