A Pandemic Silver Lining: RNA Drugs

As vaccination rates against COVID-19 plateau in the U.S. or fall short of the number needed for herd immunity, it’s worth reminding ourselves how significant a breakthrough these vaccines are and the other benefits to our health that can flow from them.

Unlike vaccines from the last century that contained weakened whole virus or purified bits of virus, the vaccines many of us have taken from Moderna and Pfizer-BioNTech contain only RNA and a simple solvent or vehicle. These messenger RNA vaccines that give us immunity to the SARS-CoV-2 virus work by giving the immune system a preview of the virus, so the body can develop an effective defense. The RNA has instructions enabling the body to make a key viral protein — a snippet of the virus — guiding our cells to make a diverse, potent set of antibodies against it.

It is like an email to the immune system: easy to create, easy to send, and promptly acted on by the email recipients.

So, where is the silver lining in a pandemic that has killed over 600,000 Americans to date?

Well, why not send RNA emails to treat other diseases?

First, the RNA vaccine used against the SARS-CoV-2 spike protein can be modified quickly as variants emerge, like the variants that are aggravating the pandemic in the U.K., South Africa and Brazil. Moderna already prepared and tested a vaccine that specifically targets these variants earlier this year. So, in the future (well, forever) as novel variants of SARS-CoV-2 inevitably emerge, modified vaccines can be made quickly.

This is a good thing because viruses with mutations occur continuously and naturally whenever the virus infects a person. As the virus grows, maybe in the lung or nose, mutations result from an error-prone or sloppy replicase, or copying enzyme. From the standpoint of the virus, not only do mistakes not matter, they are the raw material for evolution. If a variant emerges with better transmission or survival or a different host range (say, another species of animal), it will spread rapidly — as we’ve seen over the past year.

This approach could also be applied to the production of the annual influenza vaccine we are all advised to receive. I suspect that a combination vaccine against flu and SARS-CoV-2 could become routine: One shot once a year against both viruses.

The pandemic has intensified research on more traditional antiviral drugs as well. Several companies are now testing drugs (not vaccines) that block the SARS-CoV-2 genome copying enzyme (the replicase) or the protein cutting enzyme that helps the virus mature (the protease). Early reports show that these drugs quickly clear the virus from an infected person, so they can be used therapeutically. Whether they can be used to prevent infection is unclear. But a combination of these drugs is akin to how HIV is successfully treated with Truvada, a combination drug.

Likewise, engineered antibodies specific for SARS-CoV-2 have been approved by the FDA. They can be delivered by injection and delivery by inhalation is being studied. Still under development is sustained expression of anti-SARS-CoV-2 antibodies in the lining of the nose. (Anti-antibodies? Yes, an antibody that binds to and neutralizes another antibody.) This would be based on delivery of the antibody RNA or a gene. If these new strategies prove to be safe and effective, they might be appreciated by healthcare workers, people with weak immune systems or people who can’t or won’t be vaccinated.

Second, why not send an email to treat an autoimmune disease, or even cancer? BioNTech is already testing an RNA drug to treat multiple sclerosis. The intent is to stop the production of antibodies that attack the brain cells that insulate nerves (glial cells). This opens the door to treat other autoimmune disorders, especially when the target is known. Also in the research stage is the ability to improve the body’s own T cells to recognize liquid cancers like leukemia or solid tumors.

Treatments for inherited diseases are also in progress. For example, Moderna is working with Seattle Children’s Hospital to treat an inherited disease, hemophilia, with a drug that delivers the RNA for the missing clotting factor. If the benefits of one infusion of the drug fade after say six months or six years, the drug could simply be given again.

Third, there has been an increased focus on the chronic aspects of disease. Remember in early 2020 when we were told that COVID-19 was thought to be a simple respiratory illness with a two-week course? Of course, by late spring 2020 doctors and their patients realized that COVID-19 was far more dangerous than the flu; for unknown reasons, many patients were not recovering.

Now we know that about 20% of patients sick enough to be hospitalized with COVID-19 develop complex symptoms that persist after the acute illness subsides. We call this long Covid, and the patients long-haulers. Symptoms include breathing difficulties, heart palpitations, chronic headaches, digestive problems, sleep disturbances, exhaustion, anosmia and mental impairment. The symptoms can persist for six months or more, with devastating effects on lives, families and jobs.

What’s happening here? One idea is that either SARS-CoV-2 directly attacks the autonomous nervous system or indirectly provokes the immune system to do so. The autonomous nervous system controls breathing, blood pressure, heart rate, digestive activity and temperature regulation. Overall, long Covid is revealing how the immune response varies among people. We have to drop the simple idea that all patients will respond exactly the same way to SARS-CoV-2 infection and the related myth that the human immune system is a well-organized and defined mechanism. It looks more like long Covid may be similar to other poorly understood chronic conditions such as Lyme disease or chronic fatigue syndrome.

The pandemic has dramatized the variability and complexity of the human host’s response to a pathogen. The emerging hope is that ongoing studies on long Covid will help us understand the chronic problems that can follow infection.

Richard Gelinas, Ph.D., whose early work earned a Nobel prize, is a senior research scientist at the Institute for Systems Biology. He lives in Lakebay.  

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