114 Search Results for "long covid"
Understanding Long-Term COVID-19 Symptoms and Enhancing Recovery
Posted on by Walter J. Koroshetz, M.D., National Institute of Neurological Disorders and Stroke
We are in the third year of the COVID-19 pandemic, and across the world, most restrictions have lifted, and society is trying to get back to “normal.” But for many people—potentially millions globally—there is no getting back to normal just yet.
They are still living with the long-term effects of a COVID-19 infection, known as the post-acute sequelae of SARS-CoV-2 infection (PASC), including Long COVID. These people continue to experience debilitating fatigue, shortness of breath, pain, difficulty sleeping, racing heart rate, exercise intolerance, gastrointestinal and other symptoms, as well as cognitive problems that make it difficult to perform at work or school.
This is a public health issue that is in desperate need of answers. Research is essential to address the many puzzling aspects of Long COVID and guide us to effective responses that protect the nation’s long-term health.
For the past two years, NIH’s National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID), and my National Institute of Neurological Disorders and Stroke (NINDS) along with several other NIH institutes and the office of the NIH Director, have been leading NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative, a national research program to understand PASC.
The initiative studies core questions such as why COVID-19 infections can have lingering effects, why new symptoms may develop, and what is the impact of SARS-CoV-2, the virus that causes COVID-19, on other diseases and conditions? Answering these fundamental questions will help to determine the underlying biologic basis of Long COVID. The answers will also help to tell us who is at risk for Long COVID and identify therapies to prevent or treat the condition.
The RECOVER initiative’s wide scope of research is also unprecedented. It is needed because Long COVID is so complex, and history indicates that similar post infectious conditions have defied definitive explanation or effective treatment. Indeed, those experiencing Long COVID report varying symptoms, making it highly unlikely that a single therapy will work for everyone, underscoring the need to pursue multiple therapeutic strategies.
To understand Long COVID fully, hundreds of RECOVER investigators are recruiting more than 17,000 adults (including pregnant people) and more than 18,000 children to take part in cohort studies. Hundreds of enrolling sites have been set up across the country. An autopsy research cohort will also provide further insight into how COVID-19 affects the body’s organs and tissues.
In addition, researchers will analyze electronic health records from millions of people to understand how Long COVID and its symptoms change over time. The RECOVER initiative is also utilizing consistent research protocols across all the study sites. The protocols have been carefully developed with input from patients and advocates, and they are designed to allow for consistent data collection, improve data sharing, and help to accelerate the pace of research.
From the very beginning, people suffering from Long COVID have been our partners in RECOVER. Patients and advocates have contributed important perspectives and provided valuable input into the master protocols and research plans.
Now, with RECOVER underway, individuals with Long COVID, their caregivers, and community members continue to serve a critical role in the Initiative. The National Community Engagement Group (NCEG) has been established to make certain that RECOVER meets the needs of all people affected by Long COVID. The RECOVER Patient and Community Engagement Strategy outlines all the approaches that RECOVER is using to engage with and gather input from individuals impacted by Long COVID.
The NIH recently made more than 40 awards to improve understanding of the underlying biology and pathology of Long COVID. There have already been several important findings published by RECOVER scientists.
For example, in a recent study published in the journal Lancet Digital Health, RECOVER investigators used machine learning to comb through electronic health records to look for signals that may predict whether someone has Long COVID [1]. As new findings, tools, and technologies continue to emerge that help advance our knowledge of the condition, the RECOVER Research Review (R3) Seminar Series will provide a forum for researchers and our partners with up-to-date information about Long COVID research.
It is important to note that post-viral conditions are not a new concept. Many, but not all, of the symptoms reported in Long COVID, including fatigue, post-exertional malaise, chronic musculoskeletal pain, sleep disorders, postural orthostatic tachycardia (POTS), and cognitive issues, overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
ME/CFS is a serious disease that can occur following infection and make people profoundly sick for decades. Like Long COVID, ME/CFS is a heterogenous condition that does not affect everybody in the same way, and the knowledge gained through research on Long COVID may also positively impact the understanding, treatment, and prevention of POTS, ME/CFS, and other chronic diseases.
Unlike other post-viral conditions, people who experience Long COVID were all infected by the same virus—albeit different variants—at a similar point in time. This creates a unique opportunity for RECOVER researchers to study post-viral conditions in real-time.
The opportunity enables scientists to study many people simultaneously while they are still infected to monitor their progress and recovery, and to try to understand why some individuals develop ongoing symptoms. A better understanding of the transition from acute to chronic disease may offer an opportunity to intervene, identify who is at risk of the transition, and develop therapies for people who experience symptoms long after the acute infection has resolved.
The RECOVER initiative will soon announce clinical trials, leveraging data from clinicians and patients in which symptom clusters were identified and can be targeted by various interventions. These trials will investigate therapies that are indicated for other non-COVID conditions and novel treatments for Long COVID.
Through extensive collaboration across the multiple NIH institutes and offices that contribute to the RECOVER effort, our hope is critical answers will emerge soon. These answers will help us to recognize the full range of outcomes and needs resulting from PASC and, most important, enable many people to make a full recovery from COVID-19. We are indebted to the over 10,000 subjects who have already enrolled in RECOVER. Their contributions and the hard work of the RECOVER investigators offer hope for the future to the millions still suffering from the pandemic.
Reference:
[1] Identifying who has long COVID in the USA: a machine learning approach using N3C data. Pfaff ER, Girvin AT, Bennett TD, Bhatia A, Brooks IM, Deer RR, Dekermanjian JP, Jolley SE, Kahn MG, Kostka K, McMurry JA, Moffitt R, Walden A, Chute CG, Haendel MA; N3C Consortium. Lancet Digit Health. 2022 Jul;4(7):e532-e541.
Links:
COVID-19 Research (NIH)
Long COVID (NIH)
RECOVER: Researching COVID to Enhance Recovery (NIH)
“NIH builds large nationwide study population of tens of thousands to support research on long-term effects of COVID-19,” NIH News Release, September 15, 2021.
Director’s Messages (National Institute of Neurological Disorders and Stroke/NIH)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 18th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Citizen Scientists Take on the Challenge of Long-Haul COVID-19
Posted on by Dr. Francis Collins
Coronaviruses are a frequent cause of the common cold. Most of us bounce back from colds without any lasting health effects. So, you might think that individuals who survive other infectious diseases caused by coronaviruses—including COVID-19—would also return to normal relatively quickly. While that can be the case for some people, others who’ve survived even relatively mild COVID-19 are experiencing health challenges that may last for weeks or even months. In fact, the situation is so common, that some of these folks have banded together and given their condition a name: the COVID “long-haulers.”
Among the many longer-term health problems that have been associated with COVID-19 are shortness of breath, fatigue, cognitive issues, erratic heartbeat, gastrointestinal issues, low-grade fever, intolerance to physical or mental activity, and muscle and joint pains. COVID-19 survivors report that these symptoms flair up unpredictably, often in different combinations, and can be debilitating for days and weeks at a time. Because COVID-19 is such a new disease, little is known about what causes the persistence of symptoms, what is impeding full recovery, or how to help the long-haulers.
More information is now emerging from the first detailed patient survey of post-COVID syndrome, also known as Long COVID [1]. What’s unique about the survey is that it has been issued by a group of individuals who are struggling with the syndrome themselves. These citizen scientists, who belong to the online Body Politic COVID-19 Support Group, decided to take matters into their own hands. They already had a pretty good grip on what sort of questions to ask, as well as online access to hundreds of long-haulers to whom they could pose the questions.
The citizen scientists’ group, known as the Patient-led Research for COVID-19, brought a lot of talent and creativity to the table. Members reside in the United States, Canada, and England, and none have ever met face to face. But, between their day jobs, managing time differences, and health challenges, each team member spends about 20 hours per week working on their patient-led research, and are now putting the final touches on a follow-up survey that will get underway in the next few weeks.
For their first survey, the group members faced the difficult decision of whom to contact. First, they needed to define long hauler. For that, they decided to target people whose symptoms persisted for more than 2 weeks after their initial recovery from COVID-19. The 640 individuals who responded to the survey were predominately white females between the ages of 30 to 49 who lived in the United States. The members said that the gender bias may stem from women being more likely to join support groups and complete surveys, though there may be a gender component to Long COVID as well. About 10 percent of respondents reported that they had ultimately recovered from this post-COVID syndrome.
Another important issue revolved around COVID-19 testing. Most long-haulers in the online group had gotten sick in March and April, but weren’t so sick that they needed to be hospitalized. Because COVID-19 testing during those months was often limited to people hospitalized with severe respiratory problems, many long-haulers with mild or moderate COVID-like symptoms weren’t tested. Others were tested relatively late in the course of their illness, which can increase the likelihood of false negatives.
The team opted to cast a wide investigative net, concluding that limiting its data to only people who tested positive for COVID-19 might lead to the loss of essential information on long-haulers. It turns out that half of the respondents hadn’t been tested for SARS-CoV-2, the virus that causes COVID-19. The other half was divided almost equally between those who tested positive and those who tested negative. Here are some highlights of the survey’s findings:
Top 10 Symptoms: Respondents were asked to rank their most common symptoms and their relative severity. From highest to lowest, they were: mild shortness of breath, mild tightness of chest, moderate fatigue, mild fatigue, chills or sweats, mild body aches, dry cough, elevated temperature (98.8-100), mild headache, and brain fog/concentration challenges. Highlighting the value of patient-led research, the team was able to assemble an initial list of 62 symptoms that long-haulers often discuss in support groups. The survey revealed common symptoms that have been greatly underreported in the media, such as neurological symptoms. These include brain fog, concentration challenges, and dizziness.
Making a Recovery: Of the 60 respondents who had recovered, the average time to recovery was 27 days. The respondents who had not recovered had managed their symptoms for 40 days on average, with most dealing with health problems for 5 to 7 weeks. The report shows that the chance of full recovery by day 50 is less than 20 percent.
Exercise Capacity: About 65 percent of respondents now consider themselves mostly sedentary. Most had been highly physically active before developing COVID-19. Many long-haulers expressed concern that overexertion causes relapses
Testing. Respondents who reported testing positive for SARS-CoV-2 were tested on average earlier in their illness (by day 10) than those who reported testing negative (by day 16). The team noted that their findings parallel those in a recent published scientific study, which found false-negative rates for current PCR-based assays rose as the time between SARS-CoV-2 infection and testing increased [2]. In that published study, by day 21, the false-negative rate reached 66 percent. Only two symptoms (loss of smell and loss of taste) occurred more frequently in respondents who tested positive; the other 60 symptoms were statistically the same between groups. The citizen scientists speculate that testing is not capturing a subset of COVID patients, and more investigation is required.
Since issuing their survey results on May 11, the team has met with staff from the Centers for Disease Control and Prevention and the World Health Organization. Their work also been mentioned in magazine articles and even cited in some papers published in scientific journals.
In their next survey, these citizen scientists hope to fill in gaps in their first report, including examining antibody testing results, neurological symptoms, and the role of mental health. To increase geographic and demographic diversity, they will also translate the survey into 10 languages. If you’re a COVID-19 long-hauler and would like to find out how to get involved, there’s still time to take part in the next survey.
References:
[1] “What Does COVID-19 Recovery Actually Look Like?” Patient-led Research for COVID-19. May 11, 2020.
[2] Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction-Based SARS-CoV-2 Tests by Time Since Exposure. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Ann Intern Med. 2020 Aug 18;173(4):262-267.
Links:
Coronavirus (COVID-19) (NIH)
Study Shows Benefits of COVID-19 Vaccines and Boosters
Posted on by Lawrence Tabak, D.D.S., Ph.D.
As colder temperatures settle in and people spend more time gathered indoors, cases of COVID-19 and other respiratory illnesses almost certainly will rise. That’s why, along with scheduling your annual flu shot, it’s now recommended that those age 5 and up should get an updated COVID-19 booster shot [1,2]. Not only will these new boosters guard against the original strain of the coronavirus that started the pandemic, they will heighten your immunity to the Omicron variant and several of the subvariants that continue to circulate in the U.S. with devastating effects.
At last count, about 14.8 million people in the U.S.—including me—have rolled up their sleeves to receive an updated booster shot [3]. It’s a good start, but it also means that most Americans aren’t fully up to date on their COVID-19 vaccines. If you or your loved ones are among them, a new study may provide some needed encouragement to make an appointment at a nearby pharmacy or clinic to get boosted [4].
A team of NIH-supported researchers found a remarkably low incidence of severe COVID-19 illness last fall, winter, and spring among more than 1.6 million veterans who’d been vaccinated and boosted. Severe illness was also quite low in individuals without immune-compromising conditions.
These latest findings, published in the journal JAMA, come from a research group led by Dan Kelly, University of California, San Francisco. He and his team conducted their study drawing on existing health data from the Veterans Health Administration (VA) within a time window of July 2021 and May 2022.
They identified 1.6 million people who’d had a primary-care visit within the last two years and were fully vaccinated for COVID-19, which included receiving a booster shot. Almost three-quarters of those identified were 65 and older. Nearly all were male, and more than 70 percent had another pre-existing health condition that put them at greater risk of becoming seriously ill from a COVID-19 infection.
Over a 24-week follow-up period for each fully vaccinated individual, 125 per 10,000 people had a breakthrough infection. That’s about 1 percent. Just 8.9 in 10,000 fully vaccinated people—less than 0.1 percent—died or were hospitalized from COVID-19 pneumonia. Drilling down deeper into the data:
• Individuals with an immune-compromising condition had a very low rate of hospitalization or death. In this group, 39.6 per 10,000 people had a serious breakthrough infection. That translates to 0.3 percent.
• For people with other preexisting health conditions, including diabetes and heart disease, hospitalization or death totaled 0.07 percent, or 6.7 per 10,000 people.
• For otherwise healthy adults aged 65 and older, the incidence of hospitalization or death was 1.9 per 10,000 people, or 0.02 percent.
• For boosted participants 65 or younger with no high-risk conditions, hospitalization or death came to less than 1 per 10,000 people. That comes to less than 0.01 percent.
It’s worth noting that these results reflect a period when the Delta and Omicron variants were circulating, and available boosters still were based solely on the original variant. Heading into this winter, the hope is that the updated “bivalent” boosters from Pfizer and Moderna will offer even broader protection as this terrible virus continues to evolve.
The Centers for Disease Control and Prevention continues to recommend that everyone stay up to date with their COVID-19 vaccines. That means all adults and kids 5 and older are encouraged to get boosted if it has been at least two months since their last COVID-19 vaccine dose. For older people and those with other health conditions, it’s even more important given their elevated risk for severe illness.
What if you’ve had a COVID-19 infection recently? Getting vaccinated or boosted a few months after you’ve had a COVID-19 infection will offer you even better protection in the future.
So, if you are among the millions of Americans who’ve been vaccinated for COVID-19 but are now due for a booster, don’t delay. Get yourself boosted to protect your own health and the health of your loved ones as the holidays approach.
References:
[1] CDC recommends the first updated COVID-19 booster. Centers for Disease Control and Prevention. September 1, 2022.
[2] CDC expands updated COVID-19 vaccines to include children ages 5 through 11. Centers for Disease Control and Prevention, October 12, 2022.
[3] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention.
[4] Incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines. Kelly JD, Leonard S, Hoggatt KJ, Boscardin WJ, Lum EN, Moss-Vazquez TA, Andino R, Wong JK, Byers A, Bravata DM, Tien PC, Keyhani S. JAMA. 2022 Oct 11;328(14):1427-1437.
Links:
COVID-19 Research (NIH)
Dan Kelly (University of California, San Francisco)
NIH Support: National Institute of Allergy and Infectious Diseases
RADx Initiative: Bioengineering for COVID-19 at Unprecedented Speed and Scale
Posted on by Bruce J. Tromberg, Ph.D., National Institute of Biomedical Imaging and Bioengineering
As COVID-19 rapidly expanded throughout the world in April 2020, many in the biomedical technology community voiced significant concerns about the lack of available diagnostic tests. At that time, testing for SARS-CoV-2, the coronavirus that causes COVID-19, was conducted exclusively in clinical laboratories by order of a health-care provider. “Over the counter” (OTC) tests did not exist, and low complexity point of care (POC) platforms were rare. Fewer than 8 million tests were performed in the U.S. that month, and it was clear that we needed a radical transformation to make tests faster and more accessible.
By February 2022, driven by the Omicron variant surge, U.S. capacity had increased to a new record of more than 1.2 billion tests in a single month. Remarkably, the overwhelming majority of these—more than 85 percent—were “rapid tests” conducted in home and POC settings.
The story behind this practice-changing, “test-at-home” transformation is deeply rooted in technologic and manufacturing innovation. The NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), working collaboratively with multiple partners across NIH, government, academia, and the private sector, has been privileged to play a leading role in this effort via the Rapid Acceleration of Diagnostics (RADx®) initiative. On this two-year anniversary of RADx, we take a brief look back at its formation, impact, and potential for future growth.
On April 24, 2020, Congress recognized that testing was an urgent national need and appropriated $1.5 billion to NIH via an emergency supplement [1]. The goal was to substantially increase the number, type, and availability of diagnostic tests in only five to six months. Since the “normal” commercialization cycle for this type of diagnostic technology is typically more than five years, we needed an entirely new approach . . . fast.
The RADx initiative was launched just five days after that challenging Congressional directive [2]. Four NIH RADx programs were eventually created to support technology development and delivery, with the goal of matching test performance with community needs [3].The first two programs, RADx Tech and RADx Advanced Technology Platforms (ATP), were developed by NIBIB and focused on innovation for rapidly creating, scaling up, and deploying new technologies.
RADx Tech is built around NIBIB’s Point of Care Technologies Research Network (POCTRN) and includes core activities for technology review, test validation, clinical studies, regulatory authorization, and test deployment. Overall, the RADx Tech network includes approximately 900 participants from government, academia, and the private sector with unique capabilities and resources designed to decrease inherent risk and guide technologies from design and development to fully disseminated commercial products.
At the core of RADx Tech operations is the “innovation funnel” rapid review process, popularized as a shark tank [4]. A total of 824 complete applications were submitted during two open calls in a four-month period, beginning April 2020 and during a one-month period in June 2021. Forty-seven projects received phase 1 funding to validate and lower the inherent risk of developing these technologies. Meanwhile, 50 companies received phase 2 contracts to support FDA authorization studies and manufacturing expansion [5]
Beyond test development, RADx Tech has evolved to become a key contributor to the U.S. COVID-19 response. The RADx Independent Test Assessment Program (ITAP) was launched in October 2021 to accelerate regulatory authorization of new tests as a joint effort with the Food and Drug Administration (FDA) [6]. The ITAP acquires analytical and clinical performance data and works closely with FDA and manufacturers to shave weeks to months off the time it normally takes to receive Emergency Use Authorization (EUA).
The RADx Tech program also created a Variant Task Force to monitor the performance of tests against each new coronavirus “variant of concern” that emerges. This helps to ensure that marketed tests continue to remain effective. Other innovative RADx Tech projects include Say Yes! Covid Test, the first online free OTC test distribution program, and Project Rosa, which conducts real-time variant tracking across the country [7].
RADx Tech, by any measure, has exceeded even the most-optimistic expectations. In two years, RADx Tech-supported companies have received 44 EUAs and added approximately 2 billion tests and test products to the U.S. capacity. These remarkable numbers have steadily increased from more than16 million tests in September 2020, just five months after the program was established [8].
RADx Tech has also made significant contributions to the distribution of 1 billion free OTC tests via the government site, COVID.gov/tests. It has also provided critical guidance on serial testing and variants that have improved test performance and changed regulatory practice [9,10]. In addition, the RADx Mobile Application Reporting System (RADx MARS) reduces barriers to test reporting and test-to-treat strategies’ The latter offers immediate treatment options via telehealth or a POC location whenever a positive test result is reported. Finally, the When to Test website provides critical guidance on when and how to test for individuals, groups, and communities.
As we look to the future, RADx Tech has enormous potential to impact the U.S. response to other pathogens, diseases, and future pandemics. Major challenges going forward include improving home tests to work as well as lab platforms and building digital health networks for capturing and reporting test results to public health officials [11].
A recent editorial published in the journal Nature Biotechnology noted, “RADx has spawned a phalanx of diagnostic products to market in just 12 months. Its long-term impact on point of care, at-home, and population testing may be even more profound [12].” We are now poised to advance a new wave of precision medicine that’s led by innovative diagnostic technologies. It represents a unique opportunity to emerge stronger from the pandemic and achieve long-term impact.
References:
[1] Public Law 116 -139—Paycheck Protection Program and Health Care Enhancement Act.
[2] NIH mobilizes national innovation initiative for COVID-19 diagnostics, NIH news release, April 29, 2020.
[3] Rapid scaling up of Covid-19 diagnostic testing in the United States—The NIH RADx Initiative. Tromberg BJ, Schwetz TA, Pérez-Stable EJ, Hodes RJ, Woychik RP, Bright RA, Fleurence RL, Collins FS. N Engl J Med. 2020 Sep 10;383(11):1071-1077.
[4] We need more covid-19 tests. We propose a ‘shark tank’ to get us there. Alexander L. and Blunt R., Washington Post, April 20, 2020.
[5] RADx® Tech/ATP dashboard, National Institute of Biomedical Imaging and Bioengineering, NIH.
[6] New HHS actions add to Biden Administration efforts to increase access to easy-to-use over-the-counter COVID-19 tests. U.S. Department of Health and Human Services Press Office, October 25, 2021.
[7] A method for variant agnostic detection of SARS-CoV-2, rapid monitoring of circulating variants, detection of mutations of biological significance, and early detection of emergent variants such as Omicron. Lai E, et al. medRxiV preprint, January 9, 2022.
[9] Longitudinal assessment of diagnostic test performance over the course of acute SARS-CoV-2 infection. Smith RL, et al. J Infect Dis. 2021 Sep 17;224(6):976-982.
[10] Comparison of rapid antigen tests’ performance between Delta (B.1.61.7; AY.X) and Omicron (B.1.1.529; BA1) variants of SARS-CoV-2: Secondary analysis from a serial home self-testing study. Soni A, et al. MedRxiv preprint, March 2, 2022.
[11] Reporting COVID-19 self-test results: The next frontier. Health Affairs, Juluru K., et al. Health Affairs, February 11, 2022.
[12] Radical solutions. Nat Biotechnol. 2021 Apr;39(4):391.
Links:
Get Free At-Home COVID Tests (COVID.gov)
When to Test (Consortia for Improving Medicine with Innovation & Technology, Boston)
RADx Programs (NIH)
RADx® Tech and ATP Programs (National Institute of Biomedical Imaging and Biomedical Engineering/NIH)
Independent Test Assessment Program (NIBIB)
Mobile Application Reporting through Standards (NIBIB)
Point-of-Care Technologies Research Network (POCTRN) (NIBIB)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the eighth in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
Early Data Suggest Pfizer Pill May Prevent Severe COVID-19
Posted on by Dr. Francis Collins
Over the course of this pandemic, significant progress has been made in treating COVID-19 and helping to save lives. That progress includes the development of life-preserving monoclonal antibody infusions and repurposing existing drugs, to which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership has made a major contribution.
But for many months we’ve had hopes that a safe and effective oral medicine could be developed that would reduce the risk of severe illness for individuals just diagnosed with COVID-19. The first indication that those hopes might be realized came from the announcement just a month ago of a 50 percent reduction in hospitalizations from the Merck and Ridgeback drug molnupiravir (originally developed with an NIH grant to Emory University, Atlanta). Now comes word of a second drug with potentially even higher efficacy: an antiviral pill from Pfizer Inc. that targets a different step in the life cycle of SARS-CoV-2, the novel coronavirus that causes COVID-19.
The most recent exciting news started to roll out earlier this month when a Pfizer research team published in the journal Science some promising initial data involving the antiviral pill and its active compound [1]. Then came even bigger news a few days later when Pfizer announced interim results from a large phase 2/3 clinical trial. It found that, when taken within three days of developing symptoms of COVID-19, the pill reduced by 89 percent the risk of hospitalization or death in adults at high risk of progressing to severe illness [2].
At the recommendation of the clinical trial’s independent data monitoring committee and in consultation with the U.S. Food and Drug Administration (FDA), Pfizer has now halted the study based on the strength of the interim findings. Pfizer plans to submit the data to the FDA for Emergency Use Authorization (EUA) very soon.
Pfizer’s antiviral pill is a protease inhibitor, originally called PF-07321332, or just 332 for short. A protease is an enzyme that cleaves a protein at a specific series of amino acids. The SARS-CoV-2 virus encodes its own protease to help process a large virally-encoded polyprotein into smaller segments that it needs for its life cycle; a protease inhibitor drug can stop that from happening. If the term protease inhibitor rings a bell, that’s because drugs that work in this way already are in use to treat other viruses, including human immunodeficiency virus (HIV) and hepatitis C virus.
In the case of 332, it targets a protease called Mpro, also called the 3CL protease, coded for by SARS-CoV-2. The virus uses this enzyme to snip some longer viral proteins into shorter segments for use in replication. With Mpro out of action, the coronavirus can’t make more of itself to infect other cells.
What’s nice about this therapeutic approach is that mutations to SARS-CoV-2’s surface structures, such as the spike protein, should not affect a protease inhibitor’s effectiveness. The drug targets a highly conserved, but essential, viral enzyme. In fact, Pfizer originally synthesized and pre-clinically evaluated protease inhibitors years ago as a potential treatment for severe acute respiratory syndrome (SARS), which is caused by a coronavirus closely related to SARS-CoV-2. This drug might even have efficacy against other coronaviruses that cause the common cold.
In the study published earlier this month in Science [1], the Pfizer team led by Dafydd Owen, Pfizer Worldwide Research, Cambridge, MA, reported that the latest version of their Mpro inhibitor showed potent antiviral activity in laboratory tests against not just SARS-CoV-2, but all of the coronaviruses they tested that are known to infect people. Further study in human cells and mouse models of SARS-CoV-2 infection suggested that the treatment might work to limit infection and reduce damage to lung tissue.
In the paper in Science, Owen and colleagues also reported the results of a phase 1 clinical trial with six healthy people. They found that their protease inhibitor, when taken orally, was safe and could reach concentrations in the bloodstream that should be sufficient to help combat the virus.
But would it work to treat COVID-19 in an infected person? So far, the preliminary results from the larger clinical trial of the drug candidate, now known as PAXLOVID™, certainly look encouraging. PAXLOVID™ is a formulation that combines the new protease inhibitor with a low dose of an existing drug called ritonavir, which slows the metabolism of some protease inhibitors and thereby keeps them active in the body for longer periods of time.
The phase 2/3 clinical trial included about 1,200 adults from the United States and around the world who had enrolled in the clinical trial. To be eligible, study participants had to have a confirmed diagnosis of COVID-19 within a five-day period along with mild-to-moderate symptoms of illness. They also required at least one characteristic or condition associated with an increased risk for developing severe illness from COVID-19. Each individual in the study was randomly selected to receive either the experimental antiviral or a placebo every 12 hours for five days.
In people treated within three days of developing COVID-19 symptoms, the Pfizer announcement reports that 0.8 percent (3 of 389) of those who received PAXLOVID™ were hospitalized within 28 days compared to 7 percent (27 of 385) of those who got the placebo. Similarly encouraging results were observed in those who got the treatment within five days of developing symptoms. One percent (6 of 607) on the antiviral were hospitalized versus 6.7 percent (41 of 612) in the placebo group. Overall, there were no deaths among people taking PAXLOVID™; 10 people in the placebo group (1.6 percent) subsequently died.
If all goes well with the FDA review, the hope is that PAXLOVID™ could be prescribed as an at-home treatment to prevent severe illness, hospitalization, and deaths. Pfizer also has launched two additional trials of the same drug candidate: one in people with COVID-19 who are at standard risk for developing severe illness and another evaluating its ability to prevent infection in adults exposed to the coronavirus by a household member.
Meanwhile, Britain recently approved the other recently developed antiviral molnupiravir, which slows viral replication in a different way by blocking its ability to copy its RNA genome accurately. The FDA will meet on November 30 to discuss Merck and Ridgeback’s request for an EUA for molnupiravir to treat mild-to-moderate COVID-19 in infected adults at high risk for severe illness [3]. With Thanksgiving and the winter holidays fast approaching, these two promising antiviral drugs are certainly more reasons to be grateful this year.
References:
[1] An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.
Owen DR, Allerton CMN, Anderson AS, Wei L, Yang Q, Zhu Y, et al. Science. 2021 Nov 2: eabl4784.
[2] Pfizer’s novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalization or death by 89% in interim analysis of phase 2/3 EPIC-HR Study. Pfizer. November 5, 2021.
[3] FDA to hold advisory committee meeting to Discuss Merck and Ridgeback’s EUA Application for COVID-19 oral treatment. Food and Drug Administration. October 14, 2021.
Links:
COVID-19 Research (NIH)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
A Study of PF-07321332/Ritonavir in Nonhospitalized Low-Risk Adult Participants With COVID-19 (ClinicalTrials.gov)
A Post-Exposure Prophylaxis Study of PF-07321332/Ritonavir in Adult Household Contacts of an Individual With Symptomatic COVID-19 (ClinicalTrials.gov)
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