The threat of emerging COVID-19 variants and future outbreaks of SARS coronaviruses is linked

  (photo credit: Ali Munawar)
(photo credit: Ali Munawar)

Emerging COVID-19 variants are making the already prevalent challenges of the pandemic feel never-ending. Researchers at the forefront of the fight are making strides in understanding the complexity of coronavirus infections with a view to managing future outbreaks. For instance, the latest publicly-known COVID-19 variant, Omicron or B.1.1.529, was designated a variant of concern by the World Health Organization on November 26, 2021. In this short period, the Omicron variant has rapidly become one of the dominant variants alongside the Delta variant (B.1.617.2) leading to a new wave of infections and hospitalization across the globe. The Omicron variant is different from previous variants due to the high number of mutations that have developed in its proteins, some of which give it an evolutionary advantage.  

The Omicron variant has ~50 mutations of which 35 are in the spike protein of the virus alone. The spike protein is the fundamental and primary determinant of COVID-19 infection in humans. Due to its pivotal role in cell entry and determining infectious range, the spike is also the target of approved therapeutic antibodies, including ones from Regeneron and Lilly. These antibodies neutralize its function, binding it and preventing it from engaging host cell receptors. Vaccines also comprise either just the spike protein by itself or genetic material making the spike protein. Exposure to this virus component through vaccination enables the immune system to raise its own antibodies against the spike. As many people in communities around the world head in for their third vaccine dose, researchers like Ali H. Munawar, Ph.D., are among the virus specialists analyzing the mutations of the Omicron variant and how to shape effective treatment options.

The Omicron Variant and Spike Protein of the Virus

The dance between COVID-19 management and its immune evasion is primarily an interplay of the spike protein and efforts to neutralize it. Due to its immunogenic feature, the spike protein of coronavirus is at the center of managing the COVID-19 pandemic. This fundamental immunogenic feature exerts an evolutionary pressure on the spike protein of coronaviruses, leading it to mutate and evade either the therapeutic antibodies or the vaccine-induced antibodies directed against it. The large number of mutations in the spike of the Omicron variant enables immune escape. 

The Emergence of Resistance Mutants

Viruses accrue random mutations at a fast rate, making them experts at developing resistance.  Often, mutations are deleterious to the virus, since evading the immune system by modifying its structure can have adverse effects on the function of that structure. However, when the virus is able to access mutations that can avoid detection or binding antibodies while continuing to support the viral function, the threat translates into the emergence of resistant mutants. 

This scientific principal is routinely studied in labs across viruses, and virus specialists are actively studying the function and importance of mutations. One company leading the charge in this research is Orthogon Therapeutics, an organization that designs transformative medicines against challenging antiviral and anti-infective targets. In the face of COVID-19, Orthogon has equipped its team of virus specialists, opening a separate branch of its organization to deal with coronavirus related research, specifically with a view to developing broad spectrum anti-COVID strategies that are resilient to the emergence of variants.

Identifying “Highly Conserved” Sites

A barrier to developing drug or immune resistance is determined by the functional and structural constraints around a given region on the protein. Proteins by design have genetically conserved regions that are less prone to mutation. These are important to the virus’ function and very few permutations can be accepted if the virus is to remain functional or viable. These “highly conserved” sites vary less between different strains of viruses and can even transcend into other genera or families of viruses. 

Hyper-Mutable Regions

In contrast, there are regions on proteins that are hyper-mutable. These exhibit significant genetic variation between different populations or strains of the same virus. The diversity in these regions enables the virus to dodge the immune system’s recognition machinery or access orthologs of host cell receptors, making it easy to jump across hosts and overcome limitations. 

These regions that are least diverse and are already mutation prone happen to be the primary targets for receiving therapeutic or vaccine-induced neutralizing antibodies. In the case of the SARS-CoV-2, the COVID-19 virus, the region of the spike protein that recognizes a key human protein receptor to infect cells is among the regions prone to mutation. The Omicron variant has a large number of mutations in the receptor binding domain (RBD) of the spike which makes direct interactions with the human ACE2 receptor. The effortless mutation of the spike RBD compromises the potency of therapeutic and vaccine induced antibodies generated by the immune system. In addition to evading the immune response, this same feature also enables coronaviruses to expand their host range; by conveniently altering the structure of their RBD through mutation they can sample greater host range, enabling inter-species infections. Directing antibodies against this region produces a potent antiviral and protective effect. However, that effect can wane when mutations emerge.

Turning the Tide of the Disease by Blocking Viral Entry

The fact that the RBD is involved with the first step of viral infection, i.e. engaging host cells for virus entry, is why the Regeneron cocktail of antibodies has been known to turn the tide of disease around rapidly by blocking viral entry and securing uninfected cells. This RBD is also the most immunogenic region and patient sera from vaccinated patients show that most of the antibodies generated by the Pfizer, Moderna, Johnson and Johnson or AstraZeneca vaccines target the RBD of the COVID-19 spike protein.

The Best Effect in the Most Mutation Prone Region

Due to the pivotal role of the RBD region in perpetuating infection, antibodies targeting the RBD region involved with human ACE2 recognition also happen to achieve the most potent neutralizing effect. However, this same ACE2 recognition region is also one of the most mutation prone regions of the coronavirus.

Ongoing efforts must balance targeting regions on the spike RBD and outside the RBD across the family of coronaviruses. Some genetically conserved regions are easily identifiable. According to Orthogon founder and researcher Dr. Munawar, antibodies targeting the regions of the coronavirus spike protein that are not directly involved with the ACE2 receptor recognition may not have a dramatic neutralizing effect on the virus but will circumvent the resistance to mutations. The benefit of these indirect binding antibodies is that they can strike at the area of the spike which is less likely to mutate. These classes of antibodies could also be effective against other related coronaviruses that have not yet made the species jump from animals to humans.

The Future of COVID-19 Drug Development

There have already been several antibodies like those described above which were likely deprioritized in the first wave of COVID-19 drug development. Vaccine design and therapeutic antibody development strategies must look at the emergence of future variants and the zoonotic spillover of other coronaviruses from animals to humans. It’s not a coincidence that SARS-CoV-2 is the seventh coronavirus to have made the species jump into humans recently; in the last 20 years alone, there are four others on record.

Researchers must urgently identify the cell receptors used by the many coronaviruses circulating in various animal reservoirs with a view to future pandemic preparedness. Only by doing so can they predict which coronaviruses are only a few mutations away from infecting humans. Several coronaviruses from the COVID-19 family of coronaviruses are able to recognize and bind to human receptor proteins, which is the doorway for COVID-19 infections.

This article was written in cooperation with DN News Desk