The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for approximately 600 million documented cases of coronavirus disease 2019 (COVID-19), with almost 6.5 million deaths. Despite the rollout of vaccines built on multiple platforms, the virus continues to mutate and emerge in new strains, often with immune escape capabilities that lead to breakthrough infections (BTIs).
This necessitates the continued development of effective and safe therapeutics, including monoclonal antibodies (mAbs) that neutralize the virus and prevent the progression of the illness if given in time. In a note of hope, a recent study presented the results of a human neutralizing antibody that proved effective against both recent variants of concern (VOCs), Delta and Omicron, both of which have shown the ability to evade the immune response elicited by earlier variants of the virus.
As the search continues for a broad-spectrum mAb or other inhibitory small molecule drugs, the virus continues to keep one step ahead through mutations in its neutralizing epitopes, or antigenic peptides, that are recognized by specific neutralizing antibodies. The Delta VOC had several mutations in the viral spike protein that enabled it to cause BTIs and reinfections in those who had already survived a bout of COVID-19 caused by an earlier strain.
The Omicron variant was even more evasive, with over 30 mutations in the spike protein and other changes in nucleotides in other key parts of the viral genome that conferred immune escape capabilities. This, coupled with its highly transmissible nature, caused it to replace Delta as the dominant strain worldwide.
Among mAbs in use, only sotrovimab retained activity against Delta and Omicron and is used to treat mild-to-moderate COVID-19 at present, albeit under an Emergency Use Authorization (EUA). However, it has not produced benefits in patients who require hospitalization, leaving a large gap for patients at risk for severe illness.
Besides the inefficacy of most mAbs in the face of these VOCs, most current neutralizing mAbs (nmAbs) are given intravenously, adding to the cost, level of sophistication and training required for administration, and the need for higher dosage to ensure in vivo efficacy.
Earlier research had turned up the potent nmAb 58G6 from COVID-19 survivors. It neutralized the authentic ancestral Alpha and Beta variants of SARS-CoV-2. The current study, published in the journal Signal Transduction and Targeted Therapy, focused on the ability of this nmAb to neutralize Delta, Omicron, and other VOCs, as well as its efficacy when given by the intranasal route in an animal model.
What did the study show?
The results demonstrated that 58G6 could bind the viral spike protein’s receptor binding domain (RBD) in both the ancestral or wildtype variant and other more recent variants. This is achieved because some RBD regions are highly conserved or untouched by mutations. In this way, 58G6 was able to bind the Delta and Omicron RBDs.
While Delta binding required only a low nanomolar half-maximal effective concentration (EC50), identical to that required for the ancestral variant, the value increased 50-fold for the Omicron RBD, both BA.1 and BA.2. Despite this, it showed a high binding affinity for all four spike variants, probably because of its binding patterns that retain affinity for key escape mutations.
Potent broad-spectrum neutralization was also observed for a range of SARS-CoV-2 variants at very low nanomolar half-maximal inhibitory concentrations (IC50) for most of them except the Omicron VOC. This required, again, a 50-fold higher IC50, which still worked out to approximately 60 ng/mL. This is a much lower concentration than those required for many nmAbs in use today to neutralize the Omicron RBD at >10 μg/m.
In a hamster experiment, the researchers administered the nmAb intranasally to see if it protected against the Delta variant. They found that the antibody protected the animals against illness when challenged by the virus either before or after antibody administration. The levels of viral ribonucleic acid (RNA) were lower in all tested tissues in the group protected by antibodies beforehand compared to all other groups.
In fact, at 3 days post-infection, the viral titer was undetectable. Lung damage was also obviously less in this group compared to all other groups.
Similar results were found when the animals were challenged with the Omicron VOC after a 3-fold higher prophylactic dose. This indicates the ability of the nmAb to protect against both these variants.
Experimentally, it was confirmed that a dose as low as 2 mg/kg led to reduced viral replication in the hamster lungs, preventing disease symptoms and allowing the infected animals to gain weight at a rate comparable to that of control animals.
Therefore, 58G6 could be an effective agent against the Omicron variant, although most nmAbs lose neutralizing activities against the Omicron variant.”
The findings indicate that 58G6 is a potent neutralizing antibody candidate against these two variants of concern and can arrest viral replication and clear the virus when administered intranasally. The low dosage indicated to be effective in animal models could probably increase its patient-friendliness, while the intranasal route reduces the costs and difficulty of administration.
The most important aspect of 58G6 is its broad spectrum of action, enabling it to neutralize all known VOCs as of now, using conserved RBD residues. This could make it useful against future emerging variants as well.