Vaccine and Drug Development for COVID-19 – When the Cure Becomes the Problem
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The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is happening in an age of social media. There is, therefore, almost an expectation that the development of treatments should proceed and succeed as quickly as instant messaging.
As politicians decry the effect of social distancing and business closures in their rail against government bureaucracy, the lengthy process of vaccine and drug development also becomes an easy target. Also, existing drugs like hydroxychloroquine and azithromycin seem like quick and obvious solutions against COVID-19.
However, in reality, a vaccine takes an average of two to five years to develop. In addition, there are several caveats in repurposing existing drugs for COVID-19 without sufficient scientific evidence.
The research needed before vaccine development
Researchers must make sure that they are studying the most up-to-date version of the virus. Also, they need to be able to grow the virus, which may thrive in host organisms but is fragile outside of them, in cell culture. In addition, if they can establish a helpful animal model, researchers will use the model to understand the viral mechanisms before developing the vaccine. All these steps are labor-intensive and time-consuming.
When researchers can begin to develop the vaccine, they will create multiple versions and determine which version can trigger immunity against the virus (efficacy) without causing damage (safety).
The rigor needed in vaccine clinical trials
The safety and efficacy of the vaccine candidates are tested, with increasing stringency, in succeeding stages of a clinical trial. In the preclinical phase, is the vaccine effective in animal cells? In Phase I, is the vaccine safe in a small group of humans? In Phase II, is the vaccine efficacious and safe in a larger and more diverse group of humans who resemble the target population of the vaccine? In Phase III, is the vaccine safe and efficacious in thousands of humans? After obtaining government approval and market launch, many vaccines undergo more monitoring in Phase IV.
Each phase of the clinical trial takes a long time to design and set up: how many patients to recruit to ensure meaningful data, which hospitals and institutions to collaborate with for patient recruitment, and what dose to administer to patients, are some of the many considerations.
During the trial, each participant will be tested periodically; then, the enormous datasets will be collected, analyzed, and stored meticulously for submissions later. The amount of documentation involved is massive, requiring a tremendous amount of time and human resources.
After regulatory approval, the production of the vaccine needs to be scaled to the industrial level, and the supply chain needs to be set up before distribution.
Overall, the entire process takes several years.
The (slightly) faster development of a COVID-19 vaccine
In the case of the SARS-CoV-2 virus, the process can be expedited. A team of Chinese researchers have already sequenced the SARS-CoV-2 virus. Multiple institutions are already working together to characterize the virus and test in animals. As SARS and SARS-CoV-2 share about 80-90 percent of their genetic code, researchers can build on the research done on SARS.
According to Rob Grenfell, one of the scientists leading the effort to develop a COVID-19 vaccine, we have learned a great deal during the SARS outbreak. For example, the ferret model and the SARS vaccine that have been developed are applicable to the development of a SARS-CoV-2 vaccine. The previously developed SARS-CoV vaccines were inactivated viruses that have been shown to induce the production of neutralizing antibodies. The antibodies target the spike protein on the capsid of the coronavirus so that it cannot bind to its cellular receptor and, consequently, it cannot enter the cell.
As a result, researchers hope to shorten the time needed to develop the COVID-19 vaccine to 12-18 months, which represents significant progress. Therefore, claims that a vaccine against COVID-19 will be available quickly inherently lack a base in reality.
The necessity of drug clinical trials
Various public figures have promoted hydroxychloroquine and azithromycin as miracle drugs for COVID-19 patients. These public figures often cite the data from a French lab and a New York family physician as strong support for fast-tracking the drugs for approval. As a result, the FDA has, without having gone through a proper clinical trial, given emergency approval to distribute hydroxychloroquine to hospitals across the country.
However, clinical trials for drugs exist for a reason. They have the same objective as those for vaccines: to ensure the drugs are efficacious and safe for a large, diverse population of patients. After commercialization, many, if not most, drugs also undergo Phase IV trials and continue to be monitored for adverse events.
There are many cases of drugs that have passed clinical trials but go on to be demonstrated to be unsafe, sometimes with devastating side effects. For example, Thalidomide, a drug to ease morning sickness in pregnant women, caused birth defects. Vioxx, an anti-inflammatory drug, was shown to increase the risk of heart attacks. Baycol, a cholesterol-lowering drug, was found to be associated with fatal damage of skeletal muscle.
Two things are clear from the fact that drugs can still be found to be unsafe even after commercialization: one, clinical trials are essential, and two, post-approval or continuous monitoring of drugs is essential.
How the “miracle drugs” work
Hydroxychloroquine is a form of chloroquine, which targets the parasite that causes malaria. It targets the asexual form of the malaria parasite in the red blood cell by preventing the parasite from detoxifying the hemoglobin it ingests.
Azithromycin is an antibiotic used for the treatment of several bacterial infections; it prevents bacterial growth by interfering with their protein synthesis.
But SARS-CoV-2 is a virus and does not have any metabolic machinery. Little is known about how hydroxychloroquine and azithromycin act upon the virus so it remains unclear how they work against it.
It is critical to exercise caution when using a drug for which the mechanism of action is not understood, because the drug may cause unknown and unexpected side effects. For example, chloroquine is potentially dangerous when used at high doses or for prolonged periods; it can cause permanent blindness and even death.
Unfortunately, there is already a case of incorrect self-medication. A man in Arizona died after taking a form of chloroquine to prevent COVID-19, while his wife remains in a critical condition.
Data from France and New York
Recently, a French lab followed 80 patients who received a combination of hydroxychloroquine and azithromycin. Except for an 86-year-old patient who died and a 74-year-old patient who is still under intensive care, all the patients demonstrated improvement.
The sample size of the study is small enough to be what Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Disease, called “anecdotal evidence”. Second, the fact that everybody but the elderly recovered may be because the elderly were more vulnerable to COVID-19 and that the younger patients were more likely to recover anyway.
According to the authors of this study, so far, 503 patients have undergone the same treatment, and only one patient has succumbed to COVID-19. However, there is no further information as to if this study is separate or different from the published study.
Around the same time, a New York family physician, who claimed in media interviews, without the support of a peer-reviewed publication, that he had treated 699 COVID-19 patients with the same regiment to the result of zero deaths and only a few hospitalizations. The entire exercise could not be classified as a rigorous designed and tested clinical trial because there was not a control group of patients who did not receive the drug, for comparison in efficacy. In other words, without a no-drug control group, it will be impossible to distinguish the drug-related recovery of patient in the drugged group from the patients who recover even in the absence of the medication.
Most of the people who went to the doctor had mild symptoms, to begin with; otherwise, they would have gone to the emergency room. As more than 95% of the COVID-19 cases are mild, most of the patients who went to see the doctor were going to recover anyway. Lastly, the doctor treated the so-called coronavirus patients before testing became widely available. Therefore, it is unclear how many of the patients were infected with SARC-CoV-2.
Aside from their respective side effects, drug-drug interactions, which is the alteration of a drug’s action in the presence of another drug, is a concern.
There have not been any studies done on the potential drug interaction between hydroxychloroquine and azithromycin. While the patients who had taken the drug combination did not appear to have side effects, the patient sample size was relatively small, and the patients were not appropriately monitored. Therefore, the potential side effects of combination therapy remain a concern.
The burden on other disease populations
Chloroquine is widely used to treat many other diseases, such as lupus and rheumatoid arthritis. Ever since chloroquine gained a high profile from celebrity endorsements, it has gone into short supply. As a result, many lupus and rheumatoid arthritis patients have not been able to access chloroquine, which they have to take continually.
There are 1.5 million lupus patients in the U.S. and over 5 million worldwide. 0.3% to 1% of the global population suffers from rheumatoid arthritis, and 1.3 million people in the U.S. have the condition.
While it is unclear if chloroquine will work against COVID-19, the consequence of no chloroquine is clear for many lupus and rheumatoid arthritis patients. They may end up in the hospital and further burden an already overwhelmed healthcare system.
In a time of high stress, people tend to reach for easy and quick solutions, such as “miracle drugs” that appear to be supported by data. However, we should look at the data with a critical eye and not get overly excited by false positives. There should be a better understanding of the drugs, especially combined use of drugs, before deployment to the general population, so that the drugs do not create more problems than they solve and become a problem bigger than the disease itself.