Participating in a Covid Vaccine Stage III Drug Trial: Scientific Prowess Meets Pandemic Politics
Part I: My Experience as a Vaccine Clinical Trial Participant
By the early summer of 2020, as new Covid cases surged passed 50,000 daily infections across the nation due to a hurried and botched reopening of the economy, the failure by political leaders to control the pandemic became apparent. With a further flood of cases expected to be ushered in with the cool weather in September, and political will to implement preventative measures fast eroding, I began to realize that the only path to returning to an approximation of normalcy would be the successful development and rollout of a vaccine. Hence, on listless evening at my apartment in Pittsburgh, PA, I looked up whether any clinical trials for Covid vaccines were available for local participants.
At that time, signups were buried within the Pitt+Me website, which is used to recruit volunteers for the plethora of medical studies that are unfolding at any one moment across the University of Pittsburgh and the healthcare conglomerate UPMC. Scrolling through the various studies being conducted served as a reminder that Pittsburgh has become a center of gravity for advanced biomedical research, providing some comfort that this is one of the better-equipped regions to reside during a pandemic. However, it took a considerable amount of time to denote that I was interested in signing up for a Covid vaccine trial, and I became worried that aspiring volunteers without internet access or with less experience searching the web could not find a way to submit their names, skewing the pool of applicants towards a younger and more affluent group. During the pandemic, far fewer workers would see the advertisements for medical studies that are often posted inside city buses. Nonetheless, I filled out the online form and waited to see if I could qualify as a participant. In the end, I signed up because I became curious about the vaccine development process, was interested in what the experience is like for volunteers, and because I missed my friends and family and just wanted to see them again. I hoped that by participating in a vaccine trial, I could vouch for the safety and efficacy of the development process and the diligence of the researchers. If a vaccine were to be approved, I hoped to be able to convince at least one other person that it is safe and worthwhile to be inoculated.
Between late June and mid-July, I completed additional online screenings to assess whether I could participate in a study. At this stage, I was asked to sign a consent form that described the ways in which my medical data would be used by the Pittsburgh Vaccine Clinical Trials Unit Registry for determining eligibility for participating in a study. Later that month, an email was sent to all potential participants that the university would begin enrolling hundreds of adults in the first of several stage III trials for different Covid vaccines. In late August, I received a call out of the blue from the vaccine registry. The coordinator explained that they were hurriedly trying to recruit the last of 250 volunteers for the first Phase III study to take place in the city. After assessing that my laboratory job put me at elevated risk for contracting the virus, I was invited to make an appointment to enroll in the trial.
The study took place in a cramped suite inside a nondescript medical office building on the leafy outskirts of the University of Pittsburgh campus. The atmosphere here was pleasantly different from the rest of the nearly deserted university. Medical workers of all stripes dressed in full PPE bustled through the warmly lit hallways, ushering participants into and out of rooms, filling out forms, carrying samples, and quietly conferring with one another. After being led to a standard examination room, I answered a litany of health questions and was given a brief physical.
A physician then coached me through a lengthy consent form, highlighting the various risks and benefits of being a clinical trial participant, and making sure that I understood the experimental design and objectives of the study. I was informed that I would either receive two doses of the Moderna mRNA-1273 vaccine or a placebo four weeks apart. Potential risks- which had been elucidated in previous rounds of research involving fewer participants- were quite small, even at this early stage. It was already known that participants receiving the vaccine could be prone to mild fever, pain or redness at the injection site, headache, muscle and joint aches, fatigue, chills, swollen glands, or nausea. However, these effects were more of an inconvenience than a threat to one’s overall wellbeing and resolved on their own within two days. Serious side effects had not been detected. I decided on the spot that such risks were a trivial price to pay if my participation could help get an effective vaccine approved. Importantly, this was a blinded study- until the initial results were known, neither I nor the researchers would know if I had received the vaccine or a placebo. This is an important measure to remove bias from the experimental design- this way, my expectations, the researchers’ expectations, observer bias, and confirmation bias are removed from the equation. In the words of the full, published experimental protocol: “The Blinded Phase of this study is a randomized, stratified, observer-blind, placebo-controlled evaluation of the efficacy, safety, and immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine compared to placebo in adults.” The goal of blinding is to turn the hopes and fears of participants, clinicians, and scientists into mere noise rather than bias.
Once I understood the basics of the experiment, I gave informed consent to continue my participation. I knew that I could drop out at any time, and that every step along the way was voluntary. A nurse then took seven tubes of blood to gather baseline information on my general health and SARS-CoV-2 antibody status, and then administered a nasal-pharyngeal swab to assess whether I had an asymptomatic infection. Lastly, a different nurse administered an injection into my arm, I waited a half hour in case any side effects quickly manifested, and then I was allowed to leave. Over the next few months, I reported regularly for additional blood work, nasal swabs, and physicals. Research staff asked a litany of health questions every time I returned. I completed an e-diary of my health once a week as well. Lastly, I was told to return to the clinic if I ever developed Covid-like symptoms so that the researchers could undertake further testing. I was compensated monetarily for each visit to pay for transportation costs and for the time I dedicated as a participant. It was not a luxurious amount of money- one visit to the clinic covered a week of groceries- but it was enough to encourage me to make it to every appointment and remain in the study. Importantly, I was asked to proceed with life as if I received the placebo and take full precautions against contracting Covid. Therefore, I continued to wear a mask indoors and avoid crowds. Now, it was a waiting game.
On November 25th, 2020, I was contacted by the research staff with the best possible news- an independent data safety and monitoring board had met the previous week and determined that the Moderna vaccine was safe and effective- no safety concerns were detected, and initial results showed a 94.5% efficacy rate. Of the over 30,000 participants in the study, 95 contracted Covid- of those, 90 were in the placebo group, and only 5 had been in the vaccinated group. The clinical trial was to continue while additional data were collected, emergency use authorization was submitted, and research protocols were updated to open the door to having the placebo group receive the vaccine. The emergency use authorization granted in December triggered the unblinding of the study- a necessary moral imperative to offer vaccines to those in the placebo group. The On January 8th, I returned to the clinic for a much-anticipated appointment to learn whether I had received a placebo or the vaccine. I was informed that I had been in the placebo group, and much to my relief, I was immediately given the opportunity to get vaccinated. I took the shot without hesitation, knowing that it would open the door to safely seeing friends and family for the first time in nearly a year. The rigor of the experimental design and professionalism of the researchers had convinced me that taking the vaccine was the safe, correct, and necessary decision.
Part II: The Science Behind Covid Vaccines
The development of no fewer than three Covid vaccines in the US in under a year should be considered one of the greatest technical achievements of the 21st century. However, a burst of progress of this magnitude did not occur in a vacuum. Political, economic, and historical factors made the design and rollout of these vaccines simultaneously achievable and imperfect. The decades of science that went into the successful formulation of safe and effective mRNA vaccines should be celebrated and understood to push back on misinformation that the process was rushed, untested, or unsafe. The political and economic factors that hobbled vaccine production, rollout, and uptake must be sharply critiqued.
Contrary to the popular narrative that mRNA vaccines were invented in only a few months, the necessary scientific knowledge that enabled their development began exactly 60 years ago with the discovery of mRNA and its function in 1961. Similarly, the lipid nanoparticles used to deliver mRNA into cells have been under investigation for decades. Some key milestones which are described in amazing detail by Hou et al. in a peer-reviewed paper are worth discussing.
mRNAs, or messenger RNAs, are delicate and transiently expressed molecules that our cells naturally produce every time they need to use a gene. Genes are segments of DNA that encode instructions on how to build a specific protein. Specialized proteins in the nucleus read genes and transcribe their DNA instructions into mRNA. The mRNA then leaves the nucleus and attaches to small structures known as ribosomes which then translate the mRNA into a protein which will serve one of thousands of distinct biological functions. Afterwards, the mRNA is broken down into its constituent parts and recycled. This process is akin to copying a paragraph out of a book and translating it into a different language that other people can understand and use. This process doesn’t change the content or meaning of the book- likewise, mRNA does not change the content of our genome. mRNA vaccines take advantage of this natural process. For infectious disease, mRNA corresponding to a viral gene is introduced into the cell and translated by the ribosomes. The immune system recognizes the resulting viral protein as a foreign invader, and makes antibodies against it, yielding protective immunity by preparing the body for a rapid response if it is exposed to the live virus. For example, the Moderna vaccine codes for the full-length SARS-CoV-2 spike protein, which mediates the attachment and entry of the virus into host cells, making it the perfect target for the immune response. The vaccine essentially shows the immune system Covid’s battle plan before it attacks, allowing the body to mount the ideal defense in the case of infection.
Extensive mRNA vaccine research has been conducted in animal models and in human clinical trials since the 1990s. In 1990, researchers at the University of Wisconsin injected mRNA into mouse muscle, eliciting the expression of desired proteins. Five years later, an mRNA-based cancer vaccine induced an immune response in mice. Scientists designed an mRNA influenza vaccine in 1993 that successfully triggered a virus-specific immune response in mice, demonstrating that mRNA vaccines can be used to fight infectious disease and paving the way for future research in humans. Currently, clinical trials in humans for mRNA vaccines against influenza, zika, cytomegalovirus, chikungunya virus, rabies, as well as a wide array of cancers and genetic disorders are underway. They carry enormous potential for answering previously insoluble threats to human health and represent the next generation of vaccine technology.
Part III: The Politics of a Pandemic
The haphazard and inequitable rollout of the Covid vaccines leaves less to celebrate. Years of austerity budgets and underinvestment in public health infrastructure caused even the wealthiest countries to struggle to manufacture and distribute vaccines quickly for general use. Growing nationalism has led wealthy countries such as the US to hoard vaccine doses, preventing countries in the Neocolonial world from beginning mass vaccination campaigns. At the current rate, low-income countries will need 57 years to finish vaccinating their populations. Profit motives play a large role in global vaccine inequality- for example Pfizer reaped hundreds of millions in profits during the first quarter of 2021, and Moderna, which received enormous public investments, will eventually garner billions in profits. Meanwhile, the fifty poorest nations have received only 2% of all vaccine doses. The profit-motivated US embargo on Cuba has compounded this problem by preventing the island nation’s public vaccine manufacturers from precuring basic equipment and blocking the eventual distribution of 100 million doses of its publicly developed, unpatented vaccines. Furthermore, large vaccine manufacturers have bought up more essential equipment than they could use, stockpiled it, and caused small manufacturers to shutter production lines. The cost of these overlapping problems is immense- inequality is causing the pandemic to drag on, allowing for new and deadly Covid strains to spring up, and resulting in untold human suffering across the globe. This starkly illustrates of the limits of a market-based, profit-driven economic system in fighting a pandemic.
Growing vaccine hesitancy has further complicated mass vaccination campaigns and prolonged the pandemic. To combat this phenomenon, we need to understand its complex historical, economic, and social roots. Deliberate right-wing misinformation campaigns need to be fought vigorously. Anti-vaccine politicians such as Gov. Ron DeSantis of Florida and Brazilian president Jair Bolsonaro need to be met with determined protests and a concerted mass movement to block their disastrous and politicized public health policies. Additionally, we need to win over the vaccine-hesitant to the reality that immunizations are safe and effective- wishing death on those who have been deliberately mislead by political leaders is both cruel and shortsighted. It is crucial that marginalized groups are persuaded rather than excluded and written off- for example, African Americans have been abused by medical institutions for decades and legitimate institutional distrust needs to be overcome. Uninsured Americans are also under-vaccinated due to continued inaccessibility of the vaccine and distrust in profit-seeking healthcare institutions that often do more to bankrupt them than to cure them. Fighting for racial equality in medicine, for universal healthcare, and for upgraded health infrastructure in poor and isolated communities is critical for long term improvements in public health.
The United States has nearly unlimited scientific talent, demonstrated clearly in the development and rigorous clinical testing of Covid vaccines that created a new paradigm in vaccine technology. The massive public investment pumped into vaccine research shows that we can prevent and treat diseases in ways that were impossible during the 20th century. It also shows the value in publicly funding the decades of science that got us to the jumping off point for the rapid development and testing of Covid vaccines. Realizing our full potential in the future will require continued and ramped up funding of biomedical research and a long term and determined fight to eliminate global and local inequalities within the medical system. We have the technology. The question is, how do we develop the political willpower?