Core Concepts
In this article, you will investigate the biochemical basis underlying some of the most commonly-used COVID-19 medications. You will learn about their mechanisms of action, pharmacokinetic principles, and utility in fighting the formidable SARS-CoV-2 virus. You’ll also familiarize yourself with pharmaceutical targets, the rising problem of antiviral resistance, and supplemental and complementary COVID-19 treatment options.
This is the fifth article in a special ChemTalk mini-series about the intersections between chemistry and public health, using COVID-19 as a case study. Across this series, you can expect to learn about the drug discovery and development processes, chemistry’s central role in diagnosing and preventing diseases, and careers that are on the front line of chemistry and public health.
Previous Articles in This Mini-Series
> The Chemistry Behind Coronaviruses
> The Drug Discovery Process
> The Drug Development Process
> Chemistry Careers in the Public Health Field
How did COVID-19 impact the drug development process?
By now, we’ve toured the regimented steps of the pharmaceutical process and the many biomedical professionals who create medicines. That represents the “normal” picture of what drug development looks like. But during a health crisis like a pandemic, as the epidemiologic circumstances change rapidly, that picture can change rapidly too.
The public health response to COVID-19 juggled a lot of moving parts. Every time a particular city tamed a local outbreak, another cropped up elsewhere, seemingly without skipping a beat. Entire industries suffered severe economic repercussions, and some are still recovering nowadays. The consequences of long-term social isolation shifted how we interact with one another and affected some people’s mental health. All the while, health care practitioners had to manage waves of patients under stressed medical infrastructure.
One other component that had to change at the onset of the pandemic was the drug development process. What is typically a very organized, standardized operation was suddenly scrambling to keep up with the pandemic’s evolving social, economic, and political terrain. Biomedical researchers mobilized in a concerted effort to create and test COVID-19 therapeutics, and ultimately succeeded by producing new medications and vaccines that pinpoint SARS-CoV-2, the culprit behind COVID-19.
In this article, we’ll concentrate on how a few representative COVID-19 drugs work and how they fit into the overarching pandemic response. For now, let’s step back from this big-picture perspective and zoom in on the smaller-scale details of how these medications helped stave off one of the worst health crises of our time.
Why are antiviral medications used as COVID-19 treatments?
Since they target the SARS-CoV-2 virus, COVID-19 medications are a type of antiviral medication. Compared to other pathogens, viruses can be especially tricky to treat, for reasons we’ll discuss in more depth soon. We can’t “cure” or eradicate viral diseases in the strictest sense, but we can manage their symptoms while the virus runs its course. Antiviral medications are often intended to ease physical symptoms and prevent the disease from spreading to others while the patient recovers.
Antivirals stand in stark contrast to antibiotic medications, which are used to treat infections where the pathogen is a bacterium. Antibiotics have their place, but they were never a realistic COVID-19 treatment option because COVID-19 is caused by a virus, not a bacterium. The bacteria-killing techniques that an antibiotic employs do nothing to vanquish a virus — it would be like trying to eat soup with a fork.
Instead, we have to cook up a drug worthy of winning against a virus. When developing an antiviral medication, researchers first assess how that specific virus works: how it enters the body, how it infects healthy cells, how it spreads between people, and more. By understanding the virus’s mechanism, researchers can then determine the medication’s mechanism. The medication should operate in a way that interrupts or minimizes the virus’s normal function.
This strategic approach reflects the early stages of the broader drug discovery process, through which biomedical scientists take the earliest steps in designing a medication. Coronaviruses like SARS-CoV-2 hijack healthy cells’ molecular biology machinery to reproduce their own genetic material. Knowing this, researchers focused their efforts on designing a drug that would interfere with the virus’s ability to enter or use host cells. If those processes could be subdued, so could SARS-CoV-2 and the pandemic as a whole. So, this raised the next crucial question: How can we make an antiviral medication that hinders SARS-CoV-2’s typical tactics?
You might recall that we discussed routine drug discovery techniques, as well as how two example medications function, earlier in this article mini-series. In this section, we’ll revisit the creation of one of these go-to COVID-19 medications, as well as its antecedent, from a chemistry perspective. This task guided the course of scientists’ approach to resolving the pandemic. Helmed by biomedical researchers, pharmaceutical laboratories soon became a mission control center. But what exactly happened within these labs to bring COVID-19 medications to fruition?
Mastering COVID-19 Medications
It’s early 2020, and the search is on for a COVID-19 medicine as SARS-CoV-2 actively wreaks havoc around the globe. Research teams worldwide are independently and collaboratively developing drug candidates that will hopefully beat this beast of a bug. But what does that process entail? And what does it mean for the patients who are anxiously awaiting relief?
Once COVID-19 had escalated into a pandemic, scientists knew that there was no time to waste. Patients, health care practitioners, businesses, governments, and the general public were counting on them to develop a safe, effective treatment that could be distributed easily. In light of the disease’s rapid spread and the supply chain challenges happening in the background, these drug characteristics were vital. Among the most commonplace COVID-19 medications today — one that successfully achieved these criteria — is an antiviral drug called nirmatrelvir/ritonavir. You might know this drug better by its brand name, Paxlovid. Let’s briefly talk about how biomedical scientists created COVID-19 medications like this one, even in the nick of time.
Everyone Loves a Comeback Story: The Making of COVID-19 Medications
Put yourself in the (closed-toed) shoes of a pharmaceutical researcher who’s just identified the characteristics of the ideal COVID-19 drug. Next comes the most important part, and perhaps the largest obstacle you’ll face: How will you actually make it? How can you manipulate the chemistry of a few precursor substances to yield the molecule you want? Having already determined the qualities that will make our medication work, now we have to carefully consider the process of making the medication itself. We’ll evaluate this in the context of three compounds that are used as COVID-19 medications.
Nirmatrelvir/Ritonavir and Lufotrelvir
There are a few things we need from a strong synthetic route. The best synthesis approach would use few starting materials to minimize the financial cost of drug development. It would also employ quick reactions, accelerating the drug production process so the drug can reach patients faster. (This point was especially valuable when making COVID-19 medications during the heaviest waves of the pandemic!) We also want our strategy to result in as few side products as possible, so as to maximize the drug’s purity and avoid unnecessary waste. Low-effort, high-yield chemical synthesis improves the pharmaceutical manufacturer’s bottom line and ultimately translates into more efficient drug production.
Whereas researchers repurposed ritonavir (which already existed as an HIV drug) to treat COVID-19, nirmatrelvir was synthesized from scratch. It’s a descendant of another molecule, lufotrelvir, which has actually been studied in COVID-19 clinical trials too. As we’ll see shortly, the distinction between nirmatrelvir and lufotrelvir lies less in how they work (both are protease inhibitors) and more in how they’re delivered to the patient’s body.
Conquering a Pandemic? Cya-No Problem!
In drug development, there are frequently several means of achieving the same end product. What matters most is the molecule you end up with, if it has the right functional groups in the right places, and if it accomplishes its therapeutic goals. Synthesizing a new compound from a preexisting one tends to be an easy option because the desired compound’s molecular framework already exists in the starting material. To make nirmatrelvir, scientists began with the skeleton of a tripeptide chain.
There are two significant points to understand about this molecular form. First, if we look closely at nirmatrelvir, we can see two peptide bonds within its structure (highlighted in red above). This is a clue that nirmatrelvir consists of three peptides joined together. In this case, the three peptides in question don’t exist in nature; synthetic chemists have modified them. Synthesizing nirmatrelvir involves performing a series of condensation reactions to form the peptide bonds and unite the three peptides within a single molecule.
Since the peptides that comprise nirmatrelvir don’t exist in nature, nirmatrelvir is a peptidomimetic molecule. Peptidomimetics resemble peptides and mimic their functions, but because they’re synthetic, they often circumvent the problems that natural proteins exhibit. Depending on the peptidomimetic molecule in question, it might display better stability, selectivity, or potency than real peptides. All of these factors influence the drug’s effects, like how long it lasts in the body and how well it targets the pathogen of interest. So, the biggest benefit of a peptidomimetic drug is that it allows researchers to customize, through chemical synthesis, its behavior to suit the needs of a specific treatment plan. When fighting a virus that’s constantly on the move and hard to pin down, a tailor-made peptidomimetic medication is like a heat-seeking missile: powerfully precise and fixated on its target.
Second, we see that nirmatrelvir is the proud owner of a carbon-nitrogen triple bond, a feature not present in its ancestor lufotrelvir. The high-energy, relatively unstable cyano group is critical to nirmatrelvir’s function as a COVID-19 drug. Dubbed “the electrophilic warhead,” it’s the entity that targets the main proteases (Mpro) that drive SARS-CoV-2 replication. When nirmatrelvir’s cyano group makes direct contact with the Mpro‘s cysteine residue, it inhibits the Mpro‘s ability to make proteins that the virus uses to reproduce. Among members of the coronavirus family, Mpro molecules are highly conserved. That’s because they have a fundamental role in the viruses’ life cycle, but this conservation also equips nirmatrelvir to combat several different coronavirus variants. It’s profound that such a tiny pair of atoms has an intense outcome on the drug’s function and, of course, the patient’s prognosis.
The Buddy System: Ritonavir’s Role in Fighting COVID-19
However, nirmatrelvir can’t do all of this alone. It works much better with the support of another compound, ritonavir, as they carry out this demanding effort together. After the patient consumes a dose of nirmatrelvir, it (like any pill) is subjected to the metabolic wrath of the body’s digestive system. (More on that later!) For now, you should understand that the body’s digestive forces break down pills over time. The faster the pill breaks down, the shorter its therapeutic effects will last.
So, to make a COVID-19 medication like nirmatrelvir more effective for a longer duration, we need to find a way to slow the body’s metabolism of it. This is where ritonavir shines: its only job is to reduce the breakdown of nirmatrelvir so nirmatrelvir can work longer. Ritonavir inhibits CYP3A4, a cytochrome found abundantly in the liver that catalyzes drug metabolism. With its breakdown inhibited, nirmatrelvir can now successfully evade the enzymes that would normally metabolize it. This allows the patient to experience nirmatrelvir’s therapeutic gains for longer than if ritonavir were absent.
What’s so special about ritonavir’s structure that enables it to inhibit CYP3A4? Its two thiazole groups! A thiazole group is a heterocyclic ring with five atoms (including nitrogen and sulfur) and two double bonds. In ritonavir, these thiazole groups do double duty by supporting the medication in two very important ways. From a structural perspective, each ring is much larger than most other components of ritonavir. Placing a thiazole group on either end of the molecule increases ritonavir’s overall stability, making its structure more robust.
The other vital purpose of the thiazole group is that it’s where ritonavir interacts with CYP3A4. CYP3A4 contains a heme group that has an iron atom. The nitrogen in ritonavir’s thiazole group bonds closely with this iron atom, driving this selective interaction with high binding affinity. This binding is so strong, in fact, that it’s irreversible. That being said, the body will inevitably metabolize the ritonavir and nirmatrelvir molecules eventually. Regardless, this super-specific and irreversible binding action ensures the drug’s effects will last as long as possible before that happens.
Embracing Change: How Prodrugs Transform into Active Forms
Now, let’s revisit lufotrelvir, the predecessor of nirmatrelvir. When lufotrelvir reaches the bloodstream, the enzyme alkaline phosphatase cleaves it into its active form fairly rapidly. As such, lufotrelvir itself is a prodrug, the inactive precursor of a drug’s active form, which transforms into the active form in vivo. As the active form of the drug, this cleaved version of lufotrelvir is what has antiviral functions. That’s central to its success as a COVID-19 treatment. Fortunately, lufotrelvir has shown effectiveness in the face of multiple variants — a treasured trait, since we’ve witnessed the SARS-CoV-2 virus mutate many times.
Originally, lufotrelvir demonstrated lackluster stability because it tended to epimerize. Interconverting between epimers (diastereomers that have one different chiral center) can have repercussions on a molecule’s bioactivity, metabolism, and ability to resist degradation. For lufotrelvir, a tendency to degrade was an especially prominent issue. To remedy this, pharmaceutical scientists modified lufotrelvir during the drug development process. Some such modifications include a Claisen addition (extending the molecule by forming a carbon-carbon bond) and phosphorylation (generating its phosphate group). Evidently, these changes were well worth it; clinical studies show that the prodrug converts to the active form with near-completion. When a greater proportion of a medication is active, the medication is more efficient because it’s making the most of the expensive, time-consuming drug development efforts that birthed it.
Remember the cleavage of lufotrelvir into its active form happens in the bloodstream. That’s facilitated by the fact that lufotrelvir is administered intravenously, directly into the bloodstream. After lufotrelvir’s active form takes effect, the body clears the drug via amide hydrolysis, a metabolic process that we’ll see more of soon. So far, we’ve learned a lot about what COVID-19 medications do once they’re inside the body. Next, we’ll take a step back and examine a topic we’ve alluded to: how those medications get into the body in the first place.
The Intricacies of Drug Delivery
Nirmatrelvir and its precursor molecule lufotrelvir are closely related, but have some considerable differences. Out of these two drugs, nirmatrelvir (when accompanied by the compound ritonavir) is generally the preferred treatment option because it can be administered as a pill. By contrast, lufotrelvir can only be delivered intravenously, which makes it a less convenient alternative.
How a patient consumes a drug matters. Pills are convenient for patients because they’re portable, already portioned out into appropriate dosages, and the patient can take each dose without the health care provider (HCP) needing to be present. Convenience is a very desirable feature in a medication, not just from the patient’s point of view, but from the HCP’s perspective too. A patient is much more likely to follow through with taking a medication, and take it exactly as prescribed, if it’s convenient to do so. After all, prescribing a drug isn’t worth the patient nor the HCP’s time if the patient won’t use that drug properly and benefit from its effects.
The main drawback of a pill is the time required for it to take effect. When you consume a pill orally, it passes through your digestive system: your stomach acid breaks it down and then your intestines absorb it. This process is effortless from the patient’s perspective, but it takes time. As a byproduct, it also subjects the drug’s compounds to biochemical decomposition — let’s explore how.
Bioavailability and Drug Stability
At every turn of the digestive system, those compounds encounter and interact with digestive agents such as enzymes. Through chemical reactions and metabolic functions, these enzymes may modify the functional groups on the compounds’ chemical structures, deviating them from what biomedical researchers intended. If this happens before the body has absorbed the drug, then the drug will be less effective overall. (If you’ve ever been told to take a pill with or without food, this is one of the reasons why! The body might absorb some medications more effectively or less effectively, depending on whether or not food is also present in the stomach.) Translated into a health care context, these circumstances might lead the patient to experience less of a therapeutic benefit.
Conversely, intravenous drugs are delivered directly to the bloodstream, with their effects happening much faster than a pill’s. Any intravenous medication, since it skips the digestion process altogether, also demonstrates full bioavailability. Bioavailability measures the percentage of a drug that reaches the circulatory system, so intravenous drugs have a (theoretical) bioavailability of 100%. Pills exhibit lower bioavailability because, by virtue of the digestive process, some fraction of the drug will always be lost to the body’s metabolism. Scientists measure bioavailability as an indicator of a drug’s duration. With a higher bioavailability, a patient will feel the effects of a single dose persist longer compared to a drug with a lower bioavailability. Therefore, how a drug is administered makes a difference in how the patient experiences it, and for how long. Using standardized measurements like bioavailability adds to the conversation by allowing researchers to draw fair comparisons between very diverse medications.
If a drug is available in both pill and intravenous formats, each format utilizes a different dosage. This compensates for differences in the formats’ bioavailabilities. By now, we know that less of the drug manages to reach the circulatory system when the drug is a pill. When the drug is delivered as a pill, it’s delivered at a higher dosage compared to when it’s delivered intravenously. It’s evident here that bioavailability is directly related to factors like the drug’s delivery format, dosage level, and administration.
Keep in mind, too, that there are other subtle factors at play. For example, within a population of patients, researchers see individual differences in how quickly and how much of a drug gets absorbed by each patient. To an extent, researchers understand that drug absorption depends on elements like the time of day when the drug is taken, the patient’s weight and biological sex, and more. But when designing a medication, researchers can’t fully account for all of the variable idiosyncrasies that could impact absorption. Instead, they strive to design a drug that works for the majority of patients in a way that’s safe, predictable, and as effective as possible.
All of these considerations enrich the conversations surrounding drug stability. In pharmaceuticals, stability refers to a drug’s ability to maintain consistent properties from the time it’s manufactured through the time a patient uses it. Evaluating a drug’s stability happens on an ongoing basis, both inside and outside of the patient’s body. For example, pharmaceutical researchers want to ensure that a medication is shelf-stable, reliably maintains its quality and effectiveness until its expiration date, and has a meaningful effect on the patient’s health after they consume it. Lower stability indicates that a drug won’t work as well as intended for as long as intended. This could have deep consequences for patients, who obviously expect their medications to work properly.
The Looming Threats of Oxidation and Hydrolysis
Two examples of chemical reactions that routinely threaten drug stability are oxidation and hydrolysis. Oxidation reactions, where electrons are lost, can happen over time by exposing the medication to conditions like light or heat. To prevent degradation, manufacturers provide specific instructions for drug storage: in what temperature ranges, how much protection from light, etc. Just think of how many chemical reactions depend on how a compound steals, trades, loses, or earns another molecule’s electrons. If oxidation happens prematurely due to incorrect storage conditions, the drug’s chemical structure will have a different number of electrons than it should, so it won’t undergo those reactions in a typical way. In some instances, this might cause the drug itself to not work the way it should.
Simply adhering to the drug manufacturer’s storage instructions can minimize the likelihood of oxidation. But besides oxidation, a more commonly observed route to a medication’s decomposition is hydrolysis. Hydrolysis involves the use of water to break a molecule’s chemical bond. Depending on the molecule’s starting structure, a simple hydrolysis reaction can completely change its biochemical profile. In the presence of water, functional groups that are frequently found in pharmaceutical drugs — esters and amides, to name a couple — may convert to carboxylic acid or alcohol groups.
Within the body, hydrolysis happens thanks to enzymes that we find in a variety of tissues. The faster these enzymes hydrolyze a drug, the shorter that drug’s effects will last. In order to yield the same benefit as a non-hydrolyzed drug, more frequent or higher doses might be necessary. Therefore, one way to enhance a drug’s effectiveness is to design it using functional groups that are less prone to hydrolyzing in the first place.
In spite of this, the fact that a drug undergoes chemical reactions isn’t inherently bad. After all, the drug must break down eventually! If it didn’t, then drug levels would continuously build up in the body, and the patient might suffer from unpleasant side effects like toxicity or organ damage. What matters is how researchers strike the delicate balance of drug metabolism. Ideally, a drug should resist premature chemical reactions long enough to have a therapeutic effect in the patient’s body. After these effects are complete, it should surrender to metabolic chemical reactions, so the body can excrete it. Pinpointing when this metabolism ought to happen is a central question during the phases of drug development where researchers study the drug in vivo to understand how it functions among the body’s active enzymes, compounds, and tissues.
Regardless of their unique characteristics, each of the COVID-19 drugs we’ve introduced in this article functions as an antiviral medication. (Psst: a surefire way to tell is by the “-vir” ending across each of their names.) But one of these four compounds is not like the others. Ritonavir isn’t just an antiviral medication; it’s an antiretroviral medication. Let’s consider what that means in the context of COVID-19.
Back It Up: What’s a Retrovirus?
Antiviral drugs target one or more viruses, but antiretroviral drugs specifically target retroviruses. Upon infecting a host cell, a retrovirus uses its reverse transcriptase enzyme to create a DNA strand that’s complementary to its own RNA genome. Remember, the central dogma of biology states that DNA gets transcribed to RNA, which eventually makes proteins. Making DNA from RNA means reversing the typical transcription process. This RNA-to-DNA sequence is where retroviruses get their name. Once its genetic material converts to DNA, the retrovirus can take over the host cell’s natural replication machinery. This allows the retrovirus to reproduce its genome and create new copies of itself to propagate infection. Perhaps the best-known example of a retrovirus is HIV-1, the virus behind HIV/AIDS.
It’s important to note that coronaviruses, such as SARS-CoV-2, are not retroviruses. Coronaviruses and retroviruses belong to completely distinct taxonomic families. If that’s the case, then why would an antiretroviral compound like ritonavir be useful in fighting a coronavirus?
Despite their differences, there are some meaningful similarities between retroviruses and coronaviruses. Both use RNA as their genetic material, hijack host cells’ innate mechanisms to replicate themselves, and need proteases for replication. Proteases are enzymes that break down proteins. In this case, they break down proteins that the retrovirus or coronavirus requires in order to reproduce.
Nirmatrelvir and ritonavir, as well as lufotrelvir, are all protease inhibitors. Their purpose is to stop the protease enzymes that help retroviruses and coronaviruses spread. Ritonavir actually got its start as an HIV-1 treatment. During the COVID-19 pandemic, scientists repurposed ritonavir to study its impact against SARS-CoV-2. And, boy, did it have impact.
The body naturally metabolizes protease inhibitors over time, particularly in the intestines and liver. From a pharmaceutical perspective, this means that protease inhibitors will inevitably break down. To make these medications last longer in the body, we can administer another drug that slows down this metabolism. This is why nirmatrelvir, the main character in Paxlovid, is accompanied by ritonavir in a single medication. Both are protease inhibitors, but ritonavir is specially formulated to inhibit the CYP3A4 enzyme that breaks down protease inhibitors. In other words, ritonavir slows down the forces that metabolize nirmatrelvir, allowing nirmatrelvir to have a longer effect on the body. With a reduced threat of metabolism, nirmatrelvir can focus on doing what it does best: breaking down the proteins that enable COVID-19 to spread.
Repurposing a drug tends to be a game of trial and error. Using what they already know about the disease of interest, researchers predict what existing drugs might work against it. Then, in laboratory settings and clinical trials, they test how well that medication actually works against the disease of interest. If clinical trials are successful, then regulatory authorities may approve the drug to treat that disease.
What about when medications don’t work?
Once a drug hits the market, we get to see how well it truly works beyond a lab or clinical research setting. Sometimes, the drug works exactly as intended without a single hiccup. Other times, though, things don’t go as planned and new hurdles reveal themselves only after the medication reaches real patients.
Let’s look at this from the perspective of one of the biggest medical menaces of our time: antibiotic resistance. Resistance means that the pathogen that a medication targets (in this case, a disease-causing bacterium) gradually becomes more capable of withstanding that medication (the antibiotic). This has dire implications for the pharmaceutical industry, which then must devise a new bacteria-killing drug that the bacteria aren’t resistant to yet, and for the patients who suffer from incurable bacterial infections in the meantime.
Unfortunately, this phenomenon happens with protease inhibitors, too. Viruses that are normally susceptible to protease inhibitors can, over time, develop resistance to those drugs. When that happens, the protease inhibitors become less effective as antiviral medications. How does this happen in the first place?
In order to stop viral replication, a protease inhibitor must bind to a specific site on the virus’s protease. This is how protease inhibitors work under normal circumstances, as intended, to treat a viral infection. In its genome, a virus encodes the proteases that it needs for replication. But, as we know, genetic material can mutate — and any mutation can change the nature of the protease.
If a mutation changes the protease’s active site, this directly impacts its affinity for binding to the protease inhibitor. It’s possible for the active site to mutate to have a lower affinity for the drug, which limits the medication’s ability to target the protease. This is how protease inhibitor resistance arises. Without a selective target available, the protease inhibitor can’t do its job effectively, so it’s no longer a useful solution against the virus it ought to fight.
Mutations can happen spontaneously, and they tend to arise as a virus evolves over many replication cycles. This introduces a bit of a conundrum: scientists invented protease inhibitors to prevent viral reproduction, but as a result of viral reproduction itself, mutations can arise that change a protease inhibitor’s effectiveness. During the COVID-19 pandemic, we saw precisely how concerning viral evolution and mutation are, as newly-evolved mutant variants repeatedly rendered our vaccines less effective.
To overcome the challenging prospect of a protease-inhibitor–resistant virus, protease inhibitors can be used in combination with antiviral medications that have different targets. This way, even if the virus’s active site mutates to become resistant and the protease inhibitor can no longer bind there, another medication can step in to target a different structure or function of the virus instead. Spreading the virus-fighting burden across multiple diverse drug classes can help stop the virus’s spread. But wait — what’s a drug class, and what does it mean for the virus that causes COVID-19?
Class is in Session: Pinpointing the Right Medication for the Right Job
There’s no “miracle” antiviral drug that can treat every viral disease out there, but that doesn’t stop scientists from trying! Researchers group similar medications into classes based on their properties and functions. Oftentimes, these classes directly describe how the drug functions. Some familiar examples readily come to mind: drugs in the stimulant class stimulate the body or mind, contrasted with drugs of the depressant class that reduce arousal, while analgesic drugs relieve pain (the word “analgesic” comes from Greek roots that mean “without pain”).
Protease inhibitors are another class of drugs that do exactly what their name implies. By inhibiting proteases, a type of enzyme that SARS-CoV-2 particles use for reproduction, protease inhibitors interrupt the viral life cycle by preventing the virus from replicating. The virus must make many copies of itself to infect new host cells, so preventing viral replication prevents the spread of COVID-19.
Researchers already applied the same concept to fighting the viruses behind HIV/AIDS and hepatitis C. Understanding the commonalities within a particular drug class makes it easy to translate existing medications into new contexts to treat different diseases. To devise an effective antiviral medication to treat COVID-19, researchers had to understand a few simple, yet essential, points. First, they learned that the SARS-CoV-2 virus uses proteases in its replication process. Second, they knew that the viruses that cause AIDS and hepatitis C also use proteases to reproduce. Third, protease inhibitors already existed as safe, effective medications for treating HIV/AIDS and hepatitis C.
From here, scientists could apply this logic in a straightforward way in order to conclude that protease inhibitors are a viable COVID-19 treatment option. If protease inhibitor drugs are already known to work against other viruses that replicate via proteases, and SARS-CoV-2 is known to replicate via proteases too, why not pursue a protease inhibitor as a COVID-19 drug?
In some ways, drug discovery is a very sensible process. But in practice, there are a lot of factors that threaten to get impede what ought to be a smooth, uncomplicated approach. Let’s take a look.
Challenges in Treating COVID-19
Pandemics are among the most urgent public health scenarios; time is truly of the essence. To conquer the crisis, medical experts must develop and distribute a cure faster than the disease is spreading. But we know the SARS-CoV-2 virus causes COVID-19, and viral diseases, in general, cannot be cured — only managed or treated.
Facing an incurable disease, how can we devise an effective treatment, and fast? Taking on this challenge meant overcoming SARS-CoV-2’s natural evasive characteristics, drug development roadblocks, and sociocultural factors that shaped how people interacted with COVID-19. To understand why these details had such a key impact on the pandemic, let’s evaluate them in greater depth.
Virology 101: How Viruses Evade Our Efforts to Eradicate Them
We know how to take control of stubborn viruses because we’ve managed to do it many times before. For example, you’ve likely sustained a barrage of vaccines for viral diseases like chickenpox, measles, and polio. And everyone can recite by heart the cardinal rules of flu season — stay home when you’re sick, cover your mouth when you cough and sneeze, and wash your hands often. Public health principles like these are somewhat of a tradition, and we know these rules of how to beat disease. So, what happens when we encounter a virus that doesn’t play by the rules?
What makes an effective antiviral medication?
Viruses have certain properties that can make them more difficult to target than pathogens like bacteria or parasites. First of all, there’s an ongoing scientific debate as to whether viruses are living or nonliving. Viruses have their own genetic material and, inside of a host cell, they exhibit some characteristics of life, like the ability to reproduce (viral replication). However, viruses can’t function independently, and therefore can’t do much damage, without the help of a living host cell. Since they need living hosts’ support to execute their functions, many scientists view viruses, in and of themselves, as nonliving. This invites a unique conundrum: If something isn’t alive, is it actually possible to use medications to kill it?
As part of the drug discovery process, pharmaceutical researchers determine how their medication will impact its target (which might be a protein, antibody, gene, virus, bacterium, etc.). Many drugs work by impacting the target’s ability to function, but this might not be useful against viruses. For example, a drug that works by interfering with the target’s metabolism wouldn’t be an effective antiviral drug because viruses don’t have their own metabolic processes.
Living or not, we know that viruses are vulnerable to antiviral medications. Strong antiviral medications account for their target’s normal mechanisms and viral load. By closely studying those mechanisms — how the virus infects and moves through the body, infects healthy host cells, replicates its genetic material, and causes physical symptoms — scientists can pursue a drug that interferes with them.
Viral load refers to how much virus is present in a patient’s blood. Viral load can change over the course of an infection, and it can indicate how sick the patient is. For certain diseases, a higher viral load indicates that the patient is more contagious. Some antiviral medications are intended to reduce viral load, alleviating the patient’s infection and protecting other people from catching it. (In this way, reducing viral load is a goal of a long-term HIV treatment called antiretroviral therapy, or ART.)
What’s the Password?: How Viruses Enter Host Cells
Viruses are among the smallest biological agents. After all, they have to be, in order to penetrate host cells. Viruses usually enter host cells through receptor-mediated endocytosis, a process by which the viral particle binds to a receptor on the cell membrane and passes into the cell. When descending upon a new host cell, the virus hunts for specific receptors that will bind to proteins on its own membrane.
This penetrative mechanism is sometimes what an antiviral drug targets. A drug that interferes with this protein’s binding to a membrane receptor prevents the virus from reaching host cells. Researchers extended this strategy to COVID-19 vaccines that notably target SARS-CoV-2’s spike protein, which binds to host cells’ ACE2 receptors. All coronaviruses have spike proteins, but the protein’s chemical makeup can fluctuate across different viral variants. This is why scientists continuously produced COVID-19 vaccines: each new version of the vaccine targeted the spike protein’s latest disguise. We already knew about coronaviruses before COVID-19 happened, but developing a COVID-19 medication required learning about the special intricacies of SARS-CoV-2’s spike protein in particular.
For being such tiny agents, viruses sure put up a big fight. A drug spurs the body to act upon a virus, but this could inadvertently lay the groundwork for further harm. In order to damage viruses, antiviral treatments must also damage the host cells that those viruses occupy. This can have further implications for the health of the patient or the symptoms that they experience. Therefore, antiviral treatments represent a balancing act, selective toxicity, between destroying the virus and preserving the patient’s own tissues.
Unfortunately, there’s no easy solution to this dilemma. Any step in the viral life cycle would be a good target for an antiviral drug, but the host cell would probably also suffer. Some antivirals reduce the risk to the patient’s health by targeting a virus-specific molecule or behavior, leaving the host cells relatively untouched. That’s the inspiration behind COVID-19 drugs like nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir inhibits a protease that SARS-CoV-2 uses for replication, which prevents the virus from reproducing. (Other COVID-19 medications, like remdesivir, disrupt the replication process by introducing steric hindrance as the virus replicates its RNA. This steric hindrance stands in the way of RNA replicating to completion, putting a pause in the viral life cycle and the SARS-CoV-2 virus at a loss.)
With antiviral drugs, researchers must weigh the benefit of weakening the virus against the risk of weakening host cells. An antiviral medication that preserves a patient’s infected cells would be an ingenious discovery and a very promising treatment option — something to consider next time you find yourself bored in the lab!
Playing the Long Game
Recall from our previous article that public health professionals use epidemiological surveillance to track disease outbreaks on a population scale. We can extend this concept to a much smaller scale: detecting microscopic viruses within the body. Their minute size isn’t the only characteristic that can make viruses hard to detect. Some viruses are pros at staying inconspicuous for extended periods of time. During these periods, the virus in question may not cause obvious symptoms (or if so, the symptoms may be nonspecific). It may even fail to appear on test results.
Sometimes observed in viral infections like HIV, Epstein-Barr virus, and hepatitis, this phenomenon is a latency period. Latency periods happen when the virus is dormant for spans of weeks, months, years, or even decades. Dormancy means that the virus has infected a host, but isn’t actively replicating, or it’s replicating very slowly. Remember, for the infection to spread within the body, or from an infected to healthy person, the virus must replicate. The act of replication kills the host cell. Then, in the aftermath of cell death, the progeny from that replication seek new host cells and spread the infection.
Although certain viruses share some resemblances, like these particular viruses’ ability to stay surreptitious for long-term periods, viruses overall demonstrate very diverse features. For instance, SARS-CoV-2’s genome is composed of RNA, but many viruses’ genomes are made from DNA just like ours. Different viruses also boast different physical properties, replication techniques, and thrive in a range of environmental conditions. Maybe you can’t disrupt the virus’s life cycle, but can you do something to make its environmental conditions less hospitable? In light of such diverse traits, making antiviral medicines might seem like a fruitless pursuit, but keep in mind that every new trait presents a new angle to attach the virus.
Identifying a given virus’s individual idiosyncrasies helps researchers tailor a medication perfectly to that virus — but also means that most antiviral medications can only treat one or a handful of viruses. This lies in stark contrast to broad-spectrum antibiotics, which target numerous bacterial species. Not all antibiotics are broad-spectrum, but this all-encompassing quality is hard to replicate in antiviral drugs. Broad-spectrum antivirals do exist, but because viruses evolve so rapidly, the best antivirals would be able to defeat multiple existing strains while anticipating future variants, which is essentially a guessing game. A good place to start is with antivirals that target entire families of viruses, like coronaviruses or herpesviruses for example, that attack a stable characteristic which all of the family members have in common. Yet another example of how the shared features among different pathogens serve as the groundwork for building a single drug that fights all of them!
Ready, Aim, Fire! All about Drug Targets
Earlier, we discussed how protease inhibitors bind with proteases that the SARS-CoV-2, HIV-1, and hepatitis C viruses encode. Recall that this binding happens selectively, and directly leads to the inhibition of viral replication. In pharmaceutical terms, we describe this dynamic dance as the protease inhibitor targeting a particular binding site on the protease. Alternatively, we can say that the protease (more specifically, the binding site) is the target of the protease inhibitor medication. But why do medications need to have targets at all?
Drugs with Multiple Targets
Most drugs need specific targets in order to treat a particular condition. But there are indeed some drugs, like certain anti-inflammatory medications and chemotherapy treatments, that target the body as a whole. This broad approach, polypharmacology, involves one drug affecting multiple targets. Anti-inflammatory drugs reduce inflammation by acting on prostaglandins — lipids that are present all over the body. And just think of the vast array of side effects that accompany chemotherapy (fatigue, nausea, hair loss, and more). The fact a single drug causes side effects that are so different from one another, which impact different systems within the body, indicates that the drug is acting on several distinct targets.
Considering the meticulous effort that goes into seeking and identifying precise targets during the drug discovery process, it might sound surprising that scientists purposely design some medications to have many targets. But for diseases such as cancer, whose wide-ranging warpaths can span multiple organs and pose a risk to the body overall, having a less specific set of targets might be the ideal solution. Each affected organ is unique, with its own profile of cell types, enzymes, and functions. The goal here is to give patients a better chance of beating a whole-body disease with a drug whose targets live throughout the whole body.
Depending on the nature of the disease, a drug’s ability to target many molecules may be either advantageous or disadvantageous.
Drugs with One Target
Let’s face it: it’s hard to maintain this big-picture outlook when working with such tiny molecules! We saw from the protease inhibitor discussion that a single binding site in the target (and sometimes a single mutation within a single binding site) can make all the difference as to whether a medication flourishes or flounders. What muddles this problem even further is the fact that a target can have multiple domains that serve as binding sites, or two very different types of molecules could have similar binding sites that interact with the drug. How do pharmaceutical researchers make a drug that acts on one binding site of interest, while ignoring all the others?
For drugs that target only one molecule, the binding interactions between the medication and its target are extremely specific. That’s an understatement! This high specificity minimizes the risk of off-target effects that can have unpleasant or dangerous consequences on the patient’s health. Designing an effective drug that has one, and only one, target requires a deep understanding of binding affinity and the structural qualities that govern it.
Remember that the drug and the target each boast a chemical structure that’s full of functional groups. Each functional group has distinctive properties that influence its reactivity, behavior, and interactions with other molecules. This means that structural characteristics lie at the core of the drug-target binding, and therefore at the core of drug effectiveness. By manipulating the functional groups in the drug’s molecular backbone, researchers can manipulate the reactions that the drug undergoes, as well as its propensity to bond with a specific domain on the target. It’s astonishing that changing out even one little atom could introduce a different a functional group and, by extension, impact a medication’s ability to work properly! Even if the drug’s functional groups stay the same, a minor change in their spatial arrangement might completely change the medication’s function.
Consider enantiomers: molecules whose structures are mirror images. One notorious case of this chirality making or breaking a medication is thalidomide. Thalidomide is a drug that was originally marketed as a morning sickness remedy. It exists as two enantiomers: the R enantiomer has a sedative effect that alleviates symptoms like morning sickness, while the S enantiomer can cause birth defects. The only chemical difference between these two drastically different outcomes is how these molecules’ atoms are spatially arranged. To make matters worse, thalidomide can interconvert its enantiomers in vivo, so even if a patient were only administered the relatively harmless R enantiomer, the teratogenic S enantiomer may arise in the body afterwards. By contrast, medications that only exist as one enantiomer, as opposed to a racemic mixture, are enantiopure drugs.
Another example of a more-than-microscopic structural change having a larger-than-life impact is the methamphetamine molecule. Methamphetamine is a stimulant and recreational drug, with side effects like vasoconstriction and rapid breathing. Its optical isomer levmetamfetamine, meanwhile, serves as a nasal decongestant of all things! Again, we see that one small switch in these drug molecules’ atomic arrangements leads to wildly different health effects.
A recurring notion in drug development is that medications are intended to be as safe and effective as possible. However, no medication can be 100% safe nor 100% effective. No matter what, there’s always the risk of side effects, off-target effects, and unwanted interactions. Regardless, scientists can maximize safety and effectiveness by tailoring a drug’s chemical properties, like its structure and functional groups, to be as specific as possible to the target of interest.
Unfortunately, achieving that specificity can be an intense challenge, especially when only one target is desired. But when different pathogens employ the same biochemical processes or enzymes as each other — like how SARS-CoV-2, HIV-1, and hepatitis C virus all employ proteases for replication — these features serve as a good starting point for drug design. Could that common feature potentially function as the drug’s target? And since several pathogens share that feature, could the drug therefore be effective against all of the pathogens? For viruses in particular, all viruses must replicate because replication is the only way viral diseases can spread to new hosts. That’s why popular COVID-19 medications target molecules, like proteases, that have a central role in SARS-CoV-2 replication. (The same is true for the protease inhibitor drugs that treat HIV and hepatitis C infection.)
Here, we’ve seen that slight changes in the drug molecule yield big impacts on its ability to bind selectively with its target (or targets). Later, we’ll talk about another highly-specific mechanism in combating disease: the interactions between antibodies and antigens. For now, let’s dive into the question of why COVID-19 medications were unusually difficult to make.
Drug Development under Dire Circumstances
The small but significant principles that we’ve mentioned so far — the fact that antibiotics don’t work against viruses, the puzzle of creating a new medication based on clues from existing ones, the arduous task of designing a drug with meaningful targets — only complicated the hunt for efficacious COVID-19 medications. Numerous additional factors were already at play, presenting challenges for drug development during a time when we needed it most.
Some of these challenges ran deep. Hardening travel restrictions and heightened political tensions, for example, strained the pharmaceutical supply chain at its core. Patients often rely on drugs manufactured elsewhere in the world, but temporary limits on international travel jeopardized typical medication supply. Worth noting is that most active pharmaceutical ingredients (APIs), the component of a drug that gives it its therapeutic effect, are manufactured outside of the U.S. This includes being manufactured in countries that the pandemic hit hard, such as China. Importing drugs and APIs — and exporting American medicines to patients around the world — normally happens in a steady stream that ensures patients everywhere can receive their treatments when they expect to. With the short-term closures of pharmaceutical facilities and chemical plants domestically and abroad, this promise went unfulfilled in many cases. Even a brief pause in drug manufacturing can ripple into long-lasting consequences for patients.
Other points in the drug development process were interrupted, too. The Food and Drug Administration (FDA), the American pharmaceutical regulatory agency, also monitors pharmaceutical sites in foreign countries. These inspections confirm that U.S.-bound drugs comply with the same rigorous safety and quality standards as those made in America. International travel restrictions, again, delayed these investigations. Inspections must happen before any medications get distributed, so from a patient perspective, postponed inspections equates to postponed treatment.
The COVID-19 pandemic struck all steps in the pharmaceutical supply chain: manufacturing, production, approval, distribution, and everything in between. This highlighted glaring vulnerabilities in this industry’s very framework, and those vulnerabilities’ effects on patients. We expect pandemics to arise occasionally, but we can’t predict when, and no two disease outbreaks are the same. That aspect of “unexpectedness” makes it extra hard to accommodate them when they do happen. Even more urgently, it underscores the need to make our drug development processes more resilient against health emergencies like pandemics. Let’s take a moment to see what that impact looks like in the context of pharmaceutical research.
A Logistical Nightmare
As soon as the World Health Organization classed COVID-19 as a pandemic, the clinical research sector scrambled to accommodate this. Mounting concerns over a mysterious disease abruptly brought many clinical trials to an indefinite pause. By the time a clinical trial starts, the researchers have already carefully planned and committed to its study protocol. During COVID-19, social distancing guidelines forced them to reimagine studies in virtual formats when possible, and postpone them when not. Trials that hadn’t begun yet were hit even harder. The number of prospective study participants plummeted as they feared COVID-19 exposure in the medical facilities where trials often occur. Some studies couldn’t even get off the ground, but those that could suddenly found themselves stuck in midair.
What’s the problem with putting a clinical trial on pause? It’s not as simple as picking up where the study left off a few weeks afterward. Surprisingly, a lot can happen in the span of a few weeks. If study participants have already received a trial dose of the drug candidate, they might experience new side effects. Researchers need to monitor these complications closely to document and address them, and to ensure the drug’s safety. Ongoing communication is paramount during trials by ensuring patients understand the nature of the study and can express their concerns. Anything that interferes with these open lines of communication, like a brutal pandemic, potentially puts the patient’s safety at risk.
During this frantic period, coronavirus clinical trials took center stage as new COVID-19 medications, therapeutics, and vaccines evolved. A large portion of biomedical research funding, media attention, and public health efforts were diverted to these studies. There’s nothing inherently bad about this, but COVID-19 wasn’t the only disease that needed trials at the time. Pausing routine studies in favor of COVID-19 trials means neglecting, at least temporarily, patients who have other medical conditions. The timing was unlucky, but other diseases didn’t cease to exist just because the pandemic happened. Striking this balance given a wide pool of patients in need, and redirecting funding appropriately, was a big challenge as COVID-19 cases skyrocketed. It even represents complex bioethical questions: How “worth pursuing” is a particular disease compared to others? Is it even possible to “rank” the value of different diseases? Who gets to determine this value?
Among the most unsettling outcomes of the pandemic is that it brought our health care infrastructure’s flaws to light. Many individuals, especially practitioners and patients who experience the health care system firsthand, were already acutely aware of its shortcomings. But COVID-19 exposed these imperfections and made them impossible to ignore. Already stretched thin, medical staff and facilities didn’t have adequate support or resources during intense waves of COVID-19 variants. Issues surrounding health equity, like overcoming health disparities and ensuring accessibility to drug treatments, became serious problems for some patients. These problems predated COVID-19 and aren’t unique to it, but the pandemic certainly emphasized them. As we determine a path forward in a post-pandemic world, public health experts think deeply about how to solve problems like these, to help everyone pursue their healthiest self.
The COVID-19 Treatment Toolbox
So far, we’ve covered two types of antiviral COVID-19 medications in detail. That’s not the whole story, though. There are other COVID-19 antiviral drugs too, and pharmaceutical treatments aren’t limited to pills either. In this section, we’ll see how the pandemic employed a multitude of other forms of treatment, even making use of the body’s natural defense mechanisms.
Monoclonal Antibodies
Even when it’s combating an infection like COVID-19, the immune system is a very powerful force. A relentless soldier in the battle for your health, its most intrinsic mission is to protect you, and it’s determined not to give up. To achieve this goal, the immune system utilizes its diverse range of physiological intricacies, some of which researchers don’t fully understand yet. Immunologists do understand the basic mechanism of how it works, though.
When a foreign pathogen, like the SARS-CoV-2 virus, infects you, we call that pathogen an antigen. The immune system recognizes antigens as invaders and mounts an immune response to ambush them. Among other biochemical battalions, it deploys antibodies. Antibodies are proteins made by the body’s B cells that selectively bind to antigens like a key fitting a lock. Binding is a way of flagging the antigen so other immune cells can identify, attack, and neutralize or kill it. As a component in pharmaceutical treatments, antibody therapy is an auspicious option for patients whose bodies can’t mount a sufficient immune response on their own.
How do monoclonal antibodies work?
We can classify antibodies into two broad categories. Monoclonal antibodies (mAbs) are antibodies that target a single antigen. They’re man-made in the lab by cloning a single lineage of B cells, hence the name. By contrast, polyclonal antibodies (pAbs) derive from multiple immune cells, arise naturally in the body in response to an infection, and can target multiple antigens.
We usually discuss mAbs as an immunotherapy in the context of cancer, where the “antigen” that they recognize is a protein on the surface of a cancer cell. More recently, their applications have extended to other conditions, including COVID-19. (Another pharmaceutical lingo lesson: a drug whose generic name ends in “-mab” is a type of monoclonal antibody.) When administered to patients, mAbs stimulate the immune system and can improve their chances of fighting off an infection. Creating mAbs in laboratories is an opportunity to precisely tailor them to a specific condition, which can enhance patient outcomes. Pharmaceutical scientists can mass-produce them with high consistency, and off-target effects are relatively unlikely because the mAb binds to only one antigen.
How does that binding make the magic happen? Given its Y-like shape, an antibody has two arms that branch off from its body (the Y’s vertical stem). On the end of each arm is a paratope, the region that binds directly to an antigen. The antigen itself features a region called an epitope. The antibody’s paratope and antigen’s epitope are extremely specific to each other. Consequently, the molecules bind together in a selective and precise manner, like a lock and key. Once the antibody has latched on to the antigen, the immune system can take action to attack that antigen.
Over time, researchers have found that COVID-19 mAbs can have different levels of effectiveness against certain SARS-CoV-2 variants. COVID-19 mAbs tend to have a harder time fighting off recent variants compared to older ones. As the pandemic evolved, novel variants dominated new infections, and some variants even showed resistance against COVID-19 treatments. It quickly became evident that antibody therapy alone, though a valuable aid, wouldn’t be a long-term solution to COVID-19.
Newly-produced antibodies travel from the B cell (a white blood cell) to the antigen’s location via the patient’s blood plasma. Everyone has blood plasma, but COVID-19 patients may be able to supplement their treatment with convalescent plasma. Next, we’ll see what that means and why it matters.
Convalescent Plasma
We just described how an infection engages the body’s immune response, including increasing the amount of antibodies in the blood. We also mentioned that the immune system’s B cells naturally produce polyclonal antibodies during an infection.
In patients who survive the infection, those antibodies don’t disappear after their symptoms clear up. As the infection resolves, the antigens in the body dwindle. But just in case these antigens dare to show their face around these parts again (in other words, if the patient were to contract the virus again in the future), these antibodies remain in the body, lying in wait to flag them for removal.
Therefore, people who have survived COVID-19 still have COVID-19 antibodies in their blood plasma. Plasma is the part of blood that excludes blood cells and platelets. Survivors can donate this blood plasma, and HCPs then process it and transfuse it into the veins of patients who are actively sick. This was a big deal during the first phase of the pandemic, before researchers managed to make a vaccine that teaches the body’s immune system to create COVID-19 antibodies. And once the vaccines were available, vaccinated folks could donate their antibody-rich plasma to COVID-19 patients even if they’d never actually had an infection themselves.
Plasma therapy is viable particularly for immunocompromised patients, who may not be capable of launching robust immune responses without it. It’s a great way for COVID-19 survivors to pay it forward and play a personal role in helping current patients. Plasma therapy is useful due to its potential to shorten the duration or severity of infection. In 2020, when no feasible COVID-19 medications were available, having ready-made antibodies in our arsenal was practical and priceless.
Making the Most of COVID-19 Medications
Antibody therapy and plasma therapy are two non-antiviral tools that HCPs relied upon during the worst waves of the pandemic. Once COVID-19 medications hit the market, they became the go-to treatment for active infections because they successfully interrupt the viral life cycle. But if you find yourself infected with COVID-19, the medication that suits your needs might depend on factors like your age and risk of hospitalization. Each of these drugs works most effectively when taken shortly after the onset of symptoms. Why does when you take the medicine matter? It’s ideal to intervene during the initial stages of infection, before the virus has extra time to damage the body. This is especially important in severe cases, when such damage could be extensive.
As is the case with other viral infections, prioritizing rest and fluid intake can go a long way in COVID-19 recovery. In more severe cases, supplemental oxygen and around-the-clock care might be necessary to help hospitalized patients heal. Without innovative antivirals around yet, early waves of the pandemic relied heavily on supportive care techniques like these. Now approved by regulatory authorities, drugs like nirmatrelvir/ritonavir are quite accessible, as long as you have an HCP’s prescription. They’ve even surpassed supportive treatments and taken center stage as the first line of defense against an active COVID-19 infection due to their efficacy and reliability. Nonetheless, HCPs can use all of these treatment types in tandem to make their combined impact more effective.
Despite all of their advantages, antiviral drugs don’t replace other infection control tactics. Patients using COVID-19 medications are still advised to self-isolate until their infection resolves or, if that’s not an option, wear a mask and practice social distancing. Here, let’s also note that these medications only treat existing cases; they don’t do anything to protect patients against future COVID-19 infection. Instead, those prevention measures are best addressed using vaccines and prophylaxis, two tactics we’ll explore later in this mini-series, as well as old school strategies like good hand hygiene. The classics never go out of style!
Conclusion
The worst of the COVID-19 pandemic has now passed, but epidemiology demonstrates the constant skirmish between the scientific tools underlying public health and the increasing fortitude of formidable pathogens. As we anticipate future pandemics, we can plan ahead by reflecting on our past successes and shortfalls, and now we have effective treatments in case new COVID-19 cases recur in the future. These treatments, though challenging to invent and deploy, represent a great achievement in the biomedical research realm. Although we can’t fully cure viral infections, the good news is that we can prevent them. In a forthcoming article in this public health mini-series, we’ll explore the advanced array of preventive measures — including the groundbreaking mRNA vaccine technology — that stopped COVID-19’s spread in its tracks.