Should siRNA-based antivirals be added to the COVID toolbox?

By Shanet Susan AlexReviewed by Danielle Ellis, B.Sc.Jul 19 2022

A recent study published in Exploration reviewed the existing treatment modalities, including vaccines and antivirals, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It highlighted the need for a CoV disease 2019 (COVID-19) toolbox to curb the emerging viral variants.

Background

SARS-CoV-2 causes the highly contagious viral illness, COVID-19. Over 6.3 million people thus far have died because of this deadly virus globally. Undoubtedly, the worldwide distribution of COVID-19 vaccinations has prevented countless deaths by lessening the symptom severity of SARS-CoV-2 patients. 

Nevertheless, the vaccines and antivirals created to combat COVID-19 might lose their therapeutic efficacy as SARS-CoV-2 persistently evolves. Moreover, there are concerns regarding the transient and long-standing adverse impacts of repeated exposures to existing COVID-19 vaccines.

About the study

In the present review, the researchers discussed the advantages and disadvantages of the SARS-CoV-2 vaccine deployment. Besides, they aimed to support the concept of a COVID medicinal toolkit composed of various antiviral treatment options since each therapeutic class harbors its strengths and limitations in mitigating SARS-CoV-2 and its variants. 

The team also demonstrated some of the most recent therapeutic approaches currently researched to try and curb the SARS-CoV-2 and other COVID viruses that possibly come after. Finally, they analyzed the most recent research on using short interference ribonucleic acid (siRNA) therapeutic agents for staying flexible and in sync with the constantly changing mutation rate of SARS-CoV-2.

Advantages and disadvantages of COVID-19 vaccines

The authors noted that available data suggest that the SARS-CoV-2 vaccination campaigns have avoided an estimated 469,186 mortalities in 33 countries among older groups thought to be most susceptible to COVID-19. SARS-CoV-2 vaccinations, however, have also been associated with some very severe adverse reactions. 

In particular, the COVID-19 AZD1222 vaccine, touted as being convenient to store, safe and economical to manufacture, and having a shelf life of about six months, was the first to come under question. First off, due to clinical trials reporting thromboembolic effects in younger women, this vaccination was only made available to those older than 50 years. Shortly after the marketing, the safety of AZD1222 was once again questioned in the media following reports of fatalities among the first-dose vaccinated patients. Reports of neurological issues, such as myasthenic disorders and Guillain-Barre syndrome, further exacerbated these findings.

The COVID-19 BNT162b2 vaccine from Pfizer has also drawn criticism. Firstly, delivery and distribution of BNT162b2 were difficult since it requires 80°C during transportation. A single vaccine dose may also increase the risk of Bell's palsy and hemorrhagic stroke. Evidence also implies that the BNT162b2 vaccine was strongly linked to an increased risk of appendicitis, myocarditis, and lymphadenopathy. 

Interestingly, it often takes decades for a vaccine to reach the market. On the other hand, during the SARS-CoV-2 pandemic, the vaccines accomplished Phase I studies within three months or less, with Phase III trials following only a few months afterward.

Approved COVID-19 antibody approaches

The COVID-19 antibody medication AZD7442 (Evusheld) by AstraZeneca, which consists of two antibodies: cilgavimab and tixagevimab, was emerging as a promising contender. 

The Food and Drug Administration (FDA) recently granted emergency use authorization (EUA) AZD7442 after testing it in two separate trials. These study results showed that AZD7442 was 83% efficient in decreasing COVID-19 symptoms. Besides, it lowered the likelihood that patients becoming seriously ill and even diminished their mortality risk by 88% when taken three days following the onset of symptoms. These investigations, though, were conducted before the emergence of the SARS-CoV-2 Omicron strain.

Tyson was a nanobody therapy addressing the SARS-CoV-2 spike (S) protein developed using advanced nanobody technology. Nonetheless, Tyson is still in the early stages of development and has not yet undergone in vivo testing. Researchers hope to use nanobody technology to create an easily administrable intranasal version reaching the nasal cavity and lungs.

Approved drug approaches for COVID-19 management

Repurposed drugs make up most drugs approved for COVID-19 treatment. Lopinavir, ritonavir, and darunavir are some medications used to prevent viral replication. These antivirals were initially developed for acquired immunodeficiency syndrome (AIDS) treatment.

Remdesivir, belonging to this inhibitory category, was the only medication in its class created as a COVID-19 antiviral. It was an early, promising drug prospect that underwent hurried testing before entering clinical use. However, later studies discovered that remdesivir was useless at averting SARS-CoV-2-related deaths. 

Since remdesivir hastens the healing process, it is still recommended by the National Institute of Health along with antiparasitics, ivermectin, and nitazoxanide for COVID-19 treatment. Additionally, it is currently under clinical evaluation for managing COVID-19-positive pregnant women.

Repurposed SARS-CoV-2 medications that block viral entry include antimalarial agents such as hydroxychloroquine and chloroquine and influenza antiviral like Arbidol. Remarkably, a Brazilian study found that the hospitalization requirement was diminished upon fluvoxamine administration to at-risk outpatients with an early diagnosis of COVID-19.

The United Kingdom (UK) and the United States (US) have licensed molupiravir for treating SARS-CoV-2 patients experiencing mild to moderate symptoms. Further, Paxlovid from Pfizer also gained prominence after studies showed that when COVID-19 patients took Paxlovid within three days of viral infection, the number of patients necessitating hospitalization dropped by about 90% in comparison to the placebo arm.

Using decoys as neutralizing agents to treat COVID-19

Employing decoys as neutralizing agents, prioritizing the host cell over the COVID-19 virus, was an intriguing alternative SARS-CoV-2 antiviral strategy. 

For example, Zhang et al. created nanosponges by encasing a membrane coat around a polymer nanoparticle core. The findings of this investigation demonstrate that nanosponges serve as dummy particles that bind to SARS-CoV-2 and prevent viral entrance to recipient cells. After a thorough in vitro characterization, the outcomes of the in vivo study showed that nanosponges neutralize viral function and consequently lower viral titer in both early-stage and late-stage COVID-19. Additionally, they can successfully reduce COVID-19-related inflammation.

SARS-CoV-2 siRNA antiviral strategy

Since siRNA sequences could be swiftly created for any changes detected in the encoded specific COVID-19 genes, siRNA was a quickly progressing technology applicable to rapidly keep up with the mutational strength of the SARS-CoV-2 variants. The siRNA synthesis was a quick and comparatively forthright method that could be scaled up efficiently in manufacturing.

Encouragingly, siRNA has shown to be generally safe and could be carefully structured to reduce off-target toxicity. Additionally, siRNA offers a robust method to address host receptors, most prominently angiotensin-converting enzyme 2 (ACE2), preventing viral entrance while analyzing newly emergent COVID-19 gene targets.

Yet, before siRNA reaches patients, even the most encouraging candidates in pre-clinical research still need some work. Furthermore, it is implausible to believe that siRNA antivirals alone can completely resolve the current SARS-CoV-2 crisis.