New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, posing formidable challenges to vaccine efficacy and the end of the pandemic. Selective immune and vaccine pressures have guided the emergence of the mutations, often because of prolonged infections in immunocompromised individuals.
Many of these variants have aroused significant concern because of their increased transmissibility and immune escape capabilities, blocking suppression by either vaccine-induced, infection-induced or passive immunity induced by monoclonal antibodies (mAbs). These are called variants of concern (VOCs). A new paper reports for the first time that a mAb can block all VOCs known so far.
Multiple antibody-based therapeutic strategies have been deployed to fight the coronavirus disease 2019 (COVID-19) pandemic, especially in the immunocompromised, those with underlying high-risk illnesses such as cardiovascular, diabetic, or respiratory conditions, and the elderly (over 65 years). Among the first was LY-CoV555 (bamlanivimab) from Eli Lilly, tested just three months after the start of research aimed at mAb discovery.
A cocktail of bamlanivimab with etesevimab was approved for emergency use in several countries, along with others from companies like Regeneron, GSK/Vir and AstraZeneca. The most essential condition for an effective therapeutic neutralizing antibody is broadly neutralizing capability to ensure that no variant slips through the net and is thus positively selected. Moreover, potent neutralization will allow for lower clinical doses to be administered, reducing costs as well as the risk of adverse effects.
The VOCs that arose during the pandemic have mostly emerged following large-scale vaccinations in certain world regions. These have selective advantages, such as increased binding affinity for the receptor, higher infectivity or virulence, or immune escape. The underlying mechanism appears to be the mutations associated with these VOCs, such as the N501Y of the Alpha variant that led to a rise in the binding affinity with the receptor.
Again, the key mutation E484K has presented itself in several independently emerging VOCs from different parts of the world and is linked to potent resistance to antibody-mediated neutralization. Other mutations have been shown to disrupt the activity of therapeutic mAbs in various ways. This led to several attempts like the present one, to identify mAbs that target highly conserved epitopes and thus ensure broad potent neutralizing activity.
This is all the more important in that therapeutic mAbs have been shown to reduce COVID-19 severity when given promptly, decreasing the mortality rate.
Omicron has shown remarkable resistance to most of the earlier mAbs, singly and in cocktails. The current study published in the journal Cell Reports, describes a new mAb LY-CoV1404 (bebtelovimab) from Eli Lilly, with high neutralization potency with a broad spectrum of activity across all current variants.
What did the study show?
The results of the study show that despite the presence of numerous mutations that affect antibody binding to the receptor-binding domain (RBD) of the spike protein, bebtelovimab binds to all known variants and potently neutralizes them. This includes Omicron, the Delta variant, the Alpha, Beta, Gamma, and many others.
This is achieved via the binding of the antibody with high affinity to an easily accessible epitope on the spike protein. Additionally, LY-CoV1404 prevents the binding of the spike protein with the spike receptor, the angiotensin-converting enzyme 2 (ACE2), explaining its uniform and potent neutralizing activity.
Recent research has come up with several such antibodies that use this mechanism of ACE2 receptor blockade to treat COVID-19, showing it to be a very effective and safe mode of treatment. The current mAb solves the vexing problem of resistance to neutralization by these antibodies with most newer VOCs, causing a major loss of efficacy of most clinically tested antibodies.
In fact, with Omicron, even the two antibodies to SARS-CoV-2, ADG20, and S309, which showed cross-reactive responses to SARS, and were relatively immune to mutational escape, nonetheless lost 300-fold and 10-fold potency against this variant. Even here, LY-CoV-1404 retains complete functional potency in pseudotype neutralization assays, with a 50-fold increase in neutralization potency against Omicron compared to any other antibody that has reached clinical stages of testing.
This is attributable to the unique epitope of this antibody and the low number of mutations at this epitope. With increasing vaccination rates, selection pressures may lead to the emergence of specific adaptive mutations. This will necessitate the identification of alternative treatments, especially as population immunity seems unachievable in the near term, at any rate.
Especially in the immunocompromised patient with COVID-19, who are also less likely to mount an adequate immune response to COVID-19 vaccines, this antibody could not only protect the patient from severe disease but also bring about an end to chronic SARS-CoV-2 infection with increased chances of mutations and viral evolution.
Compared to another recently reported mAb, VIR-7831 (sotrovimab, GSK, 2021), with binding and neutralizing activity against current VOCs at a dose of 500 mg, LY-CoV1404 has the equal neutralizing capacity with a minor advantage in potency by several-fold. This could allow its subcutaneous administration at lower doses to prevent or treat the infection.
This antibody, LY-CoV1404, came from a convalescent SARS-CoV-2 patient and was selected for its ability to cross-react with multiple variants of the virus, indicating the presence of potent neutralizing epitopes. Another recent report describes the antibody S2X259, again with broad cross-reactivity to many SARS-CoV-2 variants as well as to several zoonotic strains, but this is less potent in neutralization assays than LYCoV1404.
What are the implications?
This study suggests that “this antibody could provide an effective therapeutic option against current VOCs and emerging variants as a complementary approach to vaccinations and other COVID-19 therapies.”
The researchers propose to build up an array of similar antibodies with potent neutralizing capacity against all known SARS-CoV-2 RBD variants. By characterizing them and preparing them for research cell banks, they hope to enable the rapid progress of manufacture, leading to their availability for clinical use in the near future.
This would help prevent future waves of COVID-19 due to new variants since the identification of the mutation and its effect on binding and neutralization are needed to select and deploy the right antibody from the panel at top speed.
This strategy of a panel of antibodies, including LY-CoV1404, which received Emergency Use Authorization in February 2022, would enable a rapid response to any emerging variant, such that early treatment could be given to the infection, preventing severe disease to a large extent.