Forty‐fifth ASPEN Presidential Address: Research in a pandemic—Why, what, how?
2021; Wiley; Volume: 45; Issue: 8 Linguagem: Inglês
10.1002/jpen.2261
ISSN1941-2444
Autores Tópico(s)Climate Change and Health Impacts
ResumoI titled my presidential address “Research in a pandemic—Why, what, how?” First, I have no relevant disclosures to this talk, but I am a consultant for a number of companies that I have listed here, none of which will be relevant to what I discuss in this talk. Here is what I am hoping you will take away from the next ∼40 min: I am going to try to characterize the research community's response to the coronavirus disease 2019 (COVID-19) pandemic. We are going to talk about some of the cool innovation that has allowed research to be done during the pandemic and is undoubtedly going to carry forward into postpandemic research times. And then, I am going to outline why it is important to conduct rigorous research to guide treatment during a pandemic. In fact, I am going to start the talk with a lot of the "why research is important" in the middle of this pandemic. Anything big happen in the last year? Any big medical news over the last 12 months? Anything that, you know, might have affected the world? Obviously, the biggest story of the last 12, really 18, months in the world (12 months in the United States) has been the SARS-CoV-2 pandemic, or COVID-19. The impact has been immense: >120 million people infected worldwide, almost 30 million infected in the United States alone, with >2.5 million deaths across the globe, and more than half a million people dead from COVID-19 in this country alone.1 As impressive as that is, the bulk of this manuscript will detail the response to this pandemic. Medical science took front and center stage. There definitely were some bad aspects, some mistakes, some areas we would like to do differently in future pandemics. Hopefully, we will not have future pandemics, but let us use the experience from the current pandemic to be better prepared. However, the medical response also had a lot of good, real innovation and some really important discoveries. Medical science is responsible for where we are today, with some known effective treatments and numerous effective vaccines. Let me see if I can describe the view from a medical scientist in the belly of the beast of SARS-CoV-2 research over the past 12 months. The US story starts in February or March 2020. As cases, hospitalizations, and, unfortunately, deaths were starting to increase, many of us in the medical profession were starting to get a pretty high level of anxiety. For us, this was a new disease; we did not know exactly what to expect. We had heard reports and we had read reports but we had not personally seen a lot of actual cases yet. We did not exactly know what we were getting into. And in fact, we labeled this a new disease, but then we argued, Is it truly a new disease? In the critical care world alone, a number of publications argued back and forth: Was COVID-19 actually a new disease? Or was it just a new virus causing a disease we had seen before? Some argued that COVID-19 was typical acute respiratory distress syndrome (ARDS).2, 3 Others argued it was different—maybe even high-altitude pulmonary edema and not ARDS at all.4, 5 Still others rebutted that it is typical ARDS, and in fact, it was almost insulting to call it high-altitude pulmonary edema.6 Yours truly even jumped into the fray and said, “We should continue to do what we know are the best treatments for patients with typical ARDS and patients who are critically ill in general7—because that is what we know is best for our patients.” We should not waver from that treatment plan and either do things that are unknown or, in some cases, follow rash recommendations to do things that the medical community had previously studied and knew to be detrimental and harmful to our patients. But instead, we should continue to practice critical care medicine as best we could.7 Also, at this time, there were numerous questions about specific COVID-19–related treatments. Almost all of the treatments were based on anecdotal reports. There was no real, rigorous research during this time, no published randomized trials, no good treatment trials that had been published. The data that were emerging were mostly case series, cohort studies, and associations. And, having lived through and tried to practice medicine during the early part of the pandemic, I would best describe it as complete chaos. It was absolute chaos. Every day somebody would think that they came up with a new treatment. Maybe we should try it? I would get calls from lots of people saying, “Hey, have you thought of this?” “Hey, have you thought of that?” And it was complete chaos. The treatment paradigm remained uncertain, with lots and lots and lots of theoretical and proposed treatments. But, at that time, none of the proposed treatments had really been rigorously studied. And we did not know whether any of these proposed treatments actually worked. We did not know whether any of these were good for patients, neutral to patients, or even harmful for patients. It was a very unsettling time to both practice medicine and try to conduct research. The problem with the data that were available for these treatments was that they largely came from cohort studies. The data came from observational studies, which often find a relationship between an exposure and an outcome. However, trying to understand whether that relationship is causal or whether it is just coincidence is, at best, difficult and, many times, impossible when using observational studies. Determining causality is frequently (or almost always) not achievable through observational studies. Look at an example of this: alcohol and lung cancer. Many moons ago, we used to think that alcohol was related to lung cancer and that alcohol maybe even caused lung cancer. Then, we realized that there might be a confounder—specifically, smoking—in the relationship between alcohol and lung cancer. We know smoking causes lung cancer. And we know there is an association between alcohol and smoking. Patients who drink a fair amount of alcoholare more likely to be smokers. It turns out that this relationship that we thought we had understood and had found between alcohol and lung cancer was merely a coincidence, as smoking was really the causative factor. And though there was an association between alcohol and smoking, alcohol really did not play any role in lung cancer at all. Smoking was the confounder in the relationship between alcohol and lung cancer and the real cause of lung cancer.8 However, early in the pandemic, observational studies were all that were available. Therefore, observational studies represented the level of science available for all of these proposed treatments for COVID-19 during the early parts of the pandemic. The treatments were associated either with better outcomes or with not contracting the disease. However, that association was not necessarily causative. The studies demonstrated an association, but that did not equal evidence of cause and effect, and the association is likely to be affected by many confounders. What were needed in order to figure out causal relationships and effective treatments were more randomized controlled trials to answer these questions. Without known effective treatments from randomized controlled trials, and only knowing treatments from numerous anecdotal reports or confounded data from observational studies, the clinical care being provided to patients varied widely. To give you an idea, early unpublished data from >40 hospitals across the United States in the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, funded by the National Heart, Lung, and Blood Institute (NHLBI), looked at treatment provided for ∼15,000 hospitalized patients with COVID-19 from March 2020 through June 2020.9 Almost two-thirds of the patients got azithromycin as a treatment for their COVID-19. More than half received hydroxychloroquine as a treatment for their COVID-19. Steroids, which later became the first known effective treatment for COVID-19 through multiple randomized trials demonstrating benefit, were only given to about one of every five or six patients with COVID-19 at that time. Again, clinicians were trying to use the data that were available at that time to direct their treatments, but the data were largely associations, not from randomized trials, and not able to answer the question of whether these treatments caused improved outcomes. What was understood at this time was there were different phases of the disease (Figure 1). Some patients who were infected were asymptomatic carriers of SARS-CoV-2 coronavirus. They transmit the virus and give it to other people and other patients. However, from a treatment and research perspective, the goal for not-yet-symptomatic patients infected with COVID-19 is to try to prevent symptoms and prevent transmission of the virus to others. The next phase is a mild phase during which people have symptoms but the symptoms are not severe enough that the patient needs to be in a hospital. At this point, the body is starting to see some viral tissue injury occurring, but not really an inflammatory injury—just early viral tissue replication and injury. This could occur in the gastrointestinal tract, causing nausea and diarrhea, but mostly occurs in the upper and lower respiratory tract, where angiotensin converting enzyme 2 (ACE-2) is largely found. This results in upper respiratory symptoms, cough, and some shortness of breath. From a research standpoint, the goal here would be to find therapies that improve symptoms and prevent people from progressing to needing to be in the hospital. Next, you have moderate COVID-19, in which patients get a little bit worse. They have some symptoms such as severe hypoxemia that requires oxygen. They need to be cared for in the hospital. In this phase, the body is experiencing some inflammatory injury, more than just the viral tissue injury. In fact, the virus may not even be actively replicating in the body anymore. The body may have cleared the virus, but now the inflammatory response is causing lung injury and other organ dysfunctions. The goal from a research standpoint in these patients with moderate COVID-19 is to try to find treatments that get these patients better faster and, if we cannot find treatments that get them better faster, at least find treatments that prevent them from progressing to more severe disease. Patients with more severe COVID-19 develop organ failures, especially respiratory failure. They are at an incredibly high risk of death and need care in the intensive care unit. In these patients who already have significant organ dysfunction, the research goal is to find therapies that prevent death and allow those organ failures to heal more quickly. Early in the pandemic, such as in February, March, and April 2020, there were no known effective therapies for patients with COVID-19. None existed. And what we said in this kind of research world was that we should provide an opportunity for every patient, no matter what stage of disease that they are in, to be enrolled in a clinical trial so that we can better understand this disease and better treat patients. It does not matter whether that is preventing them from getting symptoms or preventing them from dying and helping them recover their failing organs faster. We want opportunities and trials in each of the above phases in order to understand this disease and improve patient outcomes. What did research look like during this early February, March, and April 2020 time period? Well, dedicated funding for COVID-19 research was largely absent at that time. There really was not a lot of it around. The National Institutes of Health (NIH) did have programs that allowed researchers already funded by the NIH to submit ancillary submissions for a COVID-19 funded project, but the proposal needed to be added onto an already established and funded network or grant. Therefore, if you were not already an NIH-funded researcher or were not already part of an NIH-funded network, there really was not an opportunity for you to get large NIH funding to study COVID-19 during this early phase. Many established, NIH-funded networks actually did submit ancillary proposals for COVID-19 early in the pandemic. I am part of the PETAL Network from NHLBI, who used ancillary funds to study hydroxychloroquine in hospitalized patients and ultimately demonstrated that hydroxychloroquine did not improve outcomes in these patients.10 It was the biggest question early in the pandemic. In vitro data suggested that hydroxychloroquine might have some antiviral activity against the SARS-CoV-2 coronavirus, leading many to hypothesize that it might be an effective treatment for patients with COVID-19. In addition, numerous observational studies suggested it might be associated with improved outcomes.11-16 The PETAL Network utilized ancillary funding from NHLBI to study hydroxychloroquine in a blinded randomized controlled trial and demonstrated that it did not improve outcomes in patients hospitalized with COVID-19.10 Another NHLBI-funded network, Strategies to Innovate Emergency Care Clinical Trials Network (SIREN), is an emergency department network that received funding for evaluating convalescent plasma in outpatients with COVID-19.17 Another funding source early in the pandemic was the Biomedical Advanced Research and Development Authority (BARDA). BARDA also had some funding and was trying to fund some clinical trials, but honestly, it was a pretty archaic and slow process, and it was difficult to get funding through BARDA. Another NIH agency, the National Institute of Allergy and Infectious Diseases (NIAID), also had funding early in the pandemic to study treatments for COVID-19. NIAID had already coordinated a number of their networks into a group called the Adaptive COVID-19 Treatment Trial (ACTT). ACTT was a platform trial that NIAID had already set up prior to the pandemic reaching the United States. Because it was already in place, the ACTT study seamlessly turned out to be the infrastructure for the NIH's first trial in patients with COVID-19, named ACTT-1. ACTT-1 enrolled >1000 patients from sites both in the United States and internationally, from February 21 through April 19, 2020, and demonstrated that remdesivir got patients better faster.18 Remdesivir shortened the time to resolution of symptoms and time to recovery, which really amounted to getting out of the hospital in patients who were hospitalized with COVID-19. So this was big, because this was the first proven treatment for patients with COVID-19, and everybody sort of celebrated this treatment and was excited about the fact that finally, in April 2020, we had something that had demonstrated benefit and that was a treatment specific to patients with COVID-19. It turns out, as subsequent data came along, that maybe this was not the most effective treatment ever, but it still was sort of a morale booster for the research world because we had found something. And we had found something in just a few short months that we could at least use to treat patients who were hospitalized with COVID-19. There were other sources of funding for research beyond governmental funding early in the pandemic. Industry provided some funding for research, although it was largely supporting their specific randomized trials of their products to see if they had a beneficial treatment effect in patients with COVID-19. Many institutions had institutional funds. They were not often huge amounts of money, but they would support small projects at their institution to look at specific aspects related to COVID-19. Institutional funds were almost never large enough to support randomized controlled trials of potential therapies. Finally, we would be remiss if we did not also mention the professional medical societies. Societies such as the American Society for Parenteral and Enteral Nutrition (ASPEN)—many through their research foundations—provided funding for research projects specific to COVID-19. For example, the ASPEN Rhoads Research Foundation developed a COVID-19 research fund and funded specific projects investigating COVID-19. Other societies did similar, and so there were other sources of funding. But the NIH funding opportunities, which represented the bulk of the funding, were pretty much tied to already being an NIH-funded investigator during these early pandemic times. Some of you may have heard that there was even philanthropy that occurred during the early pandemic times. Dolly Parton, in my state of Tennessee, donated $1 million of her own money to Vanderbilt University Medical Center to do COVID-19 research. It turns out that I was fortunate enough to get some of Dolly Parton's donated money to do a trial called Passive Immunity Trial of Nashville, or PassItON. PassItON was a trial of convalescent plasma that you will hear a lot about during this talk. This multicenter randomized controlled trial started with funding from Dolly Parton. The “PassItON” name was perfect for the mnemonic for the Passive Immunity Trial of Nashville, but it also kind of went back to Dolly. As some of you may not know, Dolly Parton, decades ago, developed and has continued to fund and support a philanthropic endeavor called the Imagination Library. The Imagination Library is an organization that Dolly has set up that sends children's books to every child in the state of Tennessee. I understand it has expanded past the state of Tennessee now, but it started in Tennessee from funding from Dolly Parton. One of the books that the Imagination Library actually sends to children in the state of Tennessee is a book by Sophy Henn called Pass It On. It kind of came back home with Dolly that we named our trial PassItON because she funded the start of this trial and it is one of the books that she sends out through the Imagination Library. A little later in the pandemic, starting in May 2020, Operation Warp Speed got funded and started operations. Many of you have probably heard about Operation Warp Speed. If you have not, here are some details. On May 15, 2020, the US government officially announced the creation of Operation Warp Speed, which would serve as the funding source for future discoveries in COVID-19.19 It was really designed in late April 2020, and many people knew about it before it was officially announced. But the government officially announced its existence on May 15, 2020. Operation Warp Speed was a public-private partnership between a number of government organizations that conduct research and private firms, mostly pharmaceutical companies. The goal was to pair government organizations and private pharmaceutical companies to expedite the task of discovering effective therapeutic and preventative strategies against COVID-19. The objective of Operation Warp Speed was to facilitate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. Operation Warp Speed spent a lot, a lot of money and time on vaccines. They also had a charge to discover therapeutics and diagnostics, but a big portion of the money and their expenditures went toward COVID-19 vaccines. Through the Coronavirus Aid, Relief, and Economic Security (CARES) Act passed by Congress, Operation Warp Speed was initially funded with $10 billion, which was increased to $18 billion in October 2020. How did Operation Warp Speed spend their money? About $12 billion of their $18 billion in funding went toward vaccine development. They had two big objectives: produce and deliver 300 million doses of a safe and effective vaccine or multiple safe and effective vaccines, with the hope that the initial doses would be available for public use by January 2021. They also did something really important. They facilitated manufacturing of vaccine candidates while the vaccine remained in preapproved status during pre-final research. So what Operation Warp Speed did was contract with a number of the vaccine-producing companies (Pfizer, Moderna, Johnson & Johnson, AstraZeneca), and they said, "We are going to buy 100 million doses of your vaccine, whether it works or not. There is no risk for you to start producing it, so start mass producing it, even before the data show whether it is effective or not. If it works, great, we are going to buy it. And if it does not work, we will still buy those 100 million doses of a vaccine that does not work, just so that we do not have to wait for the research to get done to know that the vaccine is effective before we start mass producing these vaccines." This was a big reason why vaccines came to be used in the public in ∼9 months or a little less than 9 months from the start of these trials. This was a huge advancement—a monetary and financial risk, but a big advance in speeding up the process to get an effective vaccine to the population. Other Operation Warp Speed money was directed toward COVID-19 therapeutics and diagnostics, and this was pretty broad. There was funding for monoclonal antibody research. There was funding for other NIH projects and funding for the institutes within the NIH. The NHLBI of the NIH developed and funded a group called Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS), which is a group that now oversees all NHLBI COVID-19 research. It was developed from Operation Warp Speed funding around June or July 2020, and it is responsible for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) platform, which is a therapeutic platform testing treatments for both inpatients and outpatients with COVID-19. The ACTIV platform contains many different treatment arms testing a wide variety of therapeutics. Operation Warp Speed took over funding the NIAID ACTT platform; so it took over funding of the platform that had developed and studied remdesivir. Through the National Center for Advancing Translational Sciences (NCATS), another institute in the NIH, Operation Warp Speed also funded clinical trials investigating convalescent plasma as a treatment for patients with COVID-19. We already had the infrastructure in place and a trial investigating convalescent plasma up and running, thanks to some of Dolly Parton's donation. Lastly, additional funding from Operation Warp Speed went to the Centers for Disease Control and Prevention (CDC) to understand the COVID-19 disease process from an epidemiologic standpoint and to study vaccine effectiveness once the vaccines were available to the public. Let us specifically look in more detail at the NCATS convalescent plasma study. I already mentioned that Dolly Parton had given money to Vanderbilt University Medical Center, and we were fortunate to get some of that money to start our PassItON trial of convalescent plasma. This was a randomized trial, convalescent plasma vs a placebo, which turned out to be a lactated ringer's solution with multivitamin in it to make it the same color as plasma. The objective was to truly understand whether convalescent plasma was beneficial to hospitalized patients with COVID-19.20 Using some of Dolly's donation, we got this study up and running in May 2020. We actually got it enrolling, and as you can see, we were enrolling slowly in May, June, and July 2020, only enrolling hospitalized patients with COVID-19 at Vanderbilt as a single-center study (Figure 2). Throughout these months, we had numerous discussions with NCATS to try to obtain funding to do a big, multicenter, nationwide study of convalescent plasma to quickly enroll a lot of patients and efficiently get an answer to the question of whether or not convalescent plasma was beneficial for hospitalized patients with COVID-19. We had lots of back and forth with NCATS, but ultimately NCATS told us, "Operation Warp Speed kind of controls the purse strings, and until they give us the money, we do not have the funding to give you to conduct a multicenter trial." Talking back and forth, back and forth, back and forth, we suddenly get THE email. I know you are probably thinking, Well, what does that mean, Todd? What is THE email? So here is THE email: Friday, July 17, 2020, from Clare Schmitt, who is one of the program officers at NCATS, with the subject of “Urgent-Convalescent Plasma Trial Info Needed.” “Hello. When it rains it pours. This trial is now on many folks’ radar. The WH . . .” And as I read this I thought, the WH? Wait, that is the White House. “The WH and BARDA need a bit more information ASAP. I'd appreciate your responses as quickly as possible.” So it turns out that in the middle of July, the White House and the President of the United States were very interested in convalescent plasma and learning whether or not it worked to treat patients with COVID-19. Their interests led to pressure on Operation Warp Speed. After some discussion and consultation, Operation Warp Speed then provided funding to us to expand from a single-center trial just at Vanderbilt University Medical Center to a multicenter trial across the country with >30 different sites enrolling patients in this trial. And the name of the trial changed from Passive Immunity Trial of Our Nashville to Passive Immunity Trial of Our Nation. This was definitely different than what any of us who had NIH funding before had ever seen. The purse strings were a little different. The way the money flowed was a little bit different. And this was, I guarantee you, the first and the only time I will receive an email that says the White House is really interested in the research that you are conducting. Figure 2 shows what happened after that. We got money for multicenter funding in August. We started opening multiple centers in September 2020. We actually started to see a surge in cases across the country during that time, too. And we went from kind of smoldering along with enrollments to a pretty steep slope of enrollments, and currently, we have a little less than 850 patients enrolled on our way to 1000 to try to truly answer the question of whether convalescent plasma is beneficial to patients hospitalized with COVID-19. That is just one personal anecdote demonstrating the chaotic research environment that occurred during the first ∼9 months during COVID-19. It was chaotic. I am not sure it was great. It was disorganized. There were lots of people studying similar things and stepping on each other. However, despite all of the downsides, there were a number of positives that came from it. Lots of innovation has come from research in the last 9 months. Let us talk about some of this innovation. The first and the biggest innovation obviously is the vaccines, and specifically the mRNA vaccines. mRNA is messenger RNA, the actual RNA that the cells within our body use to make proteins. It is the kind of script, the directions, the recipe for making the proteins within the cells. Although technically new technology, mRNA was actually isolated in the 1990s. The potential of mRNA was already known well before the start of this pandemic.21 It was already known that mRNA technology would allow us to manipulate a cell in the human body to make it produce a protein that we wanted it to make. But honestly, scientists had encountered significant difficulty getting mRNA inserted into human cells and being able to get the cells to actually make the coded protein. Itturns out that when injecting naked mRNA by itself, some of it gets into cells, but the process is not very efficient and it does not really cause the cell to make a lot of the desired protein. In the 2010s, scientists discovered that if you put the mRNA in a lipid nanoparticle, the cell would actually take it up better. The cell would degrade the lipid nanoparticle, leaving the now naked encoded mRNA in the cell, and the cell would actually make the proteins coded for by the mRNA. This allowed for the development of mRNA vaccines—specifically, SARS-CoV-2 mRNA vaccines. The mRNA in the lipid nanoparticle gets taken up by the cell and the lipid nanoparticle degrades, leaving the naked mRNA in the cell for translation into protein. The ribosome in the cellular cytoplasm sees that mRNA and starts translating the message from that mRNA into a protein, which it then sends to the Golgi apparatus, which packages that protein up and presents it on the cell surface. In the case of this SARS-CoV-2 vaccine, the protein presented on the cell surface is the viral spike protein from SARS-CoV-2. The cell then displays that spike protein on its surface, and as it shows it on the surface of the cell, it actually will present it to the patient's immune system. The patient's immune system recognizes the protein as foreign and develops patient-derived antibodies from these proteins being presented on these cells. Then, those antibodies actually protect the patient when they are exposed to the SARS-CoV-2 virus, as they already have circulating antibodies against the spike protein. Many of you already know that the spike protein is the protein on the virus that -it uses to attach to human cells in order to put its RNA into the cell to replicate within our cells. When that spike protein on the virus is blocked by an antibody, the virus cannot attach to the cells. It cannot transmit its instructions through its RNA into the cell. It cannot manipulate the cell to make the viral proteins, and the virus essentially cannot replicate. That is how viral replication works and how the vaccines prevent viral replication and essentially protect patients from getting infected with SARS-CoV-2. However, prior to COVID-19, this mRNA and nanoparticle technology had never been used before in human vaccines. It had been used in animals; it had been used in chimpanzees; but it had never actually been used in humans before COVID-19. This is one of the reasons that the SARS-CoV-2 mRNA vaccine trials enrolled 30,000 people in them—to understand what this mRNA did in humans, what the body's response was,
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