Implications of New COVID Variant on Available Treatment
New COVID variants are an expected part of the evolution of viruses, including SARS-CoV-2 [1], and these have important implications on the epidemiological containment of and current clinical treatment protocols for each COVID variant.
Alpha
The B.1.1.7/Alpha COVID variant, first identified by the WHO in December 2020, harbors 17 mutations distinguishing it from the wild-type virus, including 8 in the spike protein. It is 43-90% more transmissible than early SARS-CoV-2 strains [2] and is associated with increased severity of infection, as assessed by number of hospitalizations and number of deaths. Unfortunately, it has also been shown to be less susceptible to neutralizing antibodies [3] [4].
Beta
In parallel, the WHO also named the 20H/501Y.V2/Beta variant in December 2020; it harbors 3 mutations on the surface of the spike protein that raised concerns. In general, this COVID variant has, similarly, been found to be more resistant to neutralization, including being less susceptible to bamlanivimab and etesevimab monoclonal antibody treatment for COVID variants, and incurring a higher risk of death [5].
Gamma
Harboring 17 amino acid substitutions, of which 10 affect the spike protein, the P.1/Gamma variant was first described by the WHO in January 2021. The Gamma variant results in reduced neutralization by monoclonal antibody therapies and post-vaccination or convalescent sera. It specifically has reduced sensitivity to bamlanivimab and etesevimab when used in the context of combined monoclonal antibody treatment. Fortuitously however, it has been demonstrated to have strong sensitivity to a number of other emergency use authorization (EUA) monoclonal antibody treatments [5].
Delta
The B.1.617.2/Delta variant was first designated a variant of concern by the WHO in May 2021. Highly mutated, it is the most dangerous SARS-CoV-2 variant to date given its high transmissibility, disease virulence, and high mortality rate. As a result, it quickly spread and sparked a new wave of infections in many regions. Indeed, the Delta variant has been shown to be more transmissible than the Alpha, Beta, and Gamma variants – including 60% more transmissible than the Alpha variant. In parallel, it is rather resistant to vaccine-induced immunity, in particular among subjects having received only one dose of a vaccine [6]. For example, AstraZeneca’s or BioNTech’s vaccines reduce the risk of COVID-19 disease by only one third for the Delta variant, in contrast to 50% for the Alpha variant. This is particularly threatening in light data confirming that it tends to be less sensitive to neutralizing antibodies [7].
Lambda
The C.37/Lambda variant was designated in June 2021 by the WHO; it contains 8 mutations, including 7 affecting the spike protein, which boost its infectiousness and help it evade the immune system. Although research has suggested that the Lambda is less concerning than other, more virulent SARS-CoV-2 strains [8], much remains unknown with regard to its transmissibility dynamics and vaccine responsiveness.
Omicron
The most recently designed variant of concern, B.1.1.529/Omicron, first reported to the WHO from South Africa in November 2021, is characterized by a heavily mutated spike protein (harboring over 30 mutations). Its high number of mutations have resulted in concerns as to its resultant transmissibility, immune system evasion tactics, and resistance to current vaccines [9]. Furthermore, it has been found not to be respond to emergency use authorized monoclonal antibody combinations, namely bamlanivimab/etesevimab (in combination) and casirivimab/imdevimab (in combination; i.e. REGEN-COV). The FDA has thus halted the use of such drugs for Omicron COVID-19 cases [10]. Research also suggests that Omicron has a higher chance of infecting those with immune protection from prior infection or vaccination. To this date however, COVID treatment and vaccine response patterns remain to be more fully elucidated by ongoing research.
Eta, Lota, and Kappa strains
Finally, Eta, Lota, and Kappa strains had emerged across a number of countries in the last 2 months of 2020. While such COVID variants may result in severe disease or death in some patients, these variants have not, overall, been considered severe enough to be designed variants of concern according to the WHO [11], and have no known implications for current COVID variant treatment.
Cross-variant treatments
Finally, a number of COVID-19 treatments have been developed that have been confirmed to be effective against most or all variants known to date. Recently, researchers from the Coronavirus Immunotherapy Consortium (CoVIC) analyzed nearly 300 monoclonal antibodies, mapping where they bind to the SARS-CoV-2 spike protein. They identified that three specific communities of antibodies were able to consistently neutralize SARS-CoV-2, irrespective of the strain, rendering these excellent candidates for future COVID-19 treatments.
In parallel, while antibody treatments to date have blocked SARS-CoV-2 by binding to one of three spike protein binding sites, thereby preventing it from attaching to and entering host cells, researchers have recently developed a new antiviral composed of “miniproteins” which can block viral receptor binding domain interaction with host ACE2 receptor. Specifically, these compounds can bind to all three spike protein binding sites. Not only did it neutralize SARS-CoV-2 more effectively than any other EUA antibody treatments to date, but the top candidate proteins also neutralized all tested SARS-CoV-2 variants [12]. Low-cost, easy to manufacture, and potentially self-administered, this new COVID variant treatment holds particular cross-variant therapeutic potential, if results can be verified through human trials
Finally, one direction of vaccine research is to target as broad a spectrum of SARS-CoV-2 variants as possible [1] – of particular importance since global vaccination rates are key to preventing the emergence of more variants [13].
References
1. Omicron, Delta, Alpha, and More: What To Know About the Coronavirus Variants > News > Yale Medicine. Available at: https://www.yalemedicine.org/news/covid-19-variants-of-concern-omicron.
2. Davies, N. G. et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science (80-. ). (2021). doi:10.1126/science.abg3055originally
3. Graham, C. et al. Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant. Immunity (2021). doi:10.1016/j.immuni.2021.03.023
4. Planas, D. et al. Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies. Nat. Med. (2021). doi:10.1038/s41591-021-01318-5
5. FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF BAMLANIVIMAB AND ETESEVIMAB AUTHORIZED USE TREATMENT. (2022).
6. Creech, C. B., Walker, S. C. & Samuels, R. J. SARS-CoV-2 Vaccines. JAMA – J. Am. Med. Assoc. (2021). doi:10.1001/jama.2021.3199
7. Planas, D. et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature (2021). doi:10.1038/s41586-021-03777-9
8. Padilla-Rojas, C. et al. Near-Complete Genome Sequence of a 2019 Novel Coronavirus (SARS-CoV-2) Strain Causing a COVID-19 Case in Peru. Microbiol. Resour. Announc. (2020). doi:10.1128/mra.00303-20
9. Sohan, M., Hossain, M. J. & Islam, M. R. The SARS-CoV-2 Omicron (B.1.1.529) variant and effectiveness of existing vaccines: What we know so far. Journal of Medical Virology (2022). doi:10.1002/jmv.27574
10. Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant | FDA. Available at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron.
11. World Health Organization. Tracking SARS-CoV-2 variants. Who (2021).
12. Hunt, A. C. et al. Multivalent designed proteins protect against SARS-CoV-2 variants of concern. bioRxiv Prepr. Serv. Biol. (2021). doi:10.1101/2021.07.07.451375
13. Rahman, F. I., Ether, S. A. & Islam, M. R. The ‘delta Plus’ COVID-19 variant has evolved to become the next potential variant of concern: Mutation history and measures of prevention. Journal of Basic and Clinical Physiology and Pharmacology (2022). doi:10.1515/jbcpp-2021-0251