A critical overview of current progress for COVID-19: development of vaccines, antiviral drugs, and therapeutic antibodies

Abstract

The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.

Keywords: COVID-19; Neutralizing antibodies; SARS-CoV-2; Small molecule antiviral drugs; Therapeutics; Vaccine development; mRNA vaccines.

Fig. 1

Global circumstances regarding COVID-19. A Resurgence of new cases is associated with increased mortality. Data were collected from the WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020; available online: https://covid19.who.int/. B Epidemic dynamics of SARS-CoV-2 dominant variants. The data for frequency of infection by each variant were collected from GISAID [251]. The death rate was calculated as weekly deaths/weekly cases from (A). C Genomic variations in spike protein of major and emerging SARS-CoV-2 variants. D Epidemic dynamics of SARS-CoV-2 Omicron variants on five continents and South Africa; represented as daily frequency of each detected sequence. Due to a lack of sufficient data from South Africa in June July 2022 (daily sequencing cases < 15), the Omicron frequency analysis for South Africa was only performed up to July 11, 2022. All data were retrieved from GISAID

Fig. 2

Global approaches in vaccines development. A Timeline of different vaccine development platforms against viral infections. The timeline represents the first vaccine developed against each pathogen outbreak. Color of the bar represents the vaccine type. Red dots indicate the years in which the pathogen was linked to diseases. B Number of candidate vaccines against SARS-CoV-2 of each vaccine platform type in various clinical stages. Data is acquired from COVID-19 vaccine tracker and landscape published by World Health Organization dated April 22, 2022. Viral vector (NR) indicates non-replicating viral vector; others include replicating viral vector, live attenuated virus, replicating viral vector plus antigen presenting cells, and non-replicating viral vector plus antigen presenting cells

Fig. 3

Schematic representation of the structure of conventional mRNA and the structure and intracellular amplification of self-amplifying mRNA. A The design of IVT mRNA is based on the blueprint of eukaryotic mRNA, and it consists of a 5’ cap, 5’ and 3’ untranslated regions (UTRs), an open reading frame (ORF) encoding antigen(s), and a 3’ poly(A) tail. The IVT mRNA can be modified in one or multiple sites, e.g., by modification of the caps, the UTRs and the poly(A) tail, to modulate the duration and kinetic profile of protein expression. B Antigen expression in different types of mRNA vaccines. The immunogen is encoded by a non-replicating RNA flanked by 5′ and 3′ UTRs. Self-amplifying RNA encodes four nonstructural proteins and a sub-genomic promoter derived from the alphavirus genome. It encodes a replicase and amplifies vaccine-antigen transcripts. Trans-amplifying RNA uses two transcripts to enable self-amplification of replicase and the target antigen

Fig. 4

Diagrammatic illustration of mRNA-LNPs complex preparation and testing. A Synthesis of IVT mRNA. 1. Restriction enzyme digestion for DNA plasmid linearization; 2. Co-transcriptional capping of IVT; 3. DNase treatment and cellulose-based purification of IVT mRNA. B Schematic representation of the LNPs-encapsulated mRNA. C In vitro assay of protein expression from mRNA-LNPs. D Immunogenicity assessment of mRNA-LNPs in vivo

Fig. 5

Chemical structure of most common lipids for mRNA delivery. A Cationic or ionizable lipid design. Analysis and summary of the representative structure of B Cationic lipids and C Ionizable lipids

Fig. 6

Structure of nAbs binding to RBD. The potent escape mutations in BA.1 variant were indicated in red. The Fab region of antibody show in Blue ribbon and RBD represent as white spheres. Complexes are visualized with PyMOL Molecular Graphics System, v2.5.2 (Schrödinger, LLC) software. The protein data bank (PDB) accession codes for the structures shown are 6XDG (casirivimab and imdevimab), 7KMG (bamlanivimab), 7C01 (etesevimab), 7R6W (sotrovimab), 7L7E (cilgavimab and tixagevimab), and 7MMO (bebtelovimab)

Fig. 7

Therapeutics drug distribution and efficacy against COVID-19. A Distribution of COVID-19 therapeutics from Nov 9, 2020 to Apr 24, 2022 in USA. B Total Distribution percentage of antiviral reagents and neutralizing antibodies doses from Nov 9, 2020 to Apr 24, 2022 in USA. The data was adopted from U.S. Department of Health & Human Service (https://aspr.hhs.gov/COVID-19/Therapeutics/Distribution/Pages/default.aspx). C Effectiveness of therapeutic reagents on reducing hospitalization and deaths of COVID-19 patients

Fig. 8

Prevention and therapy for COVID-19. A Vaccines stimulate the host immune system to generate neutralizing antibodies against COVID-19. B Small molecule drugs and therapeutic antibodies block viral replication or entry