The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses

Abstract

Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence of highly pathogenic CoVs in human. However, given the diverse nature of CoVs and our close interactions with wild, domestic and companion animals, the next epidemic zoonotic CoV could resist the existing vaccines and antivirals developed, which are primarily focused on Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS CoV). In late 2019, the novel CoV (SARS-CoV-2) emerged in Wuhan, China, causing global public health concern. In this review, we will summarize the key advancements of current vaccines and antivirals against SARS-CoV and MERS-CoV as well as discuss the challenge and opportunity in the current SARS-CoV-2 crisis. At the end, we advocate the development of a "plug-and-play" platform technologies that could allow quick manufacturing and administration of broad-spectrum countermeasures in an outbreak setting. We will discuss the potential of AAV-based gene therapy technology for in vivo therapeutic antibody delivery to combat SARS-CoV-2 outbreak and the future emergence of severe CoVs.

Keywords: 2019 nCoV; MERS- and SARS-CoV; adeno-associate virus; antivirals; coronavirus (CoV); passive immunization strategy; vaccine.

FIGURE 1

Spike and nsp12 phylogeny of representative coronaviruses. The Spike (A) and nsp12 (B) protein sequences of selected coronaviruses were aligned and phylogenetically compared. Coronavirus genera are grouped by classic subgroup designations (1, 2a-d, 3, and 4). In the Spike tree in (A), SADS-CoV is designated as 1* because of its distinctive grouping compared with more conserved proteins (e.g., nsp12, see (B)). Branches in each tree are labeled with consensus support values (in %). Sequences were aligned using free end gaps with the Blosum62 cost matrix, and the tree was constructed using the neighbor-joining method based on the multiple sequence alignment in Geneious Prime. Numbers following the underscores in each sequence correspond to the GenBank Accession number. The SARS-CoV-2 is highlighted in red. The radial phylogram was exported from Geneious and then rendered for publication using Adobe Illustrator CC 2020.

FIGURE 2

Schematic of the CoV replication cycle and key steps for antiviral targets. White text boxes indicate the subtype of antivirals that work either extracellularly or intracellularly. Different steps of the CoV replication cycle are illustrated in cartoon form, including receptor binding, membrane fusion, viral RNA replication, sub-genomic RNA transcription and translation.