Fight the Pandemic: Super Antibodies Coming to the Rescue


Summary

The development of numerous vaccines against SARS-CoV-2 worldwide within one year of the pandemic is unprecedented and undoubtedly a huge accomplishment in human history. But some of the emerging mutated SARS-CoV-2 variants can go around the antibody defenses established by developed vaccines and may lead to a broader transmission than the original one. Now, in Washington-1 (WA-1) strain infections, researchers have recognized four antibodies with potent neutralizing activity against twenty-three existing SARS-CoV-2 variants and shown that two of them, with ultrapotent ability, might even mitigate risk against future variants.

Background

COVID-19 vaccines can help people develop neutralizing antibodies against SARS-CoV-2 hence have been exploited around the world to fight against the pandemic, which has caused over 4 million global deaths. However, despite the high efficacy of many developed vaccines, it’s still too early to predict an end to the COVID-19 pandemic as variants of concern continue to emerge, challenging the long-term effectiveness of vaccination. Many of these variants carry mutations in the spike protein (S) targeted by therapeutic antibodies. Thus vaccines developed based on the original SARS-CoV-2 strain S sequence may provide reduced protection. Therefore, Wang et al. were determined to find super antibodies with increased breadth and potency against different existing and future variants.

Experiment

To find broadly reactive antibodies against SARS-CoV-2 variants of concern, Wang et al. first analyzed sera from twenty-two individuals infected by the WA-1 variant, which shares the same S sequence with the original SARS-CoV-2 strain.

Next, antibodies against WA-1 were selected and tested in other variants, including recently emerged D614G and thirteen circulating variants of concern such as B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, P.1, P.2, B.1.617.1 and B.1.617.2. Two ultrapotent antibodies against all tested variants were further selected for structural and functional analysis.

To explore possible critical spike mutations that may emerge in future variants driving resistance to ultrapotent antibodies, the researchers generated resistant viruses. Illumina-based shotgun sequencing allowed investigators to identify mutations in the S sequence  responsible for resistance. The capacity of individual antibodies or combinations to mitigate the risk of future escape variants was also evaluated.

Variable lambda and kappa light chain sequences of monoclonal antibodies involved in this study were codon optimizedsynthesized and cloned into CMV/R-based lambda or kappa chain expression vectors by GenScript.

Results

Four antibodies with high neutralizing and binding activity against the WA-1 variant were isolated and tested against a series of SARS-CoV-2 variants of concern/interest. The results showed that three of four antibodies maintained high potency against all involved variants, with A23-58.1 and B1-182.1 being the most potent. The hook-like motif and CDR crater are the structural and functional determinants of binding with variants for those two antibodies. Compared to individual antibodies, a combination of antibodies was less likely to generate escape mutants, suggesting a possible way to achieve both broad reactivity against and potent neutralization of existing variants of concern and future variants.

Reference

COVID-19 Map - Johns Hopkins Coronavirus Resource Center, (available at https://coronavirus.jhu.edu/map.html).

Wang, Lingshu, et al. "Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants." Science (2021).


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