key: cord-0990447-eqgfs9vb
authors: Boskovic, Marko; Migo, William; Likic, Robert
title: SARS‐CoV‐2 mutations: A strain on efficacy of neutralizing monoclonal antibodies?
date: 2021-04-12
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14849
sha: f0d6fb2ec1e70a70f874d216b224d88332511f3d
doc_id: 990447
cord_uid: eqgfs9vb

nan

The novel Severe Acute Respiratory Syndrome Virus 2 (SARS-CoV-2) pandemic was declared by the WHO in March 2020, with the number of new cases per day exceeding 50 000 globally. 1 tion is of particular concern as it undermines the strategy of herd immunity. 2 This wide-spread hesitancy towards vaccination necessitates the availability of alternative treatment options that could be more readily accepted. More worrisome, however, is the emergence of novel SARS-CoV-2 mutations and their resulting impact on the efficiency of vaccines and spike protein directed neutralizing monoclonal antibodies (NMAb). Data presented below examines the efficacy and use of NMAbs as post-exposure prophylaxis.

NMAbs function through inhibiting the viral spike protein (S-protein) which binds to host cells, and therefore, inhibition of the S-protein blocks viral entry into host cells. The S-protein consists of two subunits, S1 and S2, with the receptor binding domain (RBD) residing on the S1 subunit. The RBD binds to the transmembrane metalloprotein, angiotensin converting enzyme 2 (ACE-2), found abundantly in lung, small intestine epithelia as well as renal and arterial linings, supporting corresponding clinical presentations of COVID-19. 3 NMAbs have shown to be effective in reducing viral load in both animal and human trials. 8, 9 However, the impact on clinical outcomes has not been described in detail. Specifically, Regeneron's REGN-COV2 reported a response in sero-negative patients with high viral load in their interim analysis, with similar safety outcomes compared to placebo group. 10 incubated with highly neutralizing plasma from a COVID-19 convalescent patient. This plasma was found to initially neutralize the virus, however, over time in similar fashion, specific mutation events allowed for complete resistance to neutralization. 14 Taking these mutations into account with the relative lack of success of convalescent plasma, it is evident that a robust and broad effect of future SARS-CoV-2 biological treatments must be ensured in order to guarantee viral escape is minimized. It also raises the notion that caution with administration of new treatment options should be exercised. Weighing treatment options against potential selection pressure and subsequent viral mutation could prove to be decisive, in particular, in cases of chronic COVID-19 disease presentation and associated lengthy treatment times. As S-protein variants that resist neutralization are now present at low frequencies in circulating SARS-CoV-2 populations, monoclonal antibody combinations as opposed to polyclonal convalescent sera are favoured to mitigate viral escape. 15 The combination NMAbs such as BRII-196/BRII-198 and REGN-COV2 are stated to prevent viral escape by binding to two distinct neutralizing epitopes. 8, 16 In this instance, in order for viral escape to take place, two simultaneous viral mutations at two separate distinct genetic sites would need to take place.

Studies are being conducted imminently regarding current COVID-19 vaccines' effective protection against mutated SARS-CoV-2 strains. While a recent study observing the effect of Pfizer's BNT162b2 vaccine on N501 and Y501 mutations found little difference in neutralizing titers, 17 such studies should also be replicated in F I G U R E 1 Scatter graph to show number of current novel NMAb trials (indicated by Y/N criteria: Y = YES; N = NO; n = 59) versus enrolment number; Y = specific anti-SARS-CoV-2 Nmab, N = alternative target NMAbs as they represent an avenue for therapeutic intervention in high-risk individuals. Indeed, the emergence in the United Kingdom and South Africa of natural variants with similar changes demonstrates SARS-CoV-2's capability to escape an effective immune response and that monoclonal antibodies able to control emerging variants are in high demand.

Perpetuating viral mutation is the largest hurdle for the continued efforts for post-exposure prophylaxis. It is paramount that we remain vigilant and focused on mutation events in the RBD such as the E484 region. Moreover, amongst clinical effectiveness and safety concerns, producing effective NMAbs that meet supply and demand in a costeffective manner will be challenging. Finally, it will be a priority to identify those patients who could receive the highest benefit from the NMAbs, thus maximizing the appropriate use of resources. Despite all of these challenges, an alternatively promising therapy for COVID-19 is eagerly anticipated.

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