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Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies

Baum et al., Science, 21 Aug 2020, 369:6506, 1014-1018, doi:10.1126/science.abd0831
Aug 2020  
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16th treatment shown to reduce risk in March 2021
*, now known with p = 0.000018 from 28 studies, recognized in 42 countries. Efficacy is variant dependent.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,100+ studies for 60+ treatments.
In Vitro study showing that, under pressure from individual antibodies, mutant viruses were rapidly selected that evaded the blocking function of all individual antibodies tested, including antibodies that potently bind to highly-conserved regions on the spike protein. However, escape mutants could not be efficiently generated following exposure to the REGN-COV2 cocktail since it utilizes two antibodies that can simultaneously bind to distinct regions of the RBD.
Efficacy is variant dependent. In Vitro research suggests a lack of efficacy for many omicron variants Haars, Liu, Pochtovyi, Sheward, Tatham, VanBlargan.
Baum et al., 21 Aug 2020, peer-reviewed, 17 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Abstract: RES EARCH CORONAVIRUS Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies Alina Baum, Benjamin O. Fulton, Elzbieta Wloga, Richard Copin, Kristen E. Pascal, Vincenzo Russo, Stephanie Giordano, Kathryn Lanza, Nicole Negron, Min Ni, Yi Wei, Gurinder S. Atwal, Andrew J. Murphy, Neil Stahl, George D. Yancopoulos, Christos A. Kyratsous* Antibodies targeting the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present a promising approach to combat the coronavirus disease 2019 (COVID-19) pandemic; however, concerns remain that mutations can yield antibody resistance. We investigated the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared after in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Escape mutants were not generated after treatment with a noncompeting antibody cocktail. O Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. *Corresponding author. Email: Baum et al., Science 369, 1014–1018 (2020) in response to selective pressure from singleantibody treatments. To assess the efficacy of our recently described antiviral antibodies against the breadth of spike RBD variants represented in publicly available SARS-CoV-2 sequences identified through the end of March 2020 (representing more than 7000 unique genomes), we used the VSV pseudoparticle system expressing the SARS-CoV-2 spike variants. Our top eight neutralizing antibodies maintained their potency against all tested variants (Table 1), demonstrating broad coverage against circulating SARS-CoV-2. Next, escape mutants were selected under pressure of single antibodies, as well as of antibody combinations, by using a replicating VSV-SARS-CoV-2-S virus (Fig. 1A). We rapidly identified multiple independent escape mutants for each of the four individual antibodies within the first passage (Fig. 1, B and C, and Fig. 2). Some of these mutants became readily fixed in the population by the second passage, representing 100% of sequencing reads, and are resistant to antibody concentrations of up to 50 mg/ml [a factor of ~10,000 to 100,000 greater concentration than half-maximal inhibitory concentration (IC50) against parental virus]. Sequencing of escape mutants (Fig. 2) revealed that single amino acid changes can ablate binding even to antibodies that were selected for breadth against all known RBD variants (Table 1) and that neutralize parental virus at IC50 values in the low picomolar range (3). Analysis of 22,872 publicly available unique genome sequences (through the end of May 2020) demonstrated the presence of polymorphisms analogous to two of the escape amino acid residues identified in our study, albeit at an extremely low frequency of one each. Thus, although natural variants resist- 21 August 2020 1 of 4 ne promising approach to combat the coronavirus disease 2019 (COVID-19) pandemic involves development of antiviral antibodies targeting the spike protein of severe acute..
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