Could bacteriophages be the answer to the COVID-19 crisis?

KEYWORDS:

• COVID-19
• bacteriophages
• phage display
• endolysins
• socio-economic
• SARS-CoV-2

Currently, the world is facing a pandemic from the rapid spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes the COVID-19 disease. At the time of writing, there are many promising treatments and vaccine candidates in the pipeline to fight against the virus, however, there are no specific treatments available for COVID-19 yet. Owing to this and the deadly nature of the pandemic, COVID-19 has been posing unprecedented challenges in areas such as public health, the economy, and government policy. Over the past few decades, observations of diseases such as tuberculosis, HIV, and malaria have shown that without vaccinations or effective preventative treatments, the resolution of a pandemic will likely be gradual and require a multi-faceted approach. On the other hand, there are plenty of diseases, such as emergent influenza, for which vaccines have proven to be highly effective at controlling and limiting the spread. Unfortunately, at this point, it is not known how efficient any of the vaccines and treatments currently under development for SARS-CoV-2 will be. Furthermore, even if the first treatment and vaccine candidates are successful, different treatments may need to be developed for mild or severe cases, patients with other diseases or health conditions, or patients that take other medications. In drug development, there are many approaches to find leads, this editorial focuses on the potential role bacteriophages (phages) may play in controlling the COVID-19 pandemic.

Phages are viruses that predate on bacteria. A century ago, at the time of their discovery, there was a great interest in using them to treat bacterial infections but, with the discovery of antibiotics, research in this direction almost stopped. In recent years, there has been a renewed interest partially due to the rapid emergence of antibiotic resistance as well as discoveries in the use of phages for purposes other than classical phage therapy. Here, in addition to phage therapy, we focus on the two most relevant novel uses of phages: the phage display technology and endolysins (specific lytic enzymes isolated from phages).

Bacterial coinfections have been shown to increase the risk of mortality for COVID-19 patients [1], therefore the antibacterial properties of phages may be a promising avenue for treatments in the current pandemic, as speculated in [2]. Phages have been seen as an alluring alternative to antibiotic treatments and have the potential to reduce the overuse of antibiotics. The overuse of antibiotics has been particularly worrying during the pandemic as large portions of hospitalized patients have been given antibiotics both for treatment purposes and as prophylaxis [3,4]. The high rate of antibiotic administration has been used to protect patients in a situation with many unknowns, however, going forward, the development of stewardship programmes to identify cases that need antibiotic treatments, and alternatives to antibiotics, are urgently needed [3]. With the overuse of antibiotics we further the emergence of antibiotic resistance and, as a result, risk decreasing the effectiveness of antibiotics that are a cornerstone of modern medicine.

As the pandemic progresses, the use of phages as a means to control bacterial infections is becoming increasingly unlikely and therefore phage therapy will probably not be used as an alternative to antibiotics in COVID-19 patients. Phages are highly specific to individual species of bacteria, therefore additional tests would be necessary to find the combination of phages that are effective for each patient (personalised treatment). In many places, testing for COVID-19 is already a challenge and introducing new tests (with new protocols) for the treatment of patients would further strain limited resources. Additionally, the therapeutic use of phages is yet to be proven in a phase III trial for any disease. There are also many legislative challenges (at least in Europe) that surround phage therapy and complicate their use even further. Phages replicate inside patients as part of their mode of action and, as a result, may mutate and interact with both bacteria and the immune system in unforeseen ways, making their regulation even more complicated [5]. Therefore, while phage therapy may be an exciting way to reduce the use of antibiotics and slow the emergence of antibiotic resistance, this is unlikely to happen fast enough to play a direct role in combating the COVID-19 pandemic.

Endolysins may circumvent some of the issues related to classical phage therapy. Endolysins are enzymes used by bacteriophages at the end of their replication cycle to disrupt cell walls, releasing progeny phages, and killing the bacterial cells in the process. These enzymes, and their derivatives, represent an alternative to antibiotics [6], as they display a high degree of host (bacterial) specificity. As such they are harmless to ‘human-friendly’ bacteria and, as they do not replicate themselves, there is no risk of them mutating and the dose to the patient can be precisely controlled. Endolysins will be important to combat the emergence of antibiotic resistance, however similarly to phage therapy, additional diagnostic tests would be necessary to identify the bacteria responsible for co-infections. Finally, both phage therapy and endolysins have limited potential, as bacterial co-infections are present in only a small proportion COVID-19 cases. This means that we would need to allocate large amounts of resources to solve a problem that can already be mitigated by the use of antibiotics [7]. Provided, that there are appropriate measures in place to reduce their use.

Phage display, on the other hand, may have a very important function in battling both present and future pandemics. Phage display is a rapid technique to identify antibodies directed against any antigen of interest and, as a result, this technology is already in use for developing therapeutic antibodies. This technology relies on the use of phage libraries to identify the sequences with potential for creating neutralizing antibodies against a virus, which can then be produced using recombinant antibody techniques. This requires DNA information from beta cells isolated from people who already produce the relevant antibodies. Both the European Union and the United States of America have ongoing projects to collect convalescent plasma that includes antibodies that target SARS-CoV-2. However, the effectiveness of antibodies obtained from this plasma has not been sufficiently tested at this point and its use is still controversial. More research into the safety and effectiveness of using antibodies from convalescent plasma is still needed, however, assuming it is effective, phage display techniques could be a safer and more cost-effective way of obtaining sufficient quantities of antibodies than collecting them from COVID-19 survivors. This is because it avoids problems caused by batch effects such as differing quantities of antibodies in different patients, avoids the costs associated with collecting plasma, and allows for easier quality control.

Antibody treatments remain promising avenues for treating COVID-19 patients and the current antibody pipeline has dozens of leads, including one that is in phase III trials [8]. Unfortunately, antibodies created by phage display techniques are all currently in preclinical phases, although many antibodies created by other means have phase I, II and III trials underway [8]. Despite this, phage display already technically plays a role in the COVID-19 pandemic as they already provide crucial data for assessing why one compound worked better for treating patients than others and therefore to gain a clearer understanding of the disease.

While phages may have the potential to play a role in the current pandemic, it is also important to understand that there is no magic bullet for this pandemic. Finding therapeutic and preventative interventions that work are only part of the solution. Drugs have to be manufactured and their fair and effective distribution across the globe has to be ensured [9,10]. Otherwise, the socio-economic disparities within societies exposed and exacerbated by the pandemic will further deepen, as has already happened and is still ongoing in diseases such as tuberculosis and HIV. Arguably, having a diversity of interventions and drugs available would aid in this process, as it reduces the possibility of the distribution of interventions to be skewed by geopolitical hurdles. As a result, the race for finding treatments and vaccines will remain far from over, even once the first drugs start to appear on the market. The role of phages is far from decided.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.