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DEPARTMENTS: Editorial

Tracking a Vaccine and Developing Therapeutics for COVID-19

Gould, Kathleen Ahern PhD, MSN, RN

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Dimensions of Critical Care Nursing: 11/12 2020 - Volume 39 - Issue 6 - p 293-297
doi: 10.1097/DCC.0000000000000447
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Evidence is stronger than argument.

–Winston Churchill, 1897

A global effort is underway to explore ways to treat and prevent human coronavirus infections, specifically the SARS-CoV-2 virus. As I write this, we are about 8 to 10 months into the COVID-19 pandemic. Many have become sick, and many lives have been lost. Healthcare providers have been challenged on all fronts. No one has escaped some type of distress or harm.

Science and industry are working to develop new antibodies, therapeutic drugs, and vaccines. The goal is to interfere with the transmission and progression of COVID-19. Some drugs block the virus from entering cells; some delay the immune system response, and some block viral replication.1 This is challenging work when a new virus like COVID-19 arrives, as there is still much to learn about the inflammatory response to the virus and what part of the immune response is critical to prevent infection. Because this is a novel virus, vaccines do not exist and many therapeutics are untested against this virus.

Vaccine development is complex. It is a highly sophisticated science, which is labor and time intensive. Yet, we are guided by past lessons and new innovations. Clearly, we will need every tool of science and society to control and/or eradiate this virus. Significant progress has been made on all fronts. As work continues, we are learning more about T- and B-cell immunity and neutralizing antibodies. There is speculation about natural immunity and discussions about goals and logistics for the development of herd immunity through vaccination. Scientists warn us that after a vaccine becomes available, the coronavirus may continue to exist; it may still infect and even kill people. The morbidity and mortality will be lower with a vaccine and will be significantly reduced with successful therapeutics. Over time, we will learn how much protection these new vaccines and therapeutics will provide. Some traditional or existing vaccines do provide sterilizing immunity to many existing diseases, producing almost complete and long-lasting protection. Others, like the influenza vaccine, require annual vaccination. The COVID-19 vaccine candidates are still in clinical trials and will soon inform us in new ways. Immunologists report encouraging signs; new data continue to inform us, as there are many studies in progress. We must rely on data from true experiments to provide a path toward an accurate understanding of this virus, the response to therapy, and the effectiveness of our treatment decisions. This work is demanding and tedious, and it takes time. Yet, it is this focused trajectory that will guide good science.

A frequently updated, comprehensive list of all COVID-19 clinical trials can be found at ClinicalTrials.gov. As of this writing, there are 45 federally funded studies for COVID-19 and 78 for clinical studies related to COVID-19.

Reputable resources provide updated information about clinical trials and new findings (Table 1).

TABLE 1 - COVID-19 Research and Vaccine Information
• ClinicalTrials.gov: Federally funded clinical studies related to COVID-19 (https://clinicaltrials.gov/ct2/results?cond=COVID-19&fund=0&fund=1)
• WHO Trial Registry Network: COVID-19 studies from the ICTRP database: (https://clinicaltrials.gov/ct2/who_table)
• NIH: COVID-19 Treatment Guidelines (https://www.covid19treatmentguidelines.nih.gov)
• ClinicalTrials.gov: views of listed COVID-19 studies (Beta) (https://clinicaltrials.gov/ct2/covid_view)
• General information about vaccines: Vaccines.gov at https://www.vaccines.gov
• Centers for Disease Control and Prevention's vaccines and immunizations site: https://www.cdc.gov/vaccines/index.html

Work on a coronavirus vaccine is moving at an unprecedented pace. Two of the leading candidates, under development by Oxford University and the US biotech firm Moderna, are moving quickly through phase III clinical trials. At this stage, both require patients to get 2 doses of the drug at separate intervals. The COVID tracker at the Milken Institute reports that there are 204 vaccines and 316 treatments in development; many are being tested in humans and others are already in an advanced phase of clinical trials.2 Some success is expected; however, first-generation vaccines may not stop a new virus in its tracks but may help mitigate the effects of the virus. Experts such as Amesh Adalja, an infectious disease expert at Johns Hopkins University, tell us: “Right now, we just need something that's going to mitigate the damage this virus causes. Maybe it does not prevent you from getting infected, but it prevents you from getting hospitalized, or prevents you from dying…that would be huge.”3

PREPARING FOR A VACCINE CAMPAIGN

Dr Julie Morita, a pediatrician and executive vice president of the Robert Wood Johnson Foundation, tells us we need a vaccine plan now. A plan must engage the government, including tracking and mapping of an effective and equitable distribution of the vaccine. Dr Morita served as Chicago’s chief medical officer during the H1N1 pandemic of 2009, where she learned that time is not on our side. She reinforces the voice of many trusted public health officials, stressing that it is important to build a plan now.4 We must communicate using the data from science to inform and build trust before the vaccine campaigns are rolled out.

This will be difficult. Although we are guided by science, we must also build and retain trust as new information continues to emerge. As we learn more, and adjust our sails, information and logistical plans may change. This will require updates, corrections, and continued communication. There will be many hills to climb and battles to fight, some scientific, some political, and some cultural. Social justice has become a renewed guiding force, as social, economic, cultural, and racial inequities have been revealed by the pandemic and current events. Transparency and truth telling must be guided by science; as there will be many challenges. Clinicians will be called upon to provide education and clear communication as new vaccines become available. Vaccine hesitancy is fueled by misinformation and unethical research. The now retracted research linking vaccines to autism has resulted in long-term damage. However, the science is clear: vaccines do not cause autism and they are the safest way to prevent many devastating diseases. Our role includes providing education and promoting discussion to inform our patients and families. It is up to every provider to prepare a scientifically based narrative to inform patients and families as they approach the opportunity for a COVID-19 vaccine and seasonal influenza vaccines, and avoid dueling viruses as we enter flu season. I suggest that healthcare providers listen to and read Atul Gawande's words about the “mistrust of science” as he inspires new graduates at Cal tech to follow the science and to commit to a professional life that is dedicated to finding truth.5,6 His words offer timely inspiration, facts, and strategies to begin this conversation. As is often the case in healthcare, we are plagued by misinformation and, often, a distrust of science. We own this; healthcare has a long history of medical racism and distrust of vaccines, often fueled by unethical behavior within our own ranks. Our work includes rebuilding trust vaccine hesitance and social injustice are very real, and may be significant obstacles to vaccine research and a successful vaccination program.

WHAT WE CAN DO

Become Proficient in Discussing Vaccination Procedures

As we learn more about vaccines, we can disseminate basic information more effectively. There are 4 main types of traditional vaccines: (1) live-attenuated vaccines, (2) inactivated vaccines, (3) subunit, recombinant, polysaccharide, and conjugate vaccines, and (4) toxoid vaccines. Live-attenuated (weakened) vaccines introduce an antigen to trigger an immune response. This group of vaccines is used to prevent diseases such as measles and chicken pox. Inactivated vaccines consist of the disease-causing virus that has been killed and are safer for some people. These are effective for flu, polio, and rabies. Subunit, recombinant, polysaccharides, and conjugate vaccines use specific substances of the virus (protein fragments of a killed virus) and are represented in new vaccines to prevent disease caused by human papillomavirus (HPV) and shingles. Toxoid vaccines use the toxin made by the virus or bacteria. These include vaccines to prevent diphtheria and tetanus.7,8

New vaccines are being developed that engage the immune system in different ways. It is becoming clear that the future of vaccines may lie in our DNA and RNA. Gene-based vaccines are the new state of the art and are very different from the 4 traditional vaccines. They do not use the virus or part of the virus but instead carry instructions for making viral proteins. This approach uses genetic engineering to deliver nucleic acids (DNA or RNA) that carry the instructions for making the viral proteins that will trigger the immune response. Because they do not use virus or viral proteins, they are quicker to make and may be less expensive to produce.8 Another new vaccine type includes the recombinant or viral vector vaccines (platform-based vaccines), which are similar to nucleic acid vaccines but use weakened virus or vectors to get into the cell, creating a viral genetic blueprint within the cells, teaching the immune system how to fight the infection.7,8

Follow Current Clinical Trials

Engage with clinical trials and help interpret the progress and results in plain language for patients and families. This information is very new and often confusing, especially during a pandemic. Significant challenges exist when scientific and administrative communities unite to scale up vaccine research, manufacturing, distribution, tracking, and monitoring systems to support the response and to mount a vaccine program that is well tested, flexible, and scalable.1 The developmental cycles begin with an exploratory stage and move to a preclinical stage before the clinical testing begins with rigorously designed research trials consisting of phase I, II, and III and often IV. Once the vaccine has passed the threshold of safety and efficacy and clinical trials are over, there are still hurdles to cross. These include regulatory review and approval, manufacturing, and quality control. The US Food and Drug Administration (FDA) licenses a vaccine only if it is proven to be safe and effective and the benefits of the vaccine outweigh any risks. Vaccines are held to very high safety standards; for more information, see the Vaccine Safety link at https://www.vaccines.gov/basics/safety.

Phase I enrolls a small number of volunteers; typically, about 20 to 100 healthy people are recruited to ensure drug safety and tolerance. At this point, dosing is established guided by patient response as is safe and appears to work without serious adverse effects. Phase II may involve more subjects, several hundred volunteers or even thousands. In this phase, dose ranges may be established. The study focus is on common short-term adverse effects. This work will begin to measure if the vaccine can mount an immune response in the participants. This phase often serves as a pilot test, where the investigators consider the feasibility of launching a more rigorous test and continue to test/refine dosage and logistical factors. The design is experimental but may include a randomized control or quasi-experimental design. The goal is to ensure that it is safe and appears to work without serious adverse effects. Evidence begins to build to infer that the vaccine holds promise. Finally, phase III is the full test of the vaccine. Two major questions must be assured—is the vaccine safe and is the vaccine effective? During this phase, the vaccine is given to thousands of people and tested for continued safety and to develop evidence about the overall effect as the investigators seek to confirm that the participants respond by mounting an immune response that will protect them from the target virus. This is confirmation is necessary to ensure efficacy (effectiveness under controlled conditions). Participants may be randomized into groups under strictly controlled conditions in multiple sites.9,10 Normally, in phase III, recruiting enough patients and hospitals takes a long time; this is not a problem with COVID-19 research. Global efforts are directed to mobilizing clinical trials and moving toward a vaccine.

Most vaccines will continue to be studied under what may be referred to as phase IV trials. Scientists will continue to study the effectiveness and long-term effects of the vaccine in the general population. This confirms external validity (generalizability) beyond the scope of the controlled sites or conditions in phase II and III. These include continued well-designed experimental studies after the vaccine is approved and licensed. Throughout the course of these final stages, vaccine safety and efficacy are continually monitored by healthcare providers, scientists, government agencies, and regulatory organizations. In the United States; the Center for Biologics Evaluation and Research (CBER) within the FDA is responsible for regulating vaccines.

Volunteer for a Clinical Trial

Phase III clinical trials designed to evaluate if an investigational vaccine can prevent symptomatic coronavirus disease 2019 (COVID-19) in adults have begun. One vaccine, known as mRNA-1273, was codeveloped by the Cambridge, Massachusetts–based biotechnology company Moderna, Inc, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The trial, which will be conducted at US clinical research sites, is expected to enroll approximately 30 000 adult volunteers who do not have COVID-19.11

I am honored to report that I was accepted into this trial after completing a short application and clinical evaluation at Brigham and Women's Hospital in Boston. On August 27, 2020, during a 3-hour evaluation, I completed the face-to-face informed consent, nasopharyngeal swab COVID-19 test, and blood draw. Upon receiving the first dose of either the placebo or mRNA-1273 SARS-CoV-2 vaccine, my progress is now tracked through an e-diary on a mobile app “patient cloud.” The study length is 25 months and includes approximately 6 visits and 25 safety telephone calls. I will receive a total of 2 injections of study vaccine or placebo given about 1 month apart. I know that messenger ribonucleic acid (mRNA) is a recent technology and that currently there are no approved mRNA vaccines for any disease. I learned more about how mRNA-1273 is made using a new process produced entirely in the laboratory, using a short segment of mRNA. This may cause some cells to make the viral protein, which will trigger an immune response. Later, if a study subject receiving the vaccine is infected with COVID-19, their immune system may remember the protein from this vaccination and help the body fight off the virus!

Clinical research is not glamorous; it is detailed and often tedious. Research teams are humble and hopeful, but always honest and caring. As I observed the study staff and talked to many of them at length about the process, I was reassured and informed. Each person answered my questions and shared unique knowledge with guarded optimism. I, however, could barely contain my excitement. I met with physicians, nurse practitioners (including a former student), and a pharmacist. As I waited in a sparse waiting room, and later in a nondescript examination room in a back building of one of our most prestigious academic medical centers, I gazed out the window and marveled at the simple view. From the fourth floor of the clinical research building, I saw the partially rusted tops of HVAC and ventilations systems resting on tin and wooden rooftops, characteristic of Boston’s old buildings. Rising over the hospital rooftops at this angle, I could see a new hospital tower, construction of a new building at Children's Hospital, and the white marble structure of Harvard Medical School, gleaming in a light misting rain. I felt gratitude and pride for my city and dedicated colleagues.

Learn About New Therapeutics

Antiviral drugs and monoclonal antibodies continue to expand the realm of therapeutic options. Some medications may move through clinical trials more quickly because some drugs have been approved for other use and therefore have passed critical phase I and often phase II study. One such drug is remdesivir, developed by Gilead Sciences Inc, which is an investigational broad-spectrum antiviral treatment. It was previously tested in humans with Ebola virus disease and did show some promise in animal models for treating Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), which are caused by other coronaviruses.11,12

The NIH is already using an adaptive platform trial design in its first sponsored study of COVID-19 therapies, the phase III Adaptive COVID-19 Treatment Trial (ACTT), which started in February 2020 testing Gilead Sciences Inc's antiviral remdesivir against placebo.12 Adaptive pragmatic trials offer a more detail approach to resizing a trial. This is especially useful when a population is affected by the pandemic. The trials are developed including considerations to stop the trial early and including the use of group-sequential designs or sample size adjustment. Many adaptive platforms are a pathway to personalized and targeted medicine, which help us get drugs to market more quickly. These trials are evolving rapidly: the primary endpoint was changed after a planned review of the outcome scale after 100 patients, and the NIH recently announced movement to a second stage of the trial, dubbed ACTT2, combining remdesivir with Eli Lilly & Co's anti-inflammatory Olumiant (baricitinib). Currently, Olumiant is approved in the United States and in more than 65 additional countries as a treatment for adults with moderately to severely active rheumatoid arthritis.13 And, as I write this (mid-August), a new study, called the Adaptive COVID-19 Treatment Trial 3 (ACTT 3), is anticipated to enroll more than 1000 hospitalized adults with COVID-19 at as many as 100 sites in the United States and abroad. This randomized controlled clinical trial will evaluate the safety and efficacy of a treatment regimen consisting of the antiviral remdesivir plus the immunomodulator interferon β-a in patients with coronavirus disease 2019 (COVID-19).14

Monoclonal antibodies are also emerging as an effective therapy for treating COVID-19. Monoclonal antibodies are proteins that are laboratory-made versions of proteins naturally produced by the immune system in response to invading viruses or other pathogens, often referred to as targeted therapy. They are important tools in biochemistry, molecular biology, and medicine as they can be engineered to target a specific antigen, found in cancer cells or viruses. Neutralizing antibodies may be natural or monoclonal and can bind directly to portions of viruses that they use to attach to and enter cells, preventing them from initiating the infection cycle. Monoclonal antibodies may provide short-term protection from SARS-CoV-2 and could serve as important tools to treat COVID-19 until vaccines become available. These and other trials are part of the COVID-19 Prevention Network, which was recently formed to conduct large-scale trials to combat COVID-19.15

The use of steroids, anticoagulants, and high flow oxygen therapy has also increased survival. These readily available and fairly inexpensive treatments are familiar therapies in the ICU. Recent studies elucidated the role of corticosteroids in COVID-19 patients and strong evidence for use in patients with severe COVID-19. In response, the World Health Organization (WHO) currently recommends systemic corticosteroids to treat patients with severe and critical COVID-19.16,17

This impressive research was completed even as clinicians were overwhelmed with critically ill patients. The September 2nd issue of JAMA includes 3 multicenter RCTs that assessed corticosteroid therapy in critically ill patients with COVID-19, as well as the WHO-sponsored prospective meta-analysis represents an important step forward in the treatment of patients with COVID-19.18-21

Prescott’s editorial comments convey optimism and pride in the collaborate work of the scientific community with these words, “Despite the widespread morbidity and mortality, and societal disruption caused by this pandemic, the work and collaboration of these networks provide hope for advancing science and humanity through this pandemic and beyond.”18

COVID-19 will be contained and science will prevail. Every member of the healthcare community will be activated to move our planet through this difficult time. As nurses and key providers, we will create new knowledge and inform our communities as we learn and develop strategies to control and eradicate this virus. Thank you for all you do and will continue to do to keep our patients safe.

References

1. National Institutes of Health. Developing therapeutics and vaccines for coronaviruses. https://www.niaid.nih.gov/diseases-conditions/coronaviruses-therapeutics-vaccines. Accessed August 24, 2020.
2. Milken Institute. COVID-19 treatment and vaccine tracker. Updated August 27, 2020. https://covid-19tracker.milkeninstitute.org. Accessed August 28, 2020.
3. Baker S, Snyder A. It's not over when the vaccine arrives. AXIOS. July 27, 2020. https://www.axios.com/coronavirus-vaccine-what-to-expect-ab575615-a294-4127-ace3-fb0be3468085.html?utm_source=newsletter&utm_medium=email&utm_campaign=newsletter_axiosvitals&stream=top. Accessed August 22, 2020.
4. Morita J. We need a vaccine distribution plan – right now. CNN Opinion. August 16, 2020. https://edition.cnn.com/2020/08/16/opinions/covid-19-vaccine-distribution-plan-morita/index.html. Accessed August 22, 2012.
5. Gawande A. Mistrust of science. Presented at: Arthur M. Sackler Colloquium. The Science of Science Communication III (SSCIII): Inspiring Novel Collaborations and Building Capacity; November 16-17, 2017; Washington, DC. https://www.youtube.com/watch?v=xnBI9Qfe25s. Accessed August 22, 2020.
6. Gawande A. The mistrust of science. The New Yorker. June 10, 2016. https://www.newyorker.com/news/news-desk/the-mistrust-of-science and https://youtu.be/QH7yhLpqdZg. Accessed August 28, 2020.
7. US Department of Health Human Services. Vaccine types. https://www.vaccines.gov/basics/types. Accessed August 22, 2020.
8. Milken Institute. COVID-19 treatment and vaccine tracker glossary. https://covid-19tracker.milkeninstitute.org/glossary. Accessed August 28, 2020.
9. Center for Disease Control. Vaccine testing and the approval process. https://www.cdc.gov/vaccines/basics/test-approve.html. Accessed August 7, 2020.
10. Polit D, Beck CT. Nursing Research: Generating Evidence for Nursing Practice. 11th ed. Wolters Kluwer; 2020.
11. National Institute of Allergy and Infectious Diseases. Phase 3 clinical trial of investigational vaccine for COVID-19 begins. 2020. https://www.niaid.nih.gov/news-events/phase-3-clinical-trial-investigational-vaccine-covid-19-begins. Accessed August 22, 2020.
12. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. remdesivir for the treatment of COVID-19— preliminary report [published online ahead of print May 22, 2020]. N Engl J Med. doi:10.1056/NEJMoa2007764.
13. NIH Newsroom. NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins. 2020. https://www.niaid.nih.gov/news-events/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib. Accessed August 1, 2020.
14. US National Library of Medicine. Adaptive COVID-19 treatment trial (ACTT-3) clinical trails.gov identifier NCT04492475. Updated August 28, 2020. https://clinicaltrials.gov/ct2/show/NCT04492475. Accessed August 28, 2020.
15. National Institutes of Health. Press release. Clinical trials of monoclonal antibodies to prevent COVID-19 now enrolling. 2020. https://www.nih.gov/news-events/news-releases/clinical-trials-monoclonal-antibodies-prevent-covid-19-now-enrolling. Assessed August 24, 2020.
16. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17023.
17. WHO corticosteroids for Covid-19. September 2, 2020. Accessed September 8, 2020. https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1.
18. Prescott HC, Rice TW. Corticosteroids in COVID-19 ARDS: evidence and hope during the pandemic. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.16747.
19. The Writing Committee for the REMAP-CAP Investigators. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17022.
20. Tomazini BM, Maia IS, Cavalcanti AB, et al; Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17021.
21. Dequin P, Heming N, Meziani F, et al; Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.16761.
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