Analysis of Immune Escape Variants from Antibody-Based Therapeutics against COVID-19: A Systematic Review

Focosi, Daniele; Maggi, Fabrizio; Franchini, Massimo; McConnell, Scott A.; Casadevall, Arturo

doi:10.3390/ijms23010029

Cited by 48 publications

(68 citation statements)

References 63 publications

(37 reference statements)

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“…Nevertheless, vaccines that elicit systemic immunity without mucosal immunity are unlikely to end the pandemic because these prevent disease and not infection, and every case of infection involves viral replication with the opportunity for the emergence of vaccine-resistant variants. Every preventive or therapeutic human intervention against a pathogen creates selective pressure that can lead to the emergence of escape variants [124] and vaccines are no exception. This may apply to competition among lineages as well as accelerated intra-vaccinee evolution.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

Focosi¹,

Maggi

Casadevall

2022

Viruses

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Sterilizing immunity after vaccination is desirable to prevent the spread of infection from vaccinees, which can be especially dangerous in hospital settings while managing frail patients. Sterilizing immunity requires neutralizing antibodies at the site of infection, which for respiratory viruses such as SARS-CoV-2 implies the occurrence of neutralizing IgA in mucosal secretions. Systemic vaccination by intramuscular delivery induces no or low-titer neutralizing IgA against vaccine antigens. Mucosal priming or boosting, is needed to provide sterilizing immunity. On the other side of the coin, sterilizing immunity, by zeroing interhuman transmission, could confine SARS-CoV-2 in animal reservoirs, preventing spontaneous attenuation of virulence in humans as presumably happened with the endemic coronaviruses. We review here the pros and cons of each vaccination strategy, the current mucosal SARS-CoV-2 vaccines under development, and their implications for public health.

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Section: Discussionmentioning

confidence: 99%

Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

Focosi¹,

Maggi

Casadevall

2022

Viruses

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“…The RBD, which mediates the initial attachment of SARS-CoV-2 to its primary receptor, angiotensin converting enzyme 2 (ACE2), and the S1 domain overall have undergone substantial antigenic diversity since the initial emergence of SARS-CoV-2. Mutations within RBD and S1 dramatically negate the neutralizing activity of plasma antibodies (Abs) against SARS-CoV-2 VoC that are generated from vaccinated or infected individuals and enhance the transmissibility and pathogenicity of VoC (1)(2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody

Piepenbrink

Park

Deshpande

et al. 2022

Preprint

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development.

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“…2 ) have significantly increased resistance (typically three- to fivefold, but not entirely resistant) to convalescent plasma derived from patients harboring SARS-CoV-2 lacking the E484K mutation [ 42 , 164 – 168 ]. Additional mutations such as N440K, V483A, F490S, Q493R/K, and N501T also have been shown to contribute to immune evasion of CPT [ 169 ]. With these factors in mind, note that the quality of convalescent plasma with respect to new variants will change with the infected source, i.e., convalescent patients.…”

Section: Convalescent Patient and Polyclonal Therapeutic Approachesmentioning

confidence: 99%

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

Strohl

et al. 2022

BioDrugs

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The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly’s bamlanivimab and etesevimab, Regeneron’s mixture of imdevimab and casirivimab, Vir’s sotrovimab, Celltrion’s regdanvimab, and Lilly’s bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-022-00529-7.

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Analysis of Immune Escape Variants from Antibody-Based Therapeutics against COVID-19: A Systematic Review

Cited by 48 publications

References 63 publications

Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

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