Advances in SARS-CoV-2 receptor-binding domain-based COVID-19 vaccines

ABSTRACT

Introduction

The Coronavirus Disease 2019 (COVID-19) pandemic has caused devastating human and economic costs. Vaccination is an important step in controlling the pandemic. Severe acute respiratory coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, infects cells by binding a cellular receptor through the receptor-binding domain (RBD) within the S1 subunit of the spike (S) protein. Viral entry and membrane fusion are mediated by the S2 subunit.

Areas covered

SARS-CoV-2 S protein, particularly RBD, serves as an important target for vaccines. Here we review the structure and function of SARS-CoV-2 S protein and its RBD, summarize current COVID-19 vaccines targeting the RBD, and outline potential strategies for improving RBD-based vaccines. Overall, this review provides important information that will facilitate rational design and development of safer and more effective COVID-19 vaccines.

Expert opinion

The S protein of SARS-CoV-2 harbors numerous mutations, mostly in the RBD, resulting in multiple variant strains. Although many COVID-19 vaccines targeting the RBD of original virus strain (and previous variants) can prevent infection of these strains, their ability against recent dominant variants, particularly Omicron and its offspring, is significantly reduced. Collective efforts are needed to develop effective broad-spectrum vaccines to control current and future variants that have pandemic potential.

KEYWORDS:

• Coronavirus
• SARS-CoV-2
• COVID-19
• spike
• receptor-binding domain
• vaccines

Article highlights

• Coronavirus Disease 2019 (COVID-19), first reported in December 2019, caused a global pandemic, leading to millions of deaths within 3 years. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19.

• Like SARS-CoV and MERS-CoV, two other highly pathogenic coronaviruses reported in 2002 and 2012, respectively, SARS-CoV-2 is an enveloped and single-stranded RNA virus, belonging to the genus of Betacoronavirus (family Coronaviridae; and order, Nidovirales). The viral genome encodes four structural proteins, including spike (S), membrane (M), envelope (E), and nucleocapsid (N), as well as a number of non-structural proteins.

• The S protein of SARS-CoV-2 plays an important role in virus infection and pathogenesis. It comprises S1 and S2 subunits. SARS-CoV-2 infection is initiated by binding of the receptor-binding domain (RBD) in the S1 subunit to a host cellular receptor; viral entry and membrane fusion are mediated by the S2 subunit. SARS-CoV-2 and SARS-CoV use angiotensin-converting enzyme 2 (ACE2) for viral entry, whereas MERS-CoV utilizes dipeptidyl-peptidase 4 (DPP4) as its cellular receptor. Therefore, the S protein, particularly the RBD, of SARS-CoV-2 is a critical target for development of safe and effective COVID-19 vaccines.

• RBD-targeting COVID-19 vaccines prevent SARS-CoV-2 infection by inducing potent neutralizing antibodies against SARS-CoV-2, or by eliciting specific T cell responses to promote antibody production or direct killing of virus-infected cells.

• Most of the currently developed RBD-targeting COVID-19 vaccines are in preclinical development. They are categorized as recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, and other vaccine types, such as those based on viral vectors.

• Several RBD-targeting COVID-19 vaccines have proceeded to clinical trials. It is expected that promising RBD-based vaccines can be approved for use in humans to prevent SARS-CoV-2 infection.

• Unlike SARS-CoV and MERS-CoV, SARS-CoV-2 mutates rapidly, resulting in multiple variants of concern (i.e. Alpha, Beta, Gamma, Delta, and Omicron); the Omicron variant has various subvariants that transmit rapidly and represent the current dominant strains. Most of these variants are highly resistant to the current vaccines, which target the original strain or previous variants. Novel approaches are needed urgently to develop safe and effective COVID-19 vaccines, including those based on the RBD, that show improved efficacy against the current pandemic variants, as well as future variants with pandemic potential.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution

Y.Y. prepared the structural figures. X.G. prepared the other figures and participated in the writing. L.D. designed, wrote, and revised the manuscript.

Additional information

Funding

This study was supported by the National Institutes of Health (NIH) grants (R01AI157975, R01AI139092, and R01AI137472)