The emergence of the coronavirus disease (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to a global health emergency along with economic disruption.
Study: The emergence of SARS-CoV-2 variants threatens to decrease the efficacy of neutralizing antibodies and vaccines. Image Credit: Huen Structure Bio / Shutterstock.com
Background
SARS-CoV-2 is a positive-sense, enveloped single-stranded ribonucleic acid (RNA) virus that contains the spike glycoprotein on its surface. Entry of the virus inside the host cell is triggered by the binding of the receptor-binding domain (RBD) of the spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor.
The spike protein consists of S1 and S2 subunits. Cleavage of the spike protein occurs at the S1/S2 site, while S2 brings about the fusion of the host and viral membranes.
Most neutralizing antibodies and vaccines are targeted towards the viral entry mediated by the spike-ACE2 interaction. These vaccines consist of synthetic messenger ribonucleic acid (mRNA) that encodes the spike protein and delivers this mRNA to the cells through lipid nanoparticles. The efficacy of these vaccines against SARS-CoV-2 infection has been reported to be around 95% against the SARS-CoV-2 wild-type strain.
However, the emergence of highly transmissible and virulent variants of concern (VOCs) has limited the impact of neutralizing antibodies and vaccines against SARS-CoV-2. This also makes the surveying of viral evolution crucial.
A review article published in Biochemical Society Transactions focused on the efficacy of neutralizing antibodies and vaccines against the SARS-CoV-2 variants, wherein the authors highlight the need to develop and improve them continuously.
Antibodies isolated against SARS-CoV-2
Several early 2020 studies that were conducted at the beginning of the COVID-19 pandemic reported multiple neutralizing monoclonal antibodies against SARS-CoV-2. The hybridoma technology first invented in 1975 was known to provide a reliable source of mouse monoclonal antibodies.
These studies suggested that SARS-CoV-1 hybridoma produced an antibody that was effective against both SARS-CoV-1 and SARS-CoV-2. Additionally, other monoclonal antibodies against the spike protein demonstrated neutralizing activity, as well as robust performance in immunoassays.
The production of monoclonal antibodies by hybridoma is simple, low-cost, and the quality is stable. However, such antibodies can be used for treatment only if they are chimeric or humanized. Currently, human recombinant antibody production technology for the isolation of antibodies against SARS-CoV-2 is being used instead of traditional hybridoma technology since these antibodies can be used in human therapeutics more efficiently.
Single-cell cloning technology has recently been used to isolate neutralizing antibodies from convalescent patients. This has shortened the process of antibody isolation as compared to the traditional methods. Although these monoclonal antibodies are recombinant, they are humanized and can therefore be directly used in humans.
Passive immunization
Passive immunization can help to control the pandemic by providing immediate protection, as well as complementing the development of prophylactic vaccines. In this regard, convalescent plasma therapy (CPT) was considered a promising method in the control of COVID-19.
However, monoclonal antibodies are being considered a better alternative for CPT in the treatment of COVID-19. More than 20 neutralizing antibodies against SARS-CoV-2 have been used in clinical trials, several of which have been approved for emergency use by the United States Food and Drug Administration (FDA) as of July 2021.
REGN-COV2 is a cocktail of two monoclonal antibodies, casirivimab and imdevimab, that has been approved by the FDA for emergency use. Other monoclonal antibodies that have been approved for use are bamlanivimab monotherapy, a combination of bamlanivimab with etesevimab, sotrovimab, and PiN-21.
Vaccine-induced antibody
Several vaccines have received emergency use approval worldwide, with over 55.4% of the world’s population vaccinated against COVID-19 to date. Among them, mRNA vaccines received first authorization due to their flexibility and potential of rapid production of any mRNA against future SARS-CoV-2 variants.
Recently, 37 spike-binding monoclonal antibodies were isolated from three participants who received the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine BNT162b2. Out of them, 17 bound to the RBD and six recognized the N-terminal domain (NTD). In addition, three monoclonal antibodies showed cross-reactivity that was suggestive of a memory B-cell origin.
However, mRNA vaccines were found to induce more non-neutralizing antibodies as compared to neutralizing antibodies. Two of these neutralizing antibodies targeted RBD, while five recognized NTD.
Comparison of specificity of sera elicited by the Moderna vaccine and natural infection with SARS-CoV-2 indicated that vaccine-induced antibodies bind to RBD broadly across epitopes as compared to infection-induced antibodies. Also, the neutralizing activity of sera of convalescent patients was found to be lower than vaccine-induced neutralization activity. However, when the survivors were immunized, it boosted their neutralizing titers against SARS-CoV-2 variants.
Efficacy of vaccines and monoclonal antibodies against SARS-CoV-2 variants of concern
Multiple SARS-CoV-2 VOCs have been reported to date with increased pathogenicity and infectivity. As of December 2021, the five declared VOCs include the Alpha, Beta, Gamma, Delta, and Omicron variants. Among them, Delta is currently predominant worldwide since its emergence in India towards the end of 2020.
The transmission of the Delta variant is 64% higher as compared to the Alpha variant, and is also associated with higher secondary attack rates for contacts of cases. The P681R mutation of the spike protein in the Delta strain has been associated with increased replication and viral transmission. Taken together, the emergence of these VOCs threatens the treatment of SARS-CoV-2 through both passive immunization and vaccines.
The Beta and Gamma variants, both of which contain the E484K mutation, were found to be sensitive to bamlanivimab. However, the cocktail of bamlanivimab and etesevimab was not effective against the Beta and Delta variants.
The Alpha variant was found to escape recognition by etesevimab but not by bamlanivimab, while the Delta variant escaped recognition by bamlanivimab but not by etesevimab. The Gamma variant, however, escaped from both bamlanivimab and etesevimab.
The cocktail of casirivimab and imdevimab known as REGN-COV2 have been found to protect against the Alpha, Beta, Gamma, and Delta variants. Furthermore, it was found that a triple combination of non-competing antibodies including casirivimab, imdevimab, and REGN10985 could limit the emergence of new escape variants in vitro. Although sotrovimab and imdevimab have shown neutralizing activities against all these four VOCs in vitro, they might lose their effectiveness with the emergence of new variants.
The efficacy of vaccines was found to be reduced in the case of SARS-CoV-2 variants with E484K, N501Y, and K417N/E484K/N501Y mutations that were found in the Alpha, Beta, and Gamma variants. The sera of individuals who received two doses of Pfizer or AstraZeneca vaccines were found to be less potent against the Delta and Beta variants as compared to the Alpha variant.
Although the Delta variant was moderately resistant to vaccines, high effectiveness was confirmed after two doses of the vaccine. Furthermore, the sera from individuals who had received only one dose of the vaccine did not significantly inhibit variants.
The sera from convalescent patients collected 12 months after recovering from COVID-19 were found to lose their neutralizing activity, whereas these patients acquired cross-neutralizing activity against VOCs after a single dose of the vaccine.
The generation of vaccine-induced neutralizing antibodies is not the only mechanism of the clinical effectiveness of vaccines. The Pfizer-BioNTech vaccine has been found to induce a germinal center response, as well as T-follicular helper cell response.
T-cell-mediated immunity plays an important role in viral clearance and protects vaccinated individuals from severe disease. Although the emergence of variants could reduce the efficacy of the vaccines, vaccine-induced T-cell immunity is conserved and can provide protection against future variants.
Conclusion
The development of monoclonal antibodies and vaccines are considered the two most important strategies in the treatment and prevention of COVID-19. However, the emergence of new variants has affected these strategies.
Although new SARS-CoV-2 variants can reduce neutralizing activity, vaccine-induced T-cells and memory B-cells could protect vaccinated individuals against severe disease. Neutralizing antibodies and vaccines should be examined regularly to determine their efficacy against the variants. Additionally, the surveillance of new variants must be done continuously for the development of future vaccines.
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