A systemic alignment analysis of the SARS-CoV-2 genome sequences deposited in the databases revealed that there are more than 156 total variants13. The distinct variants consist of 46 missense, 52 synonymous, 2 insertion, 1 deletion, and 14 non-coding alleles. The most common variants were 8782C-T, 28144T-C, and 29095C-T. In terms of base changes, the most frequently observed one is C-T.
COVID-19 mechanism of pathogenesis
Emerging experimental data of SARS-CoV-2 viral protein structures indicate that the spike protein of SARS-CoV-2 virus SARS-2-S binds to the ACE2 receptor with high affinity to mediate SARS-CoV-2 entry into human cells15, 17. Functional studies using pseudovirus containing SARS-2-S protein and authentic SARS-CoV2 isolates from human patients also determined that SARS-2-S binds to ACE2 to enter the host cells 16. The SARS-2-S protein and the interactions between SARS-2-S and ACE2 are thus key determinants of human infection and COVID-19 pathogenesis (Fig. 1C).
Current status of development of therapeutic agents for COVID-19 therapy
Small molecule anti-viral agents. Nucleotide analog remdesivir from Gilead made headline news when a patient with COVID-19 was cured 18. Remdesivir has been in development for a few years as an RNA virus therapy and was originally developed for Ebola. Subsequent clinical trials of remdesivir as a compassionate agent found clinical improvement in 36 of 53 patients (68%) with severe COVID-19 disease19. A large clinical trial in the US has shown efficacy with 31% improvement in patient recovery time (ABC news, 04-29-2020). However, other clinical results are not consistent and the therapeutic efficacy of remdesivir remains to be further determined 20. In addition, siRNA, protease inhibitors, famotidine, ACE2 peptides, and SARS-2-S peptides have also been explored for COVID-19 therapy 21. The current effort in the anti-COVID-19 small molecule therapy has been focused on repurposing approved agents8, 22, 23.
SARS-CoC-2 vaccine development. Generally speaking, vaccine is an effective and proven agent to protect humans from infections 24. There are currently extensive efforts in developing vaccines for SARS-CoV-2, including RNA, DNA, recombinant S protein, viral vector, liver attenuated whole virion, and inactivated whole virion vaccines 24. One challenge is that developing a vaccine can take years 25. In addition, it appears to be difficult to develop effective vaccine for coronavirus 26, 27. The previous experience with the development of vaccines for SARS-CoV-1, Ebola, and MERS-CoV suggests that vaccines for SARS-CoV-2 may have a lot of challenge ahead 24, 28.
SARS-CoV-2 antibody immunotherapy. Early studies of other coronavirus such as SARS-CoV-1 and MERS indicate that treatment of patients with convalescent sera reduces the spreading of infection and mortality 29, 30. Passive antibody immunotherapy with convalescent sera is thus considered as an effective and timely approach for suppressing SARS-CoV-2 31-34. Immunotherapy by transferring the convalescent sera from recovered patients from COVID-19 to patients with severe disease resulted in improvement in their clinical status 33. The FDA is currently coordinating a national effort to develop blood-based, antibody-rich COVID-19 immunotherapies, which includes convalescent sera and the hyperimmune globulin derived from it for treatment of COVID-19 patients and for identifying persons with previous exposure to SARS-CoV-2. The challenges are availability of sufficient donors, clinical conditions, and viral kinetics, which needs to be addressed before considering convalescent serum as a therapeutic agent for COVID-19 patients 32.