Over 500 clinical studies are now registered with clinicaltrials.gov to investigate a range of therapeutic approaches to COVID-19 infection. The list includes over 70 novel vaccines at various stages of development. The following is a summary of the strategies for vaccines currently in development.

The SARS-CoV-2 virus is the third coronavirus (after SARS-CoV and MERS-CoV) to cause severe respiratory disease in humans. Genome sequencing of SARS-CoV-2 has shown that the virus is 82% identical to SARS and 50% identical to MERS-CoV (Chan et al. Emerg Microbes Infect 2020;9:221-236. Lu et al. Lancet 2020;395:565-574). The cell surface receptor for SARS-CoV-2 binding (as with SARS and CoV-NL63) is the membrane protein angiotensin converting enzyme (ACE)-2 (Wang et al. Cell 2020; epublished April 7, 2020). Cell entry is via interaction with the viral spike (S) glycoprotein, which is cleaved into S1 and S2 subunits that recognize surface receptors and fuse with the membrane. The S1 subunit is further divided into N- and C-terminal domains (NTD, CTD). (For SARS and MERS-CoV, the S1-CTD is called the receptor binding domain, RBD.) The spike protein has become the principal target of vaccines in development although other viral proteins may also serve as antigens.

SARS-CoV-2 has a four-fold greater receptor affinity with ACE2 than is seen for SARS-RBD (Wang 2020). As ACE2 expression in the upper airways is limited, this improved binding may contribute to the more severe upper respiratory symptoms and greater airborne transmissibility of SARS-CoV-2 compared to SARS (Hoffmann et al. Cell 2020; epublished April 16, 2020). In addition, SARS-CoV-2-CTD and SARS-RBD are antigenically distinct so that monoclonal antibodies targeting SARS-RBD are unable to bind to the SARS-CoV-2 S protein, indicating that there is little cross-reactivity between the two (Wrapp et al. Science 2020;367:1260-1263). As a result, vaccine candidates based on the SARS-CoV RBD would be unlikely to be useful for SARS-CoV-2 (Wang 2020).

Other potential immune targets that have been suggested are S2 regions, which show greater similarity between SARS-CoV-2 and SARS; and TMPRSS2 (transmembrane serine protease-2), which is involved in priming the S protein (Hoffmann 2020).

One COVID-19 vaccine is currently in phase II testing and eight are in phase I, according to the Vaccine Centre at the London School of Hygiene & Tropical Medicine (https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/). The candidates include:

• Ad5-nCoV (CanSino): Uses a recombinant novel coronavirus (adenovirus type 5 vector) which encodes for a full-length SARS-CoV-2 S protein. Administered once by intramuscular injection. Currently in phase II.
• mRNA-1273 (ModernaTX): encodes for a full-length stabilized SARS-CoV-2 S protein encased in a lipid nanoparticle. The vaccine is administered on days 1 and 29.
• INO-4800 (Inovio): Delivers DNA plasmids encoding SARS-CoV-2 S protein into cells using a Cellectra smart device, which uses electrical pulses to open pores. The technology was used for a MERS-CoV vaccine in phase I testing.
• ChAdOx1 (Oxford University): The ChAdOx1 viral vector was developed for MERS-CoV. For SARS-CoV-2 it will use an attenuated adenovirus that produces the S protein. Administered intramuscularly.
• aAPC (Shenzhen): uses artificial antigen-presenting cells (aAPC) modified with lectiviral vector expressing synthetic minigenes that produce viral structural and protease proteins. Injected subcutaneously on days 0, 14 and 28.
• LVSMENP-DC (Shenzhen): Similar technology as for aAPC. Uses dendritic cells modified with lentiviral vector expressing minigenes for COVID-19 antigens; administered with antigen-specific cytotoxic T cells. Given subcutaneously or by IV infusion.
• bacTRL-Spike (Symvivo): Uses live Bifidobacterium longum engineered to deliver plasmids containing synthetic DNA encoding for the SARS-CoV-2 S protein. Administered orally in one of three doses (1 mL, 3 mL, 10 mL), with each 1 mL containing 1 billion colony forming units of longum.
• BNT162 (BioNTech/Pfizer): Uses four different mRNAs (nucleoside modified, uridine-containing and self-amplifying mRNA) and different target antigens (S sequences and RBD) combined with a lipid nanoparticle. A cohort of 12 patients in Germany received the first dose on 23 April. Safety data are expected in May.
• Inactivated vaccine (Sinovac): SARS-CoV-2 inactivated vaccine. Demonstrated efficacy in animal studies. Phase I in 144 healthy volunteers has started. Announced collaboration with Dynavax, which produces adjuvant CpG 1018.

Several companies (e.g. GlaxoSmithKline, Seqirus, Dynavax) are producing adjuvants to enhance the immunogenicity of the vaccines in development by other companies. In Canada, additional vaccine research is being conducted at Western University, McMaster University, University of Alberta, Laval University, University of British Columbia, University of Saskatchewan and University of Manitoba. The Coalition for Epidemic Preparedness Innovation (CEPI) estimates that a vaccine may become available in early 2021.

For a recent review see Amanat et al. Immunity 2020;52; epublished April 14, 2020. Free full text at www.cell.com/immunity/pdf/S1074-7613(20)30120-5.pdf.